Review Article: The Genetic and Environmental Factors For Keratoconus
Review Article: The Genetic and Environmental Factors For Keratoconus
Review Article
The Genetic and Environmental Factors for Keratoconus
Copyright © 2015 Ariela Gordon-Shaag et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Keratoconus (KC) is the most common cornea ectatic disorder. It is characterized by a cone-shaped thin cornea leading to myopia,
irregular astigmatism, and vision impairment. It affects all ethnic groups and both genders. Both environmental and genetic factors
may contribute to its pathogenesis. This review is to summarize the current research development in KC epidemiology and genetic
etiology. Environmental factors include but are not limited to eye rubbing, atopy, sun exposure, and geography. Genetic discoveries
have been reviewed with evidence from family-based linkage analysis and fine mapping in linkage region, genome-wide association
studies, and candidate genes analyses. A number of genes have been discovered at a relatively rapid pace. The detailed molecular
mechanism underlying KC pathogenesis will significantly advance our understanding of KC and promote the development of
potential therapies.
a retrospective study conducted in Netherlands [35], using % which is based on keratometric value, inferior-superior
data relating to over 100,000 contact lens wearers obtained asymmetry (I-S), asymmetric bow-tie astigmatism (AST),
from four university clinics and five noncontact lens centers and skewed radial axis (SRAX) values [43]. Instruments that
between the years 1950 and 1986, the ratio of men to women are based on Scheimpflug imaging [44, 45] are especially
was 0.5. In cases diagnosed in the period from 1950 to important in light of recent studies that suggest that KC starts
1954, it remained less than 1.0 until 1970s when the number from the posterior cornea and that posterior curvature may
of male patients significantly increased while the number be the best way of identifying early KC [46–49]. Pellucid
of female patients remained virtually unchanged. The ratio marginal degeneration is easily distinguished from KC by
of KC affected men compared to women reached 1.58 for slit-lamp examination and by a distinct videokeratographic
patients diagnosed in 1985 and 1986 and this difference was pattern [3].
made more manifest with the advent of corneal topography. The measurement of corneal thickness made by optical
Several reasons may account for this observation. First, this coherence tomography (OCT) has been shown to be as
study is based on clinics instead of population or community. sensitive and as specific as the topographic KISA index [12].
Second, possible sample errors could affect the study result. Other attempts at detecting KC have been made with corneal
Third, different technologies to diagnose KC may be used aberrometers [50], since the keratoconic corneas display a
throughout the study period. Finally, hormonal differences large amount of higher order aberrations, especially vertical
have been invoked and it has been noted that keratoconus coma. However, in a study comparing the aberrations to the
develops earlier and progresses more rapidly in men than inferior-superior topographic values, the latter was proved to
women [36], which could account for its higher prevalence. be just as good as a detector of KC [51].
Early biomicroscopic signs include Fleischer’s ring, which
is a partial or complete circle of iron deposition in the 1.3. Treatment. A number of different treatments are used to
epithelium surrounding the base of the cornea and Vogt’s correct the vision caused by KC. In the early stages, the condi-
striae, which are fine vertical lines produced by compression tion is usually well managed by spectacles. As the condition
of Descemet’s membrane [37]. As the disease progresses, progresses to a mild or moderate stage with irregular astig-
a Munson’s sign, a V-shaped deformation of the lower matism, the treatment of choice is contact lenses, especially
lid, becomes noticeable as the eye looks in the downward rigid gas permeable lenses. However, about 20% of patients
position, as well as a bright reflection of the nasal area of with advanced or severe KC cannot tolerate or improve their
the limbus called Rizzuti’s sign [37]. Less common are breaks vision sufficiently with contact lenses and will eventually
in Descemet’s membrane known as hydrops, which cause need surgery. The traditional surgical intervention has been
stromal edema, vision loss, and associated pain [38, 39]. For penetrating keratoplasty in which the entire thickness of
patients who wear contact lenses, corneal scarring is a very the cornea is excised and replaced by a donor cornea. This
common feature [40]. operation has yielded better vision than the partial removal of
a superficial corneal layer (called lamellar keratoplasty) [52]
1.2. Diagnosis. Since KC is typically characterized by the but it caused more graft rejection [53]. Recently, a technique
progression of irregular astigmatism, thinner cornea, and called collagen cross-linking (CXL) has been introduced and
increased steepening of corneal curvature, KC is often first it has been proven to be successful not only at improving
detected in the course of an eye examination and patients visual acuity but also at stiffening thus arresting and, even in
may be unaware of it, even though they complain of poor many cases, regressing the progression of KC by preventing
vision and have sought ocular care [27, 41]. The practitioner enzymatic degradation of stromal collagen [54–57]. Further
may note a suspicious reduction in visual acuity, scissors research with KC will significantly improve our understand-
movements in retinoscopy, distortion of keratometric images, ing and therefore potential therapy for KC.
smaller values of pachymetric corneal thickness, which often
precedes ectasia, or some of the known signs of the disease 2. Prevalence of KC
during the slit-lamp examination.
The most sensitive method of detecting and confirming The burden of a disease in a community is evaluated by
a diagnosis of KC is unequivocally corneal topography based the knowledge of how widespread is that disease. This is
on the principles of Placido disc and Scheimpflug imaging, demonstrated by its prevalence, which is a proportion (or
the latter being the most sensitive method of assessing corneal percentage) of the total number of cases at a period in
shape. Topography has become the gold standard method to time divided by the size of the population from which the
diagnose and monitor KC [3, 42]. It allows the early detection cases have been determined. Another measure of burden
of subclinical cases, also called forme fruste or KC suspect, of disease is incidence, which is the number of new cases
as well as grading the severity of the disease by producing presenting during a defined period of time divided by the
a color-coded topographic map of the corneal surface and population size from which the cases have been determined
various indices. Several quantitative methods based on these and existing during that same period of time. Moreover, if the
indices have been developed. The most common are the disease is chronic, then prevalence = incidence × duration.
KC prediction index (KPI), which is derived from eight However, these measures of disease occurrence are used to
quantitative indices and the KC Index (KCI %) itself derived characterize the KC population at risk of the disease. In
from the KPI and four other indices [42], and the KISA particular, it is aimed at identifying the KC population at
BioMed Research International 3
risk (e.g., gender, age, parental consanguinity, and associated or incidence [27, 41, 64, 67–71], but other factors may
factors), the geographic location of greater occurrence, and confound a possible correlation with the method used, since
the time when disease occurs most frequently (e.g., exposure they come principally from the Middle East and India with
to a risk factor and introduction of computer topography). different climates and ethnic groups than Europe or North
America, even if merely diagnosed with a keratometer [33].
2.1. Hospital/Clinic Based Reports. The majority of prevalence Table 1 presents the epidemiological studies conducted in a
studies have been conducted in a hospital clinic because of hospital/clinic. Comments on the ethnic differences will be
the ease of collecting data. Although these findings offer discussed in Section 3.2.4.
an estimate of prevalence, they are likely to underestimate
the true prevalence of the disease, as patients presenting in 2.2. Population-Based Studies. Cross-sectional studies typi-
hospitals are usually symptomatic and early forms of the cally enroll people who volunteer to participate in the inves-
condition are thus missed. In addition, these studies neglect tigation, even though the population selected may represent
the number of patients treated by independent optometrists a broad socioeconomic spectrum. Nevertheless, a selection
and ophthalmologists. They do not take into consideration an bias may occur, since individuals with the disease may refrain
ascertainment bias in access to health care. Although these from participating. On the other hand, others with visual
studies are commonly cited, they must be interpreted with problems may be keen to volunteer. However, the majority of
caution. volunteers are likely to have felt no particular bias. Selection
Until a few years ago most publications on KC referred bias is unlikely to cause a significant error because in some
almost exclusively to one prevalence value obtained in Min- studies it was observed that a certain proportion of the
nesota, USA, in 1986 which had been found to be 0.054% volunteers who had been totally unaware of their condition
(54 persons out of 100,000 people) [15]. The diagnosis was were discovered to have the disease during the survey [27, 41].
based on a mixture of scissors movements in retinoscopy Therefore, population-based screening studies are the best
and keratometry, as were the majority of prevalence studies methodology to assess the true prevalence of the disease.
published prior to 2011. Nevertheless, this figure was similar Modern videokeratography is the best method to screen
to those reported in Finland [59] or Denmark [62] but much subjects in a population-based study. However, for the pur-
higher than those reported in the Urals, Russia, at 0.0004% pose of completeness we will also mention studies using less
[60] or 0.0068% in Skope, Macedonia [63]. Still, it must be reliable methodology. The first cross-sectional survey was
noted that the more precise videokeratography is likely to carried out in 1957 at the Indiana State Fair in Indianapolis
yield higher prevalence than the older methodology. Indeed, over a period of 10 days by 25 different optometrists, using
recent studies using this method report higher prevalence a Placido disc [65]. 13,345 people were thus examined and
4 BioMed Research International
50 individuals exhibited a doubtful or definite keratoconic dioptric power of the corneal apex, and inferior-superior
pattern, thereby indicating a prevalence of 0.37% for doubtful asymmetry to determine normal KC suspect and definite
and definite types and only 0.12% for definite keratoconic KC. Table 2 illustrates the population-based studies published
patterns. The possible discrepancy in subjective assessment thus far. It can be seen from the table that in the last few
of the corneal pattern through a Placido disc, an inadequate years almost all prevalence studies have relied on the use
method, by the large number of examiners rendered this of videokeratography. As shown in Table 2, these modern
study unreliable. The Central India Eye and Medical Study is a studies result in a higher prevalence of KC than previously
population-based study that included 4,667 subjects in rural thought, ranging from 0.9% to 3.3%. Comments on the
India [33] and found a prevalence of 2.3%. KC was defined ethnic and geographical differences will be discussed in
as an anterior corneal refractive power exceeding 48 D, as Section 3.2.4.
measured by keratometry. Since keratometry measures the
central corneal power, it is likely to miss some inferior
cones. In addition, not all subjects with refractive power
3. Risk Factors for KC
exceeding 48 D will have KC. Therefore, this estimation must
be viewed with caution. The population-based Beijing Eye 3.1. Environmental Factors. It is commonly accepted that the
Study included 3468 individuals [68]. Steep cornea/KC was etiology of KC is multifactorial combining environmental
found to be 0.960 ± 2%, defined as an anterior corneal and genetic factors [1, 101–103]. Moreover, it seems that an
refractive power exceeding 48 D measured using optical low environmental factor may be essential to act as a trigger of the
coherence reflectometry biometry of the right eyes only. condition in genetically predisposed individuals. Environ-
These results must be interpreted with the same caution as the mental factors, which have been recognized, are eye rubbing,
previous study. Another investigation of French army recruits atopy, and UV exposure, although the relative contribution
using videokeratography arrived at a prevalence of 1.2%, but of all these factors is currently unknown [6]. An excess of
the results of the various indices were more compatible with any of these environmental factors cause oxidative damage
suspect than definite cases [66]. to KC corneas because of the inability of KC corneas to
More definite prevalence studies have been conducted process reactive oxygen species (ROS), which leads to a
since 2009 in the Middle East and Asia, using in most degradation process leading ultimately to corneal thinning
instances videokeratography, which afford better detection. and loss of vision [104] due to a lack of corneal enzymes
For example, Millodot et al. [27] described how they such as aldehyde dehydrogenase class 3 (ALDH3), catalase, or
diagnosed KC with a combination of topographic pattern, superoxide dismutase to remove or neutralize the ROS [105].
BioMed Research International 5
3.1.1. Eye Rubbing. An association between eye rubbing and a result of increased levels of interleukin IL-1 with subsequent
KC has long been described [24, 78, 81, 102, 106, 107] and loss of stromal volume [126]. Direct experimental evidence
accepted as a risk factor. Most authors report that about of an association between KC and eye rubbing has been
half of KC patients rub their eyes, although the percentage demonstrated in a group of volunteers without the disease
varies according to the study (see review in [82]). Obviously, and not wearing contact lenses who were instructed to rub
there are some variations in this association whether the eye their eyes in a controlled fashion for 60 seconds. Basal
rubbing is gentle or vigorous [79, 108] and the usual length tears were collected before and after eye rubbing and it
of rubbing in KC patients is much longer (from 10 to 180 was found that levels of MMP-13, IL-6 and, TNF-𝛼 were
seconds) than the typically less than 15-second duration of significantly increased after rubbing. The authors concluded
rubbing in allergic or infective ocular disorders [109] and that persistent eye rubbing, common in KC patients, may
less than 5 seconds in people without any eye condition [78]. contribute to the progression of the disease by continuous
Noteworthy are cases of asymmetric KC in which the most elevated levels of these protease, inflammatory mediators and
affected eye was the one which was rubbed most vigorously protease activity [127, 128].
[78, 110, 111]. Coyle [112] reported the case of an 11-year-
old boy who, at the age of 5, discovered he could stop his 3.1.2. Atopy. Atopy is a hypersensitivity reaction, which com-
paroxysmal atrial tachycardia by vigorously massaging his prises allergy, asthma, and eczema. There are some conflicting
left eye (up to 20 minutes a day). At the age of 7, his ocular reports of an association between KC and atopy. A positive
examination was normal. By the age of 11, the child had association has been noted by many authors [80, 82, 129, 130],
developed unilateral KC in his left eye. Another case reported but others did not find a statistically significant association
a patient with a history of vigorous daily ritual massaging of when compared to a control group [24, 75, 131, 132]. It should
the left eye which had led to unilateral KC in that eye [113]. be noted that in the nonsignificant findings [75] the control
A series of cases confirm the asymmetric expression of the group came from the general population rather than an
disease in patients who habitually rub the more affected eye age- and sex-matched group. The discrepancy may stem not
[110, 111, 114]. only from different severity of the condition or methods of
Case-control studies provide the most convincing evi- assessment, which is based on patients’ self-report, but also
dence of an association between KC and eye rubbing. The from the fact that some authors did not differentiate between
first was by Bawazeer et al. [24], who conducted a logistic the effects of the hypersensitivity reaction [24, 27, 75, 131, 132],
regression analysis that included atopy and family history whereas others only assessed one symptom of atopy, such as
of KC and found that only eye rubbing was significantly allergy, but did not include asthma or eczema [78, 102] and
associated with the disease, with an odd ratio (OR) of 3.98. others assessed only allergy and asthma and not eczema [80].
This was confirmed in other logistic analyses [115, 116]. Using a multivariate logistic regression analysis, Bawazeer et
Nevertheless, this strong association has not been reported al. [24] concluded that atopy was not significantly associated
by all authors. Although they usually find a large percentage with KC but with eye rubbing. These authors suggested that
of KC patients who rub their eyes, the control group does as atopy was only associated indirectly because the itch that it
well [27, 41, 79]. The discrepancy may stem from the amount induced led to eye rubbing. Still, Kaya et al. [130] showed
of dust in dry climates inducing frequent eye rubbing in that people with KC and atopy had a steeper and thinner
both patients and controls, thus concealing a possible associa- ectatic cornea than age- and sex-matched people with KC but
tion. without atopy.
Still, most authors who reviewed the pathogenesis of Allergy, induced by pollen, dust, antibiotics, or animal
KC consider eye rubbing to be strongly associated with the fur, is often associated with KC compared to controls or
disease [6, 104, 117]. There is mechanical trauma which could the general population [11, 29, 39, 59, 78–80, 82, 115]. It is
be caused by chronic eye rubbing, as well as a result of found in about a third of KC patients, but the percentage
poorly fitted rigid contact lenses [104, 118, 119]. Nevertheless, varies according to the study (see Table 3). It should be
this association is not necessarily causative. Indeed a fair noted that most of these studies were dependent on self-
percentage of individuals develop KC without any history of reported allergies. In some of these studies the control group
eye rubbing. It could be that abnormal rubbing habits start came from the general population [29, 39, 79, 82], but a
as KC develops and vision is impaired. However, there are significant association was shown in several studies, which
a large number of patients with a history of habitual eye included an age- and sex-matched group [74, 78, 80, 115,
rubbing before the development of KC [15, 120, 121] and one 132]. Although allergy may cause eye rubbing, it is not the
is compelled to accept eye rubbing as a risk factor at least in only provocative factor, since a much higher percentage of
some forms of KC in genetically susceptible people [122]. patients rubbed their eyes than the percentage of patients
The microtrauma caused to the epithelium by rubbing with allergy. Asthma and particularly eczema are reported
KC corneas generates elevated levels of matrix metallopro- less commonly than allergy (see Table 3) and it would appear
teinases MMP-1 and MMP-13 [123, 124], which are secreted that these reactions are less frequently reported in some of the
by epithelial and stromal cells, and inflammatory mediators studies conducted in the Middle East, India, and Singapore
including IL-6 and TNF-𝛼 [5, 125]. The release of these [34, 61, 67, 81, 115, 133]. This may be due to the hot and
factors form part of the process that leads to KC and its sunny climate of these countries, although Georgiou et al.
progression. The processes include apoptosis of keratocytes as [25] reported small percentages among Asian living in the UK
6 BioMed Research International
Table 3: Percentage of allergy, asthma, and eczema in KC patients from several studies.
compared to white, suggesting an ethnic difference. Table 3 explain the discrepancy found in the English Midlands where
presents the percentage of patients with atopic reaction in Indians, Bangladeshi, and Pakistani have 4.4 and 7.5 times
several studies. [25, 30] higher KC prevalence than whites living in the same
ambient environment. And neither can it account for the
3.1.3. Sun Exposure. Ultraviolet light (UV) is a source of re- 7.9% KC prevalence reported in Tehran among non-Persians
active oxygen species (ROS) and excessive exposure to (Arabs, Turks, and Kurds) compared to 2.5% prevalence of
sunlight leads to oxidative damage to KC corneas, in which Persians [70] or the significantly steeper corneas of Indians
there is a reduced amount of the enzymes including aldehyde compared to Chinese or Malays, all living in Singapore [137].
dehydrogenase class 3 (ALDH3) and superoxide dismutase Nevertheless, it is likely that the oxidative damage caused
necessary to remove the ROS [104, 105]. Hence, the higher by UV radiations combined with a genetic factor such as
prevalence of KC in hot, sunny countries compared to consanguinity precipitates or accelerates the disease process.
Europe and North America has led to the belief that the Research is needed to elucidate the role of sun exposure in
high sun exposure in these countries accounts for the high KC, possibly in the form of a case-control investigation using
prevalence (see Tables 1 and 2). For example, in Jerusalem a validated questionnaire.
where the prevalence was found to be 2.34% [27], the mean
annual number of hours of sunshine is 3397 according 3.1.4. Miscellaneous. Exposure to environmental neurotoxins
to the “Climatological information for Jerusalem, Israel” such as nicotine in the form of cigarette smoking has not
(http://www.hko.gov.hk/wxinfo/climat/world/eng/europe/gr been found to be associated with KC, neither in a case-control
tu/jerusalem e.htm). Such weather conditions are not unlike study [115] nor in observational studies [33]. In fact, there may
those prevailing in Saudi Arabia [61], Lebanon [67], India be a negative correlation between cigarette smoking and KC
[33], and Iran [64, 69–71] in contrast to Finland [59], possibly because the by-products of smoke may lead to cross-
Minnesota [15], Urals [60], Japan [28, 58], or Denmark linking of collagen in the cornea [138]. On the other hand one
[62]. Additional evidence comes from animal experiments report from the Urals indicated more cases of KC in the urban
in which mice exposed to UV light demonstrated a centers with polluting industries than in the rural areas [60].
degeneration of stromal collagen and stromal thinning with
a marked loss of keratocytes [134]. This last study confirmed 3.2. Socioeconomic Factors
an earlier report of UV exposure of an anaesthetized rabbit
cornea, which resulted in apoptosis of cells in all layers of the 3.2.1. Age. KC onset varies between the early teenage years
cornea as well as keratocytes [135]. and young adulthood and it seldom appears after the age of
However, it must be noted that UV radiations might pro- 35 years [2]. In a cohort of 196 patients, 18 years was the most
vide a beneficial effect by inducing cross-linking of corneal frequent age of onset [59] and it was 15.39 (±3.95) in another
collagen, thus mitigating either the development or the pro- study [139]. However, most reports give the age of diagnosis,
gression of the disease [136]. Moreover, sun exposure cannot which is some years after onset because the disease is usually
BioMed Research International 7
asymptomatic at first. The mean diagnostic age ranged from influence the development of KC, especially the oxidative
20.0 years (±6.4) [140] to 24.05 (±8.97) [31] in most studies damage caused by excessive sun exposure to ultraviolet light
[29, 141–143]. Interestingly, the age of first presentation was [104]? Is there an inherent difference in the people, such as
found to be significantly younger in Asians than in white ethnic backgrounds, or could the very different styles of life
patients by 4 to 5 years in three different studies carried out with nutrition play a role? There is also the possibility that
in the English Midlands (22.3 ± 6.5 versus 26.5 ± 8.5 [30]; in these countries the disease affects more the poor people, a
21.5 versus 26.4 [25]; and 23.0 ± 7.0 versus 27.8 ± 8.1 [144]). factor known to increase the proportion of chronic diseases
Recent reports on pediatric CXL demonstrate onset at the [164]. These are puzzling questions that need elucidation to
end of the first decade of life or early in the teen years [145– better understand the pathogenesis of KC.
148]. This leads to the notion that either the age of onset has
decreased or the medical community is being more diligent 3.2.3. Parental Education. It has been suggested that there
in early diagnosis. exists an association between low parental education and KC,
Since the disease is chronic one would expect to find at because parental education is associated with socioeconomic
least a similar proportion of patients in older compared to status [165]. Children living in poverty are brought up
in younger patients. That is not the case, especially after the in environments with air, water, and waste contamination
age of 50 years and this has intrigued many authors [9, 149– problems [166], which are hazardous to their health. As
154], although in one study the number of old KC patients a consequence, these children are at risk or suffer from
was found to be substantial [155]. Most of these studies report a host of disorders, such as asthma, cancer, hyperactivity,
low percentage of KC patients beyond 50 years, ranging from and obesity [167]. Several investigators have reported an
7.4% [152] to 15% [39], with one exception 40% [155]. The association between obesity and KC [159–161, 168]. Therefore,
reason may rest in the more efficient methods of diagnosis it could be inferred that there exists an association between
of the disease in recent years, such as videokeratography, low parental education and KC since low parental education
or it may be because there are now more people with an is linked to low socioeconomic status. To the best of our
allergy in the general population [156]. Another possibility knowledge there is not as yet a report of such an association.
is that KC patients have reduced longevity compared to the
general population, as has been suggested by some authors 3.2.4. Ethnic Differences. Until some years ago it was assumed
[150, 152, 154] because of an associated fatal condition, for that KC affected all races equally [3]. However, it has now
example, mitral valve prolapse [157, 158], obesity [159, 160], been demonstrated unequivocally that there are differences
or obstructive sleep apnea [160, 161], although the mortality in KC prevalence among ethnic groups. It was first noted
rate of a population of KC patients was not found to be by Pearson et al. [30] who found that Asians (Indians,
significantly different than that of the general population Bangladeshi, and Pakistani) living in the English Midlands
[151]. Nevertheless, the question as to what happens to KC had an incidence of the disease 4.4 times higher than
patients beyond the age of 50 years remains to be elucidated,
in whites. This was confirmed in two other investigations
possibly by comparing the corneas of older KC patients with
also conducted in the Midlands where the difference in
an age-matched control group.
incidence was 7.5/1 [25] and 9.2/1 [144]. Other studies have
About 20% of KC patients will eventually require surgery, demonstrated a difference among ethnic groups of the same
although there are wide variations in percentages among the country. In Iran, KC prevalence was found to be three times
studies, with a seemingly lower percentage in the Far East less in the Persian ethnic population than in the non-Persians
(India, China, Singapore, and Japan) than in the rest of the (Arabs, Turks, and Kurds) [70]. In Singapore, steep cornea
world (see review in Kok et al. [162]). Nevertheless, the dele- possibly reflecting KC was found to be significantly steeper
terious effects of this chronic disease, in which a substantial in Indians than in Malays or Chinese [137]. In addition, the
percentage of patients will require invasive surgery and for age of onset of the disease has been found to be generally
the other patients a lifelong need for specialized contact lens younger in Asians than in Caucasians [25, 30, 79, 144]. The
fitting, represent a serious burden not only for the individual age of onset, or more specifically diagnosis, of most Asians is
but also for the national health services of a country. in the early 20s whereas it was much older in the CLEK study
(𝑛 = 1209 patients) [39]. Differences in KC prevalence and
3.2.2. Geographic Location. It was thought that KC affected age of onset among ethnic populations strongly suggest that
all countries equally [3]. However, it has become obvious, genetic influences play an important role in the pathogenesis
especially in the past decades, that KC prevalence is not the of the disease. This is discussed below.
same throughout the world, as the presently available studies
can reveal (see Tables 1 and 2). Northern Europe and the Urals 3.3. Familial Factors. A large positive family history of the
have low prevalence [25, 30, 59, 60, 163], as well as northern disease may stem from either environmental or genetic
USA [15, 65]. Prevalence is also low in Japan [28, 58]. On causes. It is not always clear which of the two is most influen-
the other hand it is relatively high in countries of the Middle tial in the pathogenesis of the disease without establishing a
East [27, 41, 61, 64, 69–71], India [33], and China [68]. The family pedigree. The recent data on the strong association of
Middle East countries in particular, as well as parts of India, parental consanguinity/endogamy with KC suggests a strong
are characterized by hot and sunny climates with very little genetic component to the development of KC in many studies
rain as distinct from the other countries. Could the climate [115].
8 BioMed Research International
3.3.1. KC in the Family. Although the most common type of a fourfold risk of KC compared with children of unrelated
KC is sporadic [102], many studies have reported the presence parents after adjusting for other factors, using multivariate
of large number of familial KC. The rate ranges from 5% logistic regression analysis [115], and this association was
to 27.9% [15, 41, 59, 79, 82, 102]. In the study in which a much stronger with parents married to first cousins than
rate of 27.9% of KC was found in at least one person in the second cousins. This result was further confirmed in a similar
family, it was further noted that affected first-degree relatives study conducted with students from an Arab College in Haifa
represented 20.5% [82]. It was much lower (3.34%) in first- in which a fivefold (or 5,1, 95% 1.41–18.33) risk of KC in
degree relatives when the family history was not self-reported offspring of consanguineous marriages [41] was found.
by the cases but determined by videokeratography [169]. This As already suggested by Georgiou et al. [25] and Cozma
was still 15–67 times higher in those who had developed the et al. [144] the large discrepancy in the prevalence of KC
disease than in those who did not have relatives with KC. between Asian, mostly of Pakistani origin, and white patients
In another study in which relatives (first-degree and others) could be attributed to the tradition of consanguineous, espe-
were evaluated topographically, 14% of family members were cially first-cousin marriages. In fact, practically all countries
found to have KC [170]. The discrepancy between the latter with a high KC prevalence as noted in Tables 1 and 2 are from
two studies may reflect a greater prevalence of KC in the the Middle East and India which have a tradition of con-
general population of the second, which was conducted in sanguinity, especially in their Muslim ethnic communities
Turkey whereas the other was in America. Most percentages [186–189]. In Pakistan, approximately 60% of marriages are
of general family history are usually lower than 20%. Typical consanguineous, over 80% of which are between first cousins
results of family history from large sample population of [190]. In Israel, population surveys have found that Israeli
KC patients are 12.4% [11], 13.5% in the Collaborative Lon- Arabs have a high rate of consanguinity, 42–45%, with 28%
gitudinal Evaluation of Keratoconus (CLEK) [39], and 17.8% being first-cousin marriages [191]. For Israeli Jews, consan-
in another large cohort [171]. Interestingly, in the Dundee guinity is much lower ranging from 1.5 to 7.1% depending
University Scottish Keratoconus Study (DUSKS) [79] the on the community, with 0.4 to 1.2% being first cousins [192].
rate for Caucasians was 5% but it was 25% for the small However, endogamy is relatively common among Israeli Jews
Asian subgroup (Indian subcontinent) who participated in and it may play a role contributing to the high prevalence of
the study. This last result is not surprising as one would expect KC in Israel [27]. The high corneal steepness found in Indians
a higher level of positive family history in communities with compared to Chinese or Malays all living in Singapore was
a greater prevalence of KC. This was the case in several also suggested to have been caused by consanguinity among
studies in which KC prevalence was high and so was family the former [137].
history, 23% [27], 22.9% [115], and 27.9% [82], as well as If both parents are first cousins, they could both be
in a study involving KC patients in families with a lot of carriers of a mutant allele at the same locus leading to
children as found in northern Finland 19% versus 9% in corneal ectasia. The result of these studies points not only
southern Finland, where families had few children [59]. The to a genetic component of the disease, but more specifically
large variation in the percentage of family members with the to an autosomal recessive inheritance. This is in contrast to
disease (3.34%–27.9%) may indicate different expression of other forms of KC in which many patients with a positive
KC with different modes of inheritance [59, 101, 115, 169]. family history described in the literature, but mainly from
western countries, present a family pedigree suggesting an
3.3.2. Consanguinity. Consanguinity, the marriage between autosomal dominant inheritance [101, 102]. Strong support
relatives, has been shown to be associated with a host of for a genetic basis for KC comes from segregation analysis
disorders: childhood mortality [172], deafness [173], sickle- of genetic models based on 95 keratoconic families evaluated
cell anemia [174], hydrocephalus, postaxial polydactyly and by videokeratography [169]. It appears undeniable that the
facial clefts [175], heart disease [176], multiple sclerosis [177], genetic effect of consanguinity plays an important role in the
tuberculosis and hepatitis B [178], preterm birth [179], and pathogenesis of KC and is the principal factor that accounts
physical and mental handicap [180–182]. for the differences in prevalence among ethnic groups and
Over the years several authors have alluded to a possible possibly geographic locations. It may, however, require to be
association between KC and consanguinity [25, 101, 144, 183]. combined with an environmental factor to be activated and
Evidence was provided by a report by van der Hoeve in lead to KC.
1924 [184] who presented a family pedigree in which three Twin studies in which there is a concordance in the
of the six children of a consanguineous couple had KC. In topographic pattern of a monozygotic pair add evidence to
another report with suggestive evidence one in 400-Pakistani a genetic contribution to KC. To date, 21 pairs have been
family, who came from a tradition of consanguinity and reported, although many of these were described before
living in England, was found to have KC compared to one the advent of videokeratography. Nevertheless, more than
in 30,000 whites [185]. However, the first study to establish half of these pairs were found to be concordant [31, 59,
a significant association was performed in a hospital in east 193–195], the others being discordant [196–198]. A study
Jerusalem in which KC Arab patients and controls, age- comparing dizygotic (DZ) and monozygotic (MZ) twins has
and sex-matched, were examined and all subjects completed been reported [142] in which significantly more concordance
a questionnaire asking about their parents’ relationship. It was found in MZ than in DZ providing further evidence of a
was found that children of consanguineous parents had genetic contribution to the disease.
BioMed Research International 9
variants may directly impact transcriptional activity of key al. [213], suggesting the genetic contribution of this region
target genes in cornea development and maintenance. More to KC susceptibility. RAB3GAP1 is involved in regulation of
research will be necessary to study whether miR-184 may RAB3 activity by forming a heterodimer with RAB3GAP2 to
regulate the expression of other KC candidate genes. convert active RAB3-GTP to the inactive form RAB3-GDP
Chr13q32 was originally identified to be linked with [214]. Interestingly, mutations in RAB3GAP1 are associated
familial KC in Ecuadorian families, under an autosomal dom- with Warburg Micro Syndrome, a rare autosomal recessive
inant model [90]. Mutation screening of 8 candidate genes syndrome with ocular and neurodevelopmental defects, such
in this region identified a potential mutation c.2262A>C (p. as microphthalmos, microcornea, congenital cataracts, and
Gln754His) in DOCK9 (dedicator of cytokinesis 9) in a large optic atrophy [214–217].
Ecuadorian KC family [91]. DOCK9 (OMIM 607325) encodes The second GWAS with KC was followed by Burdon et
a member of the DOCK protein family with GTP/GDP al. in a population of patients from Australia using pooled
exchange factor activity that specifically activates G-protein DNA from 97 KC patients and 216 controls [218]. While
CDC42 [202]. DOCK9 is expressed in human cornea [91]. no variants reached genome-wide significance, the most
However, it still requires to be replicated in other KC families significant association (9.9 × 10−7 ) was located upstream
and patients [92] as well as functional work of the reported of the HGF (hepatocyte growth factor) gene. The specific
mutation in cornea. variant was also associated with serum HGF level in normal
individuals [218]. This association has been independently
4.2. Genome-Wide Association Studies. Genome-wide associ- replicated by Sahebjada et al. [219]. HGF regulates cell
ation studies (GWAS) examine several hundred thousand to growth, cell motility, and morphogenesis by activating a
over a million SNPs in hundreds to thousands of individuals tyrosine signalling cascade [220]. The genomic region of
using high throughput DNA genotyping technology [203]. HGF has been associated with refractive error in several
GWAS has been shown to be very powerful to identify the populations including Han Chinese and Caucasians [221–
genetic factors of many complex traits and diseases, including 223]. The association of HGF with KC suggests the potential
central corneal thickness (CCT) and KC. A number of GWAS involvement of HGF-related inflammatory pathways.
reported the association of CCT with sequence variants near
or within many genes, including ZNF469, COL5A1, RXRA- 4.3. Candidate Genes. A large number of candidate genes
COL5A1, COL8A2, AKAP13, AVGR8, FOXO1, FNDC3B, TJP1, have been studied in relation to KC pathogenesis. We will
NR3C2, LRRK1, FDF9-SGCG, LCN12-PTGDS, ADAMTS6, focus on two main candidate genes, visual system homeobox
CHSY1, HS3ST3B1-PMP22, GLT8D2, SMAD3, VKORC1L1, 1 (VSX1) and superoxide dismutase 1 (SOD1). VSX1 is located
COL4A3, FAM46A-IBTK, LPAR1, ARID5B, TBL1XR1- within a linkage locus for a corneal dystrophy called posterior
KCNMB2, ARHGAP20-POU2AF1, C7ORF42, MPDZ-NF1B, polymorphous dystrophy (PPCD) [224–226], which has been
USP37, GPR15, and TIPARP [204–208]. Two CCT-associated associated with KC [227–233]. Since PPCD and KC have
genomic regions FOXO1 and FNDC3B have been associated similar corneal curvature and the involvement of posterior
with KC risk [207]. These genetic discoveries implicate the surface of cornea, specifically Descemet’s membrane, PPCD
role of the collagen and extracellular matrix pathways in and KC might be linked due to poor case definition. In 2002
the regulation of CCT [207] and potentially KC. Recently, VSX1 mutations were first reported in PPCD and KC patients
two studies identified that missense variants in ZNF469 [234], in which two mutations (R166W and L159 M) were
have been identified in 12.5% and 23.3% of sporadic KC originally identified in KC patients. VSX1 encodes a pair-
patients in UK/Switzerland and New Zealand, respectively like homeodomain protein which binds to the core of the
[209, 210], indicating the potential role of ZNF469 in the locus control region of the red and green visual pigment gene
development of KC. However, more replicative sequencing cluster and may regulate expression of the cone opsin genes
and further functional studies will need to determine the during embryonic development [235, 236]. It is expressed in
relative role of ZNF469 in the pathogenesis of KC. Recently, several ocular tissues including the retina [224, 226, 234].
our group has identified several genomic deletions in familial The expression of VSX1 in human or mouse cornea remains
KC patients in several CCT-associated regions, including unclear since many studies did not confirm the expression
RXRA-COL5A1 and HS3ST3B1-PMP22, as well as a refractive in cornea [234, 236, 237]. Mouse models with the loss of
error-associated region of GRIA4 [211]. The genetic variants VSX1 function did not show cornea-related phenotypes [235].
in ZNF469 and genomic deletions in these genes indicate the Since the original report in 2002, many studies have examined
potential contributions of these CCT-associated genes in the the potential mutations of VSX1 in KC patients [90, 238–
pathogenesis of KC. 255]. Most of the identified variants are polymorphic [199].
The first GWAS with KC was reported by Li et al. in 2011 It remains unclear whether VSX1 mutations contribute to the
in a Caucasian population of 222 patients and 3324 controls pathogenesis of KC [37, 162, 256]. It is possible that mutations
[212]. Although no genome-wide significant associations (𝑃 in VSX1 only affect a very small percentage of KC patients,
value < 5 × 10−8 ) were identified, a suggestive association which is consistent with the concept of genetic heterogeneity
(𝑃 value 1.6 × 10−7 ) was reported with a genomic region of KC. It is also more possible that VSX1 may not play a
located near the RAB3GAP1 (RAB3 GTPase activating pro- significant role in the pathogenesis of KC. We recommend
tein subunit 1 (catalytic)) gene on chromosome 2q21.3. This future research efforts focus in the identification of novel
association has been replicated in a separate study by Bae et genetic factors in KC.
BioMed Research International 11
SOD1 encodes a major cytoplasmic antioxidant enzyme of KC. This knowledge will eventually lead to future devel-
that metabolizes superoxide radicals and provides a defence opment of improved early diagnostics, targeted therapeutics,
against oxygen toxicity [257]. Mutations in SOD1 have been and potential prognosis.
implicated in familial amyotrophic lateral sclerosis (ALS)
[257, 258]. However, no corneal phenotypes have been
Conflict of Interests
reported in ALS patients. To date, it is widely accepted that
oxidative stress plays a critical role in the progression of The authors declare that they have no conflict of interests.
KC [37, 240]. An accumulation of cytotoxic by-products,
mitochondrial DNA damage, and high levels of oxidative
stress in KC-affected corneas [259–262] have been reported. Acknowledgments
SOD1 has been selected as a candidate gene and examined in
Dr. Liu acknowledges the support from the National Institute
many KC-related studies [239, 249, 255, 263–265]. However,
of Health R01 Grant EY023242 and the support from the
no mutations in SOD1 have been identified in KC patients.
Glaucoma Research Foundation, the Glaucoma Foundation,
It remains undetermined whether SOD1 plays a role in the
and the BrightFocus Foundation as well as the support from
pathogenesis of KC.
the Department of Cellular Biology and Anatomy at Georgia
Regents University.
4.4. Future Direction. Recent development in genome tech-
nology has enabled the application of novel and high
throughput genetic approaches in ocular genetics research.
References
Among these technologies, whole exome or genome sequenc- [1] J. Sugar and M. S. Macsai, “What causes keratoconus?” Cornea,
ing will be very powerful in the identification of causal vol. 31, no. 6, pp. 716–719, 2012.
mutations in multiplex families with KC [266–268]. Many [2] J. H. Krachmer, R. S. Feder, and M. W. Belin, “Keratoconus and
research laboratories around the world, including our group, related noninflammatory corneal thinning disorders,” Survey of
have applied the whole exome sequencing to identify causal Ophthalmology, vol. 28, no. 4, pp. 293–322, 1984.
mutations in multiplex KC families. Previously identified [3] Y. S. Rabinowitz, “Keratoconus,” Survey of Ophthalmology, vol.
linkage region will be tremendously helpful to assist the inter- 42, no. 4, pp. 297–319, 1998.
pretation of exome or genome sequencing data. As discussed [4] A. S. Jun, L. Cope, C. Speck et al., “Subnormal cytokine profile
earlier, the genetic heterozygosity of KC may prevent a single in the tear fluid of keratoconus patients,” PLoS ONE, vol. 6, no.
research group from identifying and replicating novel genetic 1, Article ID e16437, 2011.
mutations. It will be necessary for different KC research [5] I. Lema, T. Sobrino, J. A. Durán, D. Brea, and E. Dı́ez-Feijoo,
groups to collaborate with each other, by sharing DNA “Subclinical keratoconus and inflammatory molecules from
tears,” British Journal of Ophthalmology, vol. 93, no. 6, pp. 820–
samples and phenotype data. A genetics research consortium
824, 2009.
may be one of the approaches. The integration of next
[6] A. E. Davidson, S. Hayes, A. J. Hardcastle, and S. J. Tuft, “The
generation sequencing has recently led to the identification pathogenesis of keratoconus,” Eye, vol. 28, no. 2, pp. 189–195,
of miR-184 mutations in KC patients. We expect to see more 2014.
peer-reviewed reports using next generation sequencing in [7] C. W. McMonnies, “Inflammation and keratoconus,” Optometry
the near future. At the same time, in comparison to GWAS & Vision Science, vol. 92, no. 2, pp. e35–e41, 2015.
studies with small sample size, GWAS approach with large [8] A. Behndig, K. Karlsson, B. O. Johansson, T. Brännström, and S.
number of cases and controls in different ethnic groups L. Marklund, “Superoxide dismutase isoenzymes in the normal
will greatly improve the chances of avoiding type I errors and diseased human cornea,” Investigative Ophthalmology and
and will continue to identify novel genomic variants that Visual Science, vol. 42, no. 10, pp. 2293–2296, 2001.
are associated with KC and cornea-relative phenotypes. In [9] A. Ertan and O. Muftuoglu, “Keratoconus clinical findings
addition, gene expression profile in normal and diseased according to different age and gender groups,” Cornea, vol. 27,
human cornea will provide further information to help no. 10, pp. 1109–1113, 2008.
narrow down the list of potential causal genes. [10] S. J. Tuft, L. C. Moodaley, W. M. Gregory, C. R. Davison,
and R. J. Buckley, “Prognostic factors for the progression of
keratoconus,” Ophthalmology, vol. 101, no. 3, pp. 439–447, 1994.
5. Conclusion [11] C. A. Jordan, A. Zamri, C. Wheeldon, D. V. Patel, R. Johnson,
and C. N. J. McGhee, “Computerized corneal tomography
In summary, KC is the most common ectatic disorder of and associated features in a large New Zealand keratoconic
cornea with the onset of puberty. It affects both genders and population,” Journal of Cataract and Refractive Surgery, vol. 37,
all ethnic groups worldwide. Both environmental and genetic no. 8, pp. 1493–1501, 2011.
factors contribute to the pathogenesis of KC. Significant [12] Y. Li, D. M. Meisler, M. Tang et al., “Keratoconus diagnosis
achievements have been made in the understanding of its with optical coherence tomography pachymetry mapping,”
epidemiology and etiology. Newly developed genetic tech- Ophthalmology, vol. 115, no. 12, pp. 2159–2166, 2008.
nologies including whole exome or genome sequencing and [13] M. Millodot and H. Owens, “Sensitivity and fragility in kerato-
genome-wide association technologies have promoted and conus,” Acta Ophthalmologica (Copenh), vol. 61, no. 5, pp. 908–
will continue to improve our knowledge on the pathogenesis 917, 1983.
12 BioMed Research International
[14] M. Zabala and E. A. Archila, “Corneal sensitivity and topogom- The American Journal of Ophthalmology, vol. 148, no. 5, pp. 760–
etry in keratoconus,” CLAO Journal, vol. 14, no. 4, pp. 210–212, 765, 2009.
1988. [34] J. S. Saini, V. Saroha, P. Singh, J. S. Sukhija, and A. K. Jain,
[15] R. H. Kennedy, W. M. Bourne, and J. A. Dyer, “A 48-year clinical “Keratoconus in Asian eyes at a tertiary eye care facility,” Clinical
and epidemiologic study of keratoconus,” The American Journal & Experimental Optometry, vol. 87, no. 2, pp. 97–101, 2004.
of Ophthalmology, vol. 101, no. 3, pp. 267–273, 1986. [35] F. P. Eggink, A. J. L. G. Pinckers, and E. P. van Puyenbroek,
[16] M. Amsler, “Some data on the problem of keratoconus,” Bulletin “Keratoconus, a retrospective study,” Contact Lens Journal, vol.
de la Société Belge d’Ophtalmologie, vol. 129, pp. 331–354, 1961. 16, pp. 204–306, 1998.
[17] D. R. Holland, N. Maeda, S. B. Hannush et al., “Unilateral [36] B. A. Fink, H. Wagner, K. Steger-May et al., “Differences in
keratoconus: incidence and quantitative topographic analysis,” keratoconus as a function of gender,” The American Journal of
Ophthalmology, vol. 104, no. 9, pp. 1409–1413, 1997. Ophthalmology, vol. 140, no. 3, pp. 459–468, 2005.
[18] L. R. Lee, L. W. Hirst, and G. Readshaw, “Clinical detection of [37] M. Romero-Jiménez, J. Santodomingo-Rubido, and J. S. Wolff-
unilateral keratoconus,” Australian and New Zealand Journal of sohn, “Keratoconus: a review,” Contact Lens & Anterior Eye, vol.
Ophthalmology, vol. 23, no. 2, pp. 129–133, 1995. 33, no. 4, pp. 157–166, 205, 2010.
[19] A. J. Phillips, “Can true monocular keratoconus occur?” Clinical [38] J. T. Barr, K. B. Schechtman, B. A. Fink et al., “Corneal scarring
and Experimental Optometry, vol. 86, no. 6, pp. 399–402, 2003. in the Collaborative Longitudinal Evaluation of Keratoconus
[20] Y. S. Rabinowitz and P. J. McDonnell, “Computer-assisted (CLEK) study: baseline prevalence and repeatability of detec-
corneal topography in keratoconus,” Refractive and Corneal tion,” Cornea, vol. 18, no. 1, pp. 34–46, 1999.
Surgery, vol. 5, no. 6, pp. 400–408, 1989. [39] K. Zadnik, J. T. Barr, T. B. Edrington et al., “Baseline findings
[21] Y. S. Rabinowitz, A. B. Nesburn, and P. J. McDonnell, “Videok- in the Collaborative Longitudinal Evaluation of Keratoconus
eratography of the fellow eye in unilateral keratoconus,” Oph- (CLEK) study,” Investigative Ophthalmology and Visual Science,
thalmology, vol. 100, no. 2, pp. 181–186, 1993. vol. 39, no. 13, pp. 2537–2546, 1998.
[22] S. E. Wilson, D. T. C. Lin, and S. D. Klyce, “Corneal topography [40] J. T. Barr, B. S. Wilson, M. O. Gordon et al., “Estimation of
of keratoconus,” Cornea, vol. 10, no. 1, pp. 2–8, 1991. the incidence and factors predictive of corneal scarring in the
[23] X. Li, Y. S. Rabinowitz, K. Rasheed, and H. Yang, “Longitudinal Collaborative Longitudinal Evaluation of Keratoconus (CLEK)
study of the normal eyes in unilateral keratoconus patients,” study,” Cornea, vol. 25, no. 1, pp. 16–25, 2006.
Ophthalmology, vol. 111, no. 3, pp. 440–446, 2004. [41] E. Shneor, M. Millodot, A. Gordon-Shaag et al., “Prevalence of
[24] A. M. Bawazeer, W. G. Hodge, and B. Lorimer, “Atopy and Keratoconus amoung young Arab students in Israel,” Interna-
keratoconus: a multivariate analysis,” British Journal of Ophthal- tional Journal of Keratoconus and Ectatic Corneal Diseases, vol.
mology, vol. 84, no. 8, pp. 834–836, 2000. 3, no. 1, pp. 9–14, 2014.
[25] T. Georgiou, C. L. Funnell, A. Cassels-Brown, and R. O’Conor, [42] N. Maeda, S. D. Klyce, M. K. Smolek, and H. W. Thompson,
“Influence of ethnic origin on the incidence of keratoconus and “Automated keratoconus screening with corneal topography
associated atopic disease in Asians and white patients,” Eye, vol. analysis,” Investigative Ophthalmology and Visual Science, vol.
18, no. 4, pp. 379–383, 2004. 35, no. 6, pp. 2749–2757, 1994.
[26] N. Lim and U. Vogt, “Characteristics and functional outcomes [43] Y. S. Rabinowitz and K. Rasheed, “KISA% index: a quantitative
of 130 patients with keratoconus attending a specialist contact videokeratography algorithm embodying minimal topographic
lens clinic,” Eye, vol. 16, no. 1, pp. 54–59, 2002. criteria for diagnosing keratoconus,” Journal of Cataract and
[27] M. Millodot, E. Shneor, S. Albou, E. Atlani, and A. Gordon- Refractive Surgery, vol. 25, no. 10, pp. 1327–1335, 1999.
Shaag, “Prevalence and associated factors of keratoconus in [44] G. Savini, P. Barboni, M. Carbonelli, and K. J. Hoffer, “Repeata-
jerusalem: a cross-sectional study,” Ophthalmic Epidemiology, bility of automatic measurements by a new Scheimpflug camera
vol. 18, no. 2, pp. 91–97, 2011. combined with Placido topography,” Journal of Cataract and
[28] R. Ota, K. Fujiki, and K. Nakayasu, “Estimation of patient visit Refractive Surgery, vol. 37, no. 10, pp. 1809–1816, 2011.
rate and incidence of keratoconus in the 23 wards of Tokyo,” [45] G. Savini, M. Carbonelli, A. Sbreglia, P. Barboni, G. Deluigi, and
Nihon Ganka Gakkai Zasshi, vol. 106, no. 6, pp. 365–372, 2002. K. J. Hoffer, “Comparison of anterior segment measurements
[29] H. Owens and G. Gamble, “A profile of keratoconus in New by 3 Scheimpflug tomographers and 1 Placido corneal topogra-
Zealand,” Cornea, vol. 22, no. 2, pp. 122–125, 2003. pher,” Journal of Cataract and Refractive Surgery, vol. 37, no. 9,
[30] A. R. Pearson, B. Soneji, N. Sarvananthan, and J. H. Sanford- pp. 1679–1685, 2011.
Smith, “Does ethnic origin influence the incidence or severity [46] U. de Sanctis, C. Loiacono, L. Richiardi, D. Turco, B. Mutani,
of keratoconus?” Eye, vol. 14, part 4, pp. 625–628, 2000. and F. M. Grignolo, “Sensitivity and specificity of posterior
[31] K. H. Weed, C. J. MacEwen, and C. N. J. McGhee, “The variable corneal elevation measured by Pentacam in discriminating
expression of keratoconus within monozygotic twins: dundee keratoconus/subclinical keratoconus,” Ophthalmology, vol. 115,
University Scottish Keratoconus Study (DUSKS),” Contact Lens no. 9, pp. 1534–1539, 2008.
and Anterior Eye, vol. 29, no. 3, pp. 123–126, 2006. [47] K. Miháltz, I. Kovács, Á. Takács, and Z. Z. Nagy, “Evaluation
[32] L. Lim, R. H. Wei, W. K. Chan, and D. T. H. Tan, “Evaluation of keratometric, pachymetric, and elevation parameters of
of keratoconus in Asians: role of Orbscan II and Tomey TMS-2 keratoconic corneas with pentacam,” Cornea, vol. 28, no. 9, pp.
corneal topography,” The American Journal of Ophthalmology, 976–980, 2009.
vol. 143, no. 3, pp. 390–400, 2007. [48] H. L. Rao, A. U. Kumar, A. Kumar et al., “Evaluation of central
[33] J. B. Jonas, V. Nangia, A. Matin, M. Kulkarni, and K. Bhojwani, corneal thickness measurement with RTVue spectral domain
“Prevalence and associations of keratoconus in rural maharash- optical coherence tomography in normal subjects,” Cornea, vol.
tra in central India: the Central India Eye and Medical Study,” 30, no. 2, pp. 121–126, 2011.
BioMed Research International 13
[49] A. Tomidokoro, T. Oshika, S. Amano, S. Higaki, N. Maeda, [66] P. Y. Santiago, M. Assouline, F. Ducoussau et al., “Epidemiology
and K. Miyata, “Changes in anterior and posterior corneal of keratoconus and corneal topography in normal young male
curvatures in keratoconus,” Ophthalmology, vol. 107, no. 7, pp. subjects,” Investigative Ophthalmology & Visual Science, vol. 36,
1328–1332, 2000. p. S307, 1995.
[50] M. Gobbe and M. Guillon, “Corneal wavefront aberration [67] N. Waked, A. M. Fayad, A. Fadlallah, and H. El Rami, “Kera-
measurements to detect keratoconus patients,” Contact Lens and toconus screening in a Lebanese students’ population,” Journal
Anterior Eye, vol. 28, no. 2, pp. 57–66, 2005. Francais d’Ophtalmologie, vol. 35, no. 1, pp. 23–29, 2012.
[51] A. Gordon-Shaag, M. Millodot, R. Ifrah, and E. Shneor, “Aber- [68] L. Xu, Y. X. Wang, Y. Guo, Q. S. You, and J. B. Jonas, “Prevalence
rations and topography in normal, keratoconus-suspect, and and associations of steep cornea/keratoconus in greater beijing.
keratoconic eyes,” Optometry and Vision Science, vol. 89, no. 4, The Beijing Eye Study,” PLoS ONE, vol. 7, no. 7, Article ID e39313,
pp. 411–418, 2012. 2012.
[52] S. L. Watson, A. Ramsay, J. K. G. Dart, C. Bunce, and E. Craig, [69] H. Hashemi, A. Beiranvand, M. Khabazkhoob et al., “Preva-
“Comparison of deep lamellar keratoplasty and penetrating lence of keratoconus in a population-based study in Shahroud,”
keratoplasty in patients with keratoconus,” Ophthalmology, vol. Cornea, vol. 32, no. 11, pp. 1441–1445, 2013.
111, no. 9, pp. 1676–1682, 2004. [70] H. Hashemi, M. Khabazkhoob, and A. Fotouhi, “Topographic
[53] B. Vabres, M. Bosnjakowski, L. Bekri, M. Weber, and A. keratoconus is not rare in an Iranian population: the Tehran
Pechereau, “Deep lamellar keratoplasty versus penetrating ker- eye study,” Ophthalmic Epidemiology, vol. 20, no. 6, pp. 385–391,
atoplasty for keratoconus,” Journal Francais d’Ophtalmologie, 2013.
vol. 29, no. 4, pp. 361–371, 2006. [71] H. Hashemi, M. Khabazkhoob, N. Yazdani et al., “The preva-
[54] A. Caporossi, C. Mazzotta, S. Baiocchi, T. Caporossi, and lence of keratoconus in a young population in Mashhad, Iran,”
A. L. Paradiso, “Transepithelial corneal collagen crosslinking Ophthalmic and Physiological Optics, vol. 34, no. 5, pp. 519–527,
for keratoconus: qualitative investigation by in vivo HRT II 2014.
confocal analysis,” European Journal of Ophthalmology, vol. 22, [72] P. W. Copeman, “Eczema and keratoconus,” British Medical
supplement 7, pp. S81–S88, 2012. Journal, vol. 2, no. 5468, pp. 977–979, 1965.
[55] K. M. Meek and S. Hayes, “Corneal cross-linking—a review,” [73] A. G. Karseras and M. Ruben, “Aetiology of keratoconus,”
Ophthalmic and Physiological Optics, vol. 33, no. 2, pp. 78–93, British Journal of Ophthalmology, vol. 60, no. 7, pp. 522–525,
2013. 1976.
[56] F. Raiskup-Wolf, A. Hoyer, E. Spoerl, and L. E. Pillunat, [74] A. Rahi, P. Davies, M. Ruben, D. Lobascher, and J. Menon,
“Collagen crosslinking with riboflavin and ultraviolet-A light “Keratoconus and coexisting atopic disease,” British Journal of
in keratoconus: long-term results,” Journal of Cataract and Ophthalmology, vol. 61, no. 12, pp. 761–764, 1977.
Refractive Surgery, vol. 34, no. 5, pp. 796–801, 2008. [75] A. R. Gasset, W. A. Hinson, and J. L. Frias, “Keratoconus and
[57] G. Wollensak, “Crosslinking treatment of progressive kerato- atopic diseases,” Annals of Ophthalmology, vol. 10, no. 8, pp. 991–
conus: new hope,” Current Opinion in Ophthalmology, vol. 17, 994, 1978.
no. 4, pp. 356–360, 2006. [76] P. G. Swann and H. E. Waldron, “Keratoconus: the clinical
spectrum,” Journal of the American Optometric Association, vol.
[58] U. Tanabe, K. Fujiki, A. Ogawa, S. Ueda, and A. Kanai,
57, no. 3, pp. 204–209, 1986.
“Prevalence of keratoconus patients in Japan,” Nihon Ganka
Gakkai Zasshi, vol. 89, no. 3, pp. 407–411, 1985. [77] R. J. Harrison, P. T. Klouda, D. L. Easty, M. Manku, J. Charles,
and J. C. C. M. Stewart, “Association between keratoconus and
[59] A. Ihalainen, “Clinical and epidemiological features of kerato-
atopy,” British Journal of Ophthalmology, vol. 73, no. 10, pp. 816–
conus genetic and external factors in the pathogenesis of the
822, 1989.
disease,” Acta Ophthalmologica. Supplement, vol. 178, pp. 1–64,
1986. [78] C. W. Mcmonnies and G. C. Boneham, “Keratoconus, allergy,
itch, eye-rubbing and hand-dominance,” Clinical and Experi-
[60] E. N. Gorskova and E. N. Sevost’ianov, “Epidemiology of mental Optometry, vol. 86, no. 6, pp. 376–384, 2003.
keratoconus in the Urals,” Vestnik Oftalmologii, vol. 114, no. 4,
[79] K. H. Weed, C. J. MacEwen, T. Giles, J. Low, and C. N. J. McGhee,
pp. 38–40, 1998.
“The Dundee University Scottish Keratoconus study: demo-
[61] A. A. Assiri, B. I. Yousuf, A. J. Quantock, P. J. Murphy, and A. A. graphics, corneal signs, associated diseases, and eye rubbing,”
Assiri, “Incidence and severity of keratoconus in Asir province, Eye, vol. 22, no. 4, pp. 534–541, 2008.
Saudi Arabia,” British Journal of Ophthalmology, vol. 89, no. 11,
[80] A. Y. Nemet, S. Vinker, I. Bahar, and I. Kaiserman, “The
pp. 1403–1406, 2005.
association of keratoconus with immune disorders,” Cornea,
[62] K. Nielsen, J. Hjortdal, E. A. Nohr, and N. Ehlers, “Incidence and vol. 29, no. 11, pp. 1261–1264, 2010.
prevalence of keratoconus in Denmark,” Acta Ophthalmologica [81] W. B. Khor, R. H. Wei, L. Lim, C. M. Chan, and D. T. Tan,
Scandinavica, vol. 85, no. 8, pp. 890–892, 2007. “Keratoconus in Asians: demographics, clinical characteristics
[63] A. D. Ljubic, “Keratoconus and its prevalence in Macedonia,” and visual function in a hospital-based population,” Clinical and
Macedonian Journal of Medical Sciences, vol. 2, no. 1, pp. 58–62, Experimental Ophthalmology, vol. 39, no. 4, pp. 299–307, 2011.
2009. [82] E. Shneor, M. Millodot, S. Blumberg, I. Ortenberg, S. Behrman,
[64] H. Ziaei, M. R. Jafarinasab, M. A. Javadi et al., “Epidemiology and A. Gordon-Shaag, “Characteristics of 244 patients with
of keratoconus in an Iranian population,” Cornea, vol. 31, no. 9, keratoconus seen in an optometric contact lens practice,”
pp. 1044–1047, 2012. Clinical and Experimental Optometry, vol. 96, no. 2, pp. 219–224,
[65] H. W. Hofstetter, “A keratoscopic survey of 13,395 eyes,” The 2013.
American Journal of Optometry and Archives of American [83] K. P. Burdon, D. J. Coster, J. C. Charlesworth et al., “Apparent
Academy of Optometry, vol. 36, no. 1, pp. 3–11, 1959. autosomal dominant keratoconus in a large Australian pedigree
14 BioMed Research International
accounted for by digenic inheritance of two novel loci,” Human [98] H. Tyynismaa, P. Sistonen, S. Tuupanen et al., “A locus for
Genetics, vol. 124, no. 4, pp. 379–386, 2008. autosomal dominant keratoconus: linkage to 16q22.3-q23.1
[84] D. M. Nowak, J. A. Karolak, J. Kubiak et al., “Substitution at in Finnish families,” Investigative Ophthalmology and Visual
IL1RN and deletion at SLC4A11 segregating with phenotype in Science, vol. 43, no. 10, pp. 3160–3164, 2002.
familial Keratoconus,” Investigative Ophthalmology and Visual [99] A. Hameed, S. Khaliq, M. Ismail et al., “A novel locus for
Science, vol. 54, no. 3, pp. 2207–2215, 2013. Leber congenital amaurosis (LCA4) with anterior keratoconus
[85] H. Hutchings, H. Ginisty, M. le Gallo et al., “Identification of a mapping to chromosome 17p13,” Investigative Ophthalmology
new locus for isolated familial keratoconus at 2p24,” Journal of and Visual Science, vol. 41, no. 3, pp. 629–633, 2000.
Medical Genetics, vol. 42, no. 1, pp. 88–94, 2005. [100] J. Fullerton, P. Paprocki, S. Foote, D. A. Mackey, R. Williamson,
and S. Forrest, “Identity-by-descent approach to gene localisa-
[86] F. Brancati, E. M. Valente, A. Sarkozy et al., “A locus for
tion in eight individuals affected by keratoconus from north-
autosomal dominant keratoconus maps to human chromosome
west Tasmania, Australia,” Human Genetics, vol. 110, no. 5, pp.
3p14-q13,” Journal of Medical Genetics, vol. 41, no. 3, pp. 188–192,
462–470, 2002.
2004.
[101] M. Edwards, C. N. J. McGhee, and S. Dean, “The genetics of
[87] L. Bisceglia, P. de Bonis, C. Pizzicoli et al., “Linkage analysis
keratoconus,” Clinical and Experimental Ophthalmology, vol. 29,
in keratoconus: replication of locus 5q21.2 and identification of
no. 6, pp. 345–351, 2001.
other suggestive Loci,” Investigative Ophthalmology and Visual
[102] Y. S. Rabinowitz, “The genetics of keratoconus,” Ophthalmology
Science, vol. 50, no. 3, pp. 1081–1086, 2009.
Clinics of North America, vol. 16, no. 4, pp. 607–620, 2003.
[88] Y. G. Tang, Y. S. Rabinowitz, K. D. Taylor et al., “Genomewide
[103] D. Patel and C. Mcghee, “Understanding keratoconus: what
linkage scan in a multigeneration Caucasian pedigree identifies
have we learned from the New Zealand perspective?” Clinical
a novel locus for keratoconus on chromosome 5q14.3-q21.1,”
and Experimental Optometry, vol. 96, no. 2, pp. 183–187, 2013.
Genetics in Medicine, vol. 7, no. 6, pp. 397–405, 2005.
[104] M. C. Kenney and D. J. Brown, “The cascade hypothesis of
[89] X. Li, Y. S. Rabinowitz, Y. G. Tang et al., “Two-stage genome- keratoconus,” Contact Lens and Anterior Eye, vol. 26, no. 3, pp.
wide linkage scan in keratoconus sib pair families,” Investigative 139–146, 2003.
Ophthalmology and Visual Science, vol. 47, no. 9, pp. 3791–3795,
[105] T. D. Gondhowiardjo, N. J. van Haeringen, H. J. Volker-Dieben
2006.
et al., “Analysis of corneal aldehyde dehydrogenase patterns in
[90] M. Gajecka, U. Radhakrishna, D. Winters et al., “Localization pathologic corneas,” Cornea, vol. 12, no. 2, pp. 146–154, 1993.
of a gene for keratoconus to a 5.6-Mb interval on 13q32,” [106] A. Gordon-Shaag, E. Shneor, and M. Millodot, “The epidemi-
Investigative Ophthalmology and Visual Science, vol. 50, no. 4, ology and etiology of Keratoconus,” International Journal of
pp. 1531–1539, 2009. Keratoconus and Ectatic Corneal Diseases, vol. 1, no. 1, pp. 7–15,
[91] M. Czugala, J. A. Karolak, D. M. Nowak et al., “Novel mutation 2012.
and three other sequence variants segregating with phenotype [107] R. H. Wei, W.-B. Khor, L. Lim, and D. T. Tan, “Contact
at keratoconus 13q32 susceptibility locus,” European Journal of lens characteristics and contrast sensitivity of patients with
Human Genetics, vol. 20, no. 4, pp. 389–397, 2012. keratoconus,” Eye and Contact Lens, vol. 37, no. 5, pp. 307–311,
[92] J. A. Karolak, P. Polakowski, J. Szaflik, J. P. Szaflik, and M. 2011.
Gajecka, “Molecular screening of keratoconus susceptibility [108] C. W. McMonnies, “Mechanisms of rubbing-related corneal
sequence variants in VSX1, TGFBI, DOCK9, STK24, and IPO5 trauma in keratoconus,” Cornea, vol. 28, no. 6, pp. 607–615,
genes in polish patients and novel TGFBI variant identification,” 2009.
Ophthalmic Genetics, 2014. [109] A. N. Carlson, “Expanding our understanding of eye rubbing
[93] P. Liskova, P. G. Hysi, N. Waseem, N. D. Ebenezer, S. S. and keratoconus,” Cornea, vol. 29, no. 2, p. 245, 2010.
Bhattacharya, and S. J. Tuft, “Evidence for keratoconus suscep- [110] B. Jafri, H. Lichter, and R. D. Stulting, “Asymmetric keratoconus
tibility locus on chromosome 14: a genome-wide linkage screen attributed to eye rubbing,” Cornea, vol. 23, no. 6, pp. 560–564,
using single-nucleotide polymorphism markers,” Archives of 2004.
Ophthalmology, vol. 128, no. 9, pp. 1191–1195, 2010. [111] K. Zadnik, K. Steger-May, B. A. Fink et al., “Between-eye
[94] A. E. Hughes, D. T. Bradley, M. Campbell et al., “Mutation asymmetry in keratoconus,” Cornea, vol. 21, no. 7, pp. 671–679,
altering the miR-184 seed region causes familial keratoconus 2002.
with cataract,” The American Journal of Human Genetics, vol. 89, [112] J. T. Coyle, “Keratoconus and eye rubbing,” The American
no. 5, pp. 628–633, 2011. Journal of Ophthalmology, vol. 97, no. 4, pp. 527–528, 1984.
[95] A. E. Hughes, D. P. Dash, A. J. Jackson, D. G. Frazer, and G. [113] D. C. Gritz and P. J. McDonnell, “Keratoconus and ocular
Silvestri, “Familial keratoconus with cataract: linkage to the massage,” The American Journal of Ophthalmology, vol. 106, no.
long arm of chromosome 15 and exclusion of candidate genes,” 6, pp. 757–758, 1988.
Investigative Ophthalmology and Visual Science, vol. 44, no. 12, [114] S. B. Koenig, “Bilateral recurrent self-induced keratoconus,” Eye
pp. 5063–5066, 2003. & Contact Lens, vol. 34, no. 6, pp. 343–344, 2008.
[96] Y. Bykhovskaya, A. L. C. Canedo, K. W. Wright, and Y. S. [115] A. Gordon-Shaag, M. Millodot, M. Essa, J. Garth, M. Ghara,
Rabinowitz, “C.57 C > T mutation in MIR 184 is responsible and E. Shneor, “Is consanguinity a risk factor for keratoconus?”
for congenital cataracts and corneal abnormalities in a five- Optometry and Vision Science, vol. 90, no. 5, pp. 448–454, 2013.
generation family from Galicia, Spain,” Ophthalmic Genetics, [116] H. Kim and C.-K. Joo, “Measure of keratoconus progression
2014. using Orbscan II,” Journal of Refractive Surgery, vol. 24, no. 6,
[97] J. Lechner, H. A. Bae, J. Guduric-Fuchs et al., “Mutational pp. 600–605, 2008.
analysis of MIR184 in sporadic keratoconus and myopia,” [117] C. N. Mcghee, “Keratoconus: the arc of past, present and future,”
Investigative Ophthalmology & Visual Science, vol. 54, no. 8, pp. Clinical and Experimental Optometry, vol. 96, no. 2, pp. 137–139,
5266–5272, 2013. 2013.
BioMed Research International 15
[118] J. Hartstein, “Keratoconus that developed in patients wearing [137] C. W. Pan, C. Y. Cheng, C. Sabanayagam et al., “Ethnic variation
corneal contact lenses. Report of four cases,” Archives of Oph- in central corneal refractive power and steep cornea in Asians,”
thalmology, vol. 80, no. 3, pp. 345–346, 1968. Ophthalmic Epidemiology, vol. 21, no. 2, pp. 99–105, 2014.
[119] C. W. McMonnies, “The biomechanics of keratoconus and rigid [138] E. Spoerl, F. Raiskup-Wolf, E. Kuhlisch, and L. E. Pillunat,
contact lenses,” Eye and Contact Lens, vol. 31, no. 2, pp. 80–92, “Cigarette smoking is negatively associated with keratoconus,”
2005. Journal of Refractive Surgery, vol. 24, no. 7, pp. S737–S740, 2008.
[120] F. Ridley, “Eye-Rubbing and Contact Lenses,” The British Journal [139] J. L. O. Jiménez, J. C. G. Jurado, F. J. B. Rodriguez, and D.
of Ophthalmology, vol. 45, no. 9, article 631, 1961. S. Laborda, “Keratoconus: age of onset and natural history,”
[121] D. L. Korb, C. D. Greiner, and J. V. Prevalence, “Prevalence Optometry and Vision Science, vol. 74, no. 3, pp. 147–151, 1997.
and characteristics of eye rubbing for keratoconic and non- [140] R. Sharma, J. S. Titiyal, G. Prakash, N. Sharma, R. Tandon, and
keratoconic subjects,” Investigative Ophthalmology & Visual R. B. Vajpayee, “Clinical profile and risk factors for keratoplasty
Science, vol. 32, p. 1057, 1991, (ARVO abstract). and development of hydrops in North Indian patients with
[122] C. W. McMonnies, “Abnormal rubbing and keratectasia,” Eye keratoconus,” Cornea, vol. 28, no. 4, pp. 367–370, 2009.
and Contact Lens, vol. 33, no. 6, part 1, pp. 265–271, 2007. [141] L. K. Bilgin, Ş. Yilmaz, B. Araz, S. B. Yüksel, and T. Sezen,
[123] Z. Mackiewicz, M. Määttä, M. Stenman, L. Konttinen, T. “30 Years of contact lens prescribing for keratoconic patients in
Tervo, and Y. T. Konttinen, “Collagenolytic proteinases in Turkey,” Contact Lens and Anterior Eye, vol. 32, no. 1, pp. 16–21,
keratoconus,” Cornea, vol. 25, no. 5, pp. 603–610, 2006. 2009.
[124] H. P. S. Seppälä, M. Määttä, M. Rautia et al., “EMMPRIN and [142] S. J. Tuft, H. Hassan, S. George, D. G. Frazer, C. E. Willoughby,
MMP1 in keratoconus,” Cornea, vol. 25, no. 3, pp. 325–330, 2006. and P. Liskova, “Keratoconus in 18 pairs of twins,” Acta Ophthal-
[125] L. Zhou, S. Z. Zhao, S. K. Koh et al., “In-depth analysis of the mologica, vol. 90, no. 6, pp. e482–e486, 2012.
human tear proteome,” Journal of Proteomics, vol. 75, no. 13, pp. [143] R. Mahadevan, A. O. Arumugam, V. Arunachalam, and B.
3877–3885, 2012. Kumaresan, “Keratoconus—a review from a tertiary eye-care
[126] S. E. Wilson, Y.-G. He, J. Weng et al., “Epithelial injury induces center,” Journal of Optometry, vol. 2, no. 4, pp. 166–172, 2009.
keratocyte apoptosis: hypothesized role for the interleukin-1 [144] I. Cozma, C. Atherley, N. J. James et al., “Influence of ethnic
system in the modulation of corneal tissue organization and origin on the incidence of keratoconus and associated atopic
wound healing,” Experimental Eye Research, vol. 62, no. 4, pp. disease in Asian and white patients,” Eye, vol. 19, no. 8, pp. 924–
325–337, 1996. 926, 2005.
[127] S. A. Balasubramanian, D. C. Pye, and M. D. P. Willcox, “Effects [145] R. Arora, D. Gupta, J. L. Goyal, and P. Jain, “Results of
of eye rubbing on the levels of protease, protease activity corneal collagen cross-linking in pediatric patients,” Journal of
and cytokines in tears: relevance in keratoconus,” Clinical and Refractive Surgery, vol. 28, no. 11, pp. 759–762, 2012.
Experimental Optometry, vol. 96, no. 2, pp. 214–218, 2013. [146] L. Buzzonetti and G. Petrocelli, “Transepithelial corneal cross-
[128] S. A. Balasubramanian, V. C. Wasinger, D. C. Pye, and M. D. linking in pediatric patients: early results,” Journal of Refractive
P. Willcox, “Preliminary identifcation of differentially expressed Surgery, vol. 28, no. 11, pp. 763–767, 2012.
tear proteins in keratoconus,” Molecular Vision, vol. 19, pp. 2124– [147] P. G. Zotta, K. A. Moschou, V. F. Diakonis et al., “Corneal
2134, 2013. collagen cross-linking for progressive keratoconus in pediatric
[129] M. J. Crews, W. T. Driebe Jr., and G. A. Stern, “The clinical patients: a feasibility study,” Journal of Refractive Surgery, vol.
management of keratoconus: a 6 year retrospective study,” 28, no. 11, pp. 793–799, 2012.
Contact Lens Association of Ophthalmologists Journal, vol. 20, [148] R. Barbara, J. Pikkel, H. Garzozi, and A. Barbara, “Collagen
no. 3, pp. 194–197, 1994. cross-linking and keratoconus in pediatric patients,” Interna-
[130] V. Kaya, M. Karakaya, C. A. Utine, S. Albayrak, O. F. Oge, and O. tional Journal of Keratoconus and Ectatic Corneal Diseases, vol.
F. Yilmaz, “Evaluation of the corneal topographic characteristics 1, no. 1, pp. 57–60, 2012.
of keratoconus with Orbscan II in patients with and without [149] J. H. Lass, R. G. Lembach, S. B. Park et al., “Clinical management
atopy,” Cornea, vol. 26, no. 8, pp. 945–948, 2007. of keratoconus. A multicenter analysis,” Ophthalmology, vol. 97,
[131] F. C. Lowell and J. M. Carroll, “A study of the occurrence of no. 4, pp. 433–445, 1990.
atopic traits in patients with keratoconus,” Journal of Allergy, [150] C. W. McMonnies, “Where are the older keratoconus patients?”
vol. 46, no. 1, pp. 32–39, 1970. Cornea, vol. 28, no. 7, p. 836, 2009.
[132] L. Wachtmeister, S. O. Ingemansson, and E. Moller, “Atopy and [151] L. C. M. Moodaley, E. G. Woodward, C. S. C. Liu, and R. J.
HLA antigens in patients with keratoconus,” Acta Ophthalmo- Buckley, “Life expectancy in keratoconus,” British Journal of
logica, vol. 60, no. 1, pp. 113–122, 1982. Ophthalmology, vol. 76, no. 10, pp. 590–591, 1992.
[133] R. H. Wei, S. Z. Zhao, L. Lim, and D. T. H. Tan, “Incidence and [152] C. Pobelle-Frasson, S. Velou, V. Huslin, B. Massicault, and
characteristics of unilateral keratoconus classified on corneal J. Colin, “Keratoconus: what happens with older patients?”
topography,” Journal of Refractive Surgery, vol. 27, no. 10, pp. Journal Français d’Ophtalmologie, vol. 27, no. 7, pp. 779–782,
745–751, 2011. 2004.
[134] K. M. Newkirk, H. L. Chandler, A. E. Parent et al., “Ultraviolet [153] S. W. Reeves, L. B. Ellwein, T. Kim, R. Constantine, and P. P. Lee,
radiation-induced corneal degeneration in 129 mice,” Toxico- “Keratoconus in the Medicare population,” Cornea, vol. 28, no.
logic Pathology, vol. 35, no. 6, pp. 819–826, 2007. 1, pp. 40–42, 2009.
[135] A. Podskochy, L. Gan, and P. Fagerholm, “Apoptosis in UV- [154] K. T. Yeung, J. H. Tai, and B. A. Weissman, “Where have all the
exposed rabbit corneas,” Cornea, vol. 19, no. 1, pp. 99–103, 2000. keratoconic patients gone?” International Contact Lens Clinic,
[136] E. Chan and G. R. Snibson, “Current status of corneal collagen vol. 25, no. 4, pp. 109–113, 1998.
cross-linking for keratoconus: a review,” Clinical and Experi- [155] E. H. Yildiz, G. F. Diehl, E. J. Cohen, K. M. Hammersmith, P.
mental Optometry, vol. 96, no. 2, pp. 155–164, 2013. R. Laibson, and C. J. Rapuano, “Demographics of patients older
16 BioMed Research International
than 50 years with keratoconus,” Eye and Contact Lens, vol. 35, [174] M. M. Al-Qurashi, M. I. El-Mouzan, A. S. Al-Herbish, A. A.
no. 6, pp. 309–311, 2009. Al-Salloum, and A. A. Al-Omar, “The prevalence of sickle cell
[156] S. Romagnani, “The increased prevalence of allergy and disease in Saudi children and adolescents. A community-based
the hygiene hypothesis: missing immune deviation, reduced survey,” Saudi Medical Journal, vol. 29, no. 10, pp. 1480–1483,
immune suppression, or both?” Immunology, vol. 112, no. 3, pp. 2008.
352–363, 2004. [175] M. Rittler, R. Liascovich, J. Lopez-Camelo, and E. E. Castilla,
[157] T. L. Beardsley and G. N. Foulks, “An association of keratoconus “Parental consanguinity in specific types of congenital anoma-
and mitral valve prolapse,” Ophthalmology, vol. 89, no. 1, pp. 35– lies,” The American Journal of Medical Genetics, vol. 102, no. 1,
37, 1982. pp. 36–43, 2001.
[158] Z. Rabbanikhah, M. A. Javadi, P. Rostami et al., “Association [176] S. M. Becker, Z. Al Halees, C. Molina, and R. M. Paterson,
between acute corneal hydrops in patients with keratoconus and “Consanguinity and congenital heart disease in Saudi Arabia,”
mitral valve prolapse,” Cornea, vol. 30, no. 2, pp. 154–157, 2011. American Journal of Medical Genetics, vol. 99, no. 1, pp. 8–13,
[159] J. K. Kristinsson, A. N. Carlson, and T. Kim, “Keratoconus and 2001.
obesity: a connection?” Investigative Ophthalmology & Visual [177] D. F. Roberts, “Consanguinity and multiple sclerosis in Orkney,”
Science, vol. 44, Abstract 812, 2003, ARVO E-abstract. Genetic Epidemiology, vol. 8, no. 3, pp. 147–151, 1991.
[160] M. S. Pihlblad and D. P. Schaefer, “Eyelid laxity, obesity, and [178] E. J. Lyons, A. J. Frodsham, L. Zhang, A. V. S. Hill, and W.
obstructive sleep apnea in keratoconus,” Cornea, vol. 32, no. 9, Amos, “Consanguinity and susceptibility to infectious diseases
pp. 1232–1236, 2013. in humans,” Biology Letters, vol. 5, no. 4, pp. 574–576, 2009.
[161] P. K. Gupta, S. S. Stinnett, and A. N. Carlson, “Prevalence of
[179] G. Mumtaz, A. H. Nassar, Z. Mahfoud et al., “Consanguinity:
sleep apnea in patients with keratoconus,” Cornea, vol. 31, no. 6,
a risk factor for preterm birth at less than 33 weeks’ gestation,”
pp. 595–599, 2012.
The American Journal of Epidemiology, vol. 172, no. 12, pp. 1424–
[162] Y. O. Kok, G. F. Ling Tan, and S. C. Loon, “Review: keratoconus 1430, 2010.
in Asia,” Cornea, vol. 31, no. 5, pp. 581–593, 2012.
[180] A. H. Bittles and M. L. Black, “The impact of consanguinity on
[163] K. Nielsen, J. Hjortdal, M. Pihlmann, and T. J. Corydon, “Update
neonatal and infant health,” Early Human Development, vol. 86,
on the keratoconus genetics,” Acta Ophthalmologica, vol. 91, no.
no. 11, pp. 737–741, 2010.
2, pp. 106–113, 2013.
[164] R. Nugent, “Chronic diseases in developing countries: health [181] A. H. Bittles and M. L. Black, “Consanguinity, human evolution,
and economic burdens,” Annals of the New York Academy of and complex diseases,” Proceedings of the National Academy of
Sciences, vol. 1136, pp. 70–79, 2008. Sciences of the United States of America, vol. 107, supplement 1,
pp. 1779–1786, 2010.
[165] L. Moraeus, L. Lissner, A. Yngve, E. Poortvliet, U. Al-Ansari,
and A. Sjöberg, “Multi-level influences on childhood obesity [182] L. Jaber, T. Shohat, J. I. Rotter, and M. Shohat, “Consanguinity
in Sweden: societal factors, parental determinants and child’s and common adult diseases in Israeli Arab communities,” The
lifestyle,” International Journal of Obesity (Lond), vol. 36, no. 7, American Journal of Medical Genetics, vol. 70, no. 4, pp. 346–
pp. 969–976, 2012. 348, 1997.
[166] D. L. Powell and V. Stewart, “Children. The unwitting target of [183] C. Thomas, The Cornea, Charles Thomas Publisher, Springfield,
environmental injustices,” Pediatric Clinics of North America, Ill, USA, 1955.
vol. 48, no. 5, pp. 1291–1305, 2001. [184] S. Duke-Elder and A. G. Leigh, System of Ophthalmology:
[167] S. Cureton, “Environmental victims: environmental injustice Disease of the Outer Eye, vol. 8, part 2, Henry Kimpton, London,
issues that threaten the health of children living in poverty,” UK, 1965.
Reviews on Environmental Health, vol. 26, no. 3, pp. 141–147, 2011. [185] M. Ansar, M. Ramzan, T. L. Pham et al., “Localization of a
[168] M. A. Saidel, J. Y. Paik, C. Garcia, P. Russo, D. Cao, and C. novel autosomal recessive non-syndromic hearing impairment
Bouchard, “Prevalence of sleep apnea syndrome and high-risk locus (DFNB38) to 6q26-q27 in a consanguineous kindred from
characteristics among keratoconus patients,” Cornea, vol. 31, no. Pakistan,” Human Heredity, vol. 55, no. 1, pp. 71–74, 2003.
6, pp. 600–603, 2012. [186] L. Al-Gazali and H. Hamamy, “Consanguinity and dysmorphol-
[169] Y. Wang, Y. S. Rabinowitz, J. I. Rotter, and H. Yang, “Genetic ogy in Arabs,” Human Heredity, vol. 77, no. 1–4, pp. 93–107, 2014.
epidemiological study of keratoconus: evidence for major gene
[187] L. Al-Gazali, H. Hamamy, and S. Al-Arrayad, “Genetic disor-
determination,” American Journal of Medical Genetics, vol. 93,
ders in the Arab world,” British Medical Journal, vol. 333, no.
no. 5, pp. 403–409, 2000.
7573, pp. 831–834, 2006.
[170] F. Karimian, S. Aramesh, H. M. Rabei, M. A. Javadi, and N.
Rafati, “Topographic evaluation of relatives of patients with [188] A. H. Bittles and R. Hussain, “An analysis of consanguineous
keratoconus,” Cornea, vol. 27, no. 8, pp. 874–878, 2008. marriage in the Muslim population of india at regional and state
levels,” Annals of Human Biology, vol. 27, no. 2, pp. 163–171, 2000.
[171] L. Szczotka-Flynn, M. Slaughter, T. McMahon et al., “Disease
severity and family history in keratoconus,” British Journal of [189] M. Saadat, M. Ansari-Lari, and D. D. Farhud, “Consanguineous
Ophthalmology, vol. 92, no. 8, pp. 1108–1111, 2008. marriage in Iran,” Annals of Human Biology, vol. 31, no. 2, pp.
[172] J. Pedersen, “Determinants of infant and child mortality in the 263–269, 2004.
West Bank and Gaza Strip,” Journal of Biosocial Science, vol. 32, [190] R. Hussain and A. H. Bittles, “Sociodemographic correlates of
no. 4, pp. 527–546, 2000. consanguineous marriage in the Muslim population of India,”
[173] J. Zlotogora and S. A. Shalev, “The consequences of consanguin- Journal of Biosocial Science, vol. 32, no. 4, pp. 433–442, 2000.
ity on the rates of malformations and major medical conditions [191] R. Vardi-Saliternik, Y. Friedlander, and T. Cohen, “Consanguin-
at birth and in early childhood in inbred populations,” American ity in a population sample of Israeli Muslim Arabs, Christian
Journal of Medical Genetics A, vol. 152, no. 8, pp. 2023–2028, Arabs and Druze,” Annals of Human Biology, vol. 29, no. 4, pp.
2010. 422–431, 2002.
BioMed Research International 17
[192] T. Cohen, R. Vardi-Saliternik, and Y. Friedlander, “Consan- [209] J. Lechner, L. F. Porter, A. Rice et al., “Enrichment of pathogenic
guinity, intracommunity and intercommunity marriages in a alleles in the brittle cornea gene, ZNF469, in keratoconus,”
population sample of Israeli Jews,” Annals of Human Biology, Human Molecular Genetics, vol. 23, no. 20, pp. 5527–5535, 2014.
vol. 31, no. 1, pp. 38–48, 2004. [210] A. L. Vincent, C. A. Jordan, M. J. Cadzow, T. R. Merriman,
[193] S. J. Bechara, G. O. Waring III, and M. S. Insler, “Keratoconus and C. N. McGhee, “Mutations in the zinc finger protein
in two pairs of identical twins,” Cornea, vol. 15, no. 1, pp. 90–93, gene, ZNF469, contribute to the pathogenesis of keratoconus,”
1996. Investigative Ophthalmology & Visual Science, vol. 55, no. 9, pp.
[194] A. Franceschetti, K. Lisch, and D. Klein, “2 Pairs of identical 5629–5635, 2014.
twins with concordant keratoconus,” Klin Monbl Augenheilkd [211] Y. Liu, K. K. Abu-Amero, Y. Bykhovskaya et al., “Genomic dele-
Augenarztl Fortbild, vol. 133, no. 1, pp. 15–30, 1958. tions of RXRA-COL5A1, FAM46A-IBTK, HS3ST3B1-PMP22,
and GRIA4 in familial keratoconus patients,” in Proceedings of
[195] K. Zadnik, M. J. Mannis, and C. A. Johnson, “An analysis
the Annual Meeting of ARVO, Orlando, Fla, USA, May 2014.
of contrast sensitivity in identical twins with keratoconus,”
Cornea, vol. 3, no. 2, pp. 99–103, 1984. [212] X. Li, Y. Bykhovskaya, T. Haritunians et al., “A genome-wide
association study identifies a potential novel gene locus for
[196] T. T. McMahon, J. A. Shin, A. Newlin, T. B. Edrington, J. Sugar, keratoconus, one of the commonest causes for corneal trans-
and K. Zadnik, “Discordance for keratoconus in two pairs of plantation in developed countries,” Human Molecular Genetics,
monozygotic twins,” Cornea, vol. 18, no. 4, pp. 444–451, 1999. vol. 21, no. 2, pp. 421–429, 2012.
[197] J. Parker, W. W. Ko, G. Pavlopoulos, P. J. Wolfe, Y. S. Rabinowitz, [213] H. A. Bae, R. A. D. Mills, R. G. Lindsay et al., “Replication
and S. T. Feldman, “Videokeratography of keratoconus in and meta-analysis of candidate loci identified variation at
monozygotic twins,” Journal of Refractive Surgery, vol. 12, no. RAB3GAP1 associated with keratoconus,” Investigative Ophthal-
1, pp. 180–183, 1996. mology & Visual Science, vol. 54, no. 7, pp. 5132–5135, 2013.
[198] H. Owens and G. A. Walters, “Keratoconus in monozygotic [214] I. A. Aligianis, C. A. Johnson, P. Gissen et al., “Mutations
twins in New Zealand,” Clinical and Experimental Optometry, of the catalytic subunit of RAB3GAP cause Warburg Micro
vol. 78, no. 4, pp. 125–129, 1995. syndrome,” Nature Genetics, vol. 37, no. 3, pp. 221–223, 2005.
[199] J. Wheeler, M. A. Hauser, N. A. Afshari, R. R. Allingham, and [215] M. T. Handley, D. J. Morris-Rosendahl, S. Brown et al., “Muta-
Y. Liu, “The genetics of keratoconus: a review,” Reproductive tion spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and
System & Sexual Disorders, supplement 6, article 001, 2012. genotype-phenotype correlations in Warburg Micro syndrome
[200] Y. Bykhovskaya, X. Li, K. D. Taylor, T. Haritunians, J. I. and Martsolf syndrome,” Human Mutation, vol. 34, no. 5, pp.
Rotter, and Y. S. Rabinowitz, “Linkage analysis of high-density 686–696, 2013.
SNPs confirms keratoconus locus at 5q Chromosomal region,” [216] D. J. Morris-Rosendahl, R. Segel, A. P. Born et al., “New
Ophthalmic Genetics, 2014. RAB3GAP1 mutations in patients with Warburg Micro syn-
[201] B. W. Iliff, S. A. Riazuddin, and J. D. Gottsch, “Documenting drome from different ethnic backgrounds and a possible
the corneal phenotype associated with the MIR184 c.57C>T founder effect in the Danish,” European Journal of Human
mtation,” The American Journal of Human Genetics, vol. 90, no. Genetics, vol. 18, no. 10, pp. 1100–1106, 2010.
5, pp. 934–935, 2012. [217] A. Yüksel, G. Yesil, C. Aras, and M. Seven, “Warburg Micro
syndrome in a Turkish boy,” Clinical Dysmorphology, vol. 16, no.
[202] M. A. Kwofie and J. Skowronski, “Specific recognition of
2, pp. 89–93, 2007.
Rac2 and Cdc42 by DOCK2 and DOCK9 guanine nucleotide
exchange factors,” Journal of Biological Chemistry, vol. 283, no. [218] K. P. Burdon, S. Macgregor, Y. Bykhovskaya et al., “Association
6, pp. 3088–3096, 2008. of polymorphisms in the hepatocyte growth factor gene pro-
moter with keratoconus,” Investigative Ophthalmology & Visual
[203] T. A. Manolio, “Genomewide association studies and assess-
Science, vol. 52, no. 11, pp. 8514–8519, 2011.
ment of the risk of disease,” The New England Journal of
Medicine, vol. 363, no. 2, pp. 166–176, 2010. [219] S. Sahebjada, M. Schache, A. J. Richardson, G. Snibson, M.
Daniell, and P. N. Baird, “Association of the hepatocyte growth
[204] Y. Lu, D. P. Dimasi, P. G. Hysi et al., “Common genetic variants factor gene with keratoconus in an Australian population,” PLoS
near the Brittle Cornea Syndrome locus ZNF469 influence the ONE, vol. 9, no. 1, Article ID e84067, 2014.
blinding disease risk factor central corneal thickness,” PLoS
[220] F. Cecchi, D. C. Rabe, and D. P. Bottaro, “Targeting the
Genetics, vol. 6, no. 5, Article ID e1000947, 2010.
HGF/Met signalling pathway in cancer,” European Journal of
[205] V. Vitart, G. Benčić, C. Hayward et al., “New loci associated Cancer, vol. 46, no. 7, pp. 1260–1270, 2010.
with central cornea thickness include COL5A1, AKAP13 and [221] S. Veerappan, K. K. Pertile, A. F. M. Islam et al., “Role of the hep-
AVGR8,” Human Molecular Genetics, vol. 19, no. 21, pp. 4304– atocyte growth factor gene in refractive error,” Ophthalmology,
4311, 2010. vol. 117, no. 2, pp. 239.e2–245.e2, 2010.
[206] E. N. Vithana, T. Aung, C. C. Khor et al., “Collagen-related genes [222] T. Yanovitch, Y.-J. Li, R. Metlapally, D. Abbott, K.-N. T. Viet,
influence the glaucoma risk factor, central corneal thickness,” and T. L. Young, “Hepatocyte growth factor and myopia: genetic
Human Molecular Genetics, vol. 20, no. 4, pp. 649–658, 2011. association analyses in a caucasian population,” Molecular
[207] Y. Lu, V. Vitart, K. P. Burdon et al., “Genome-wide association Vision, vol. 15, pp. 1028–1035, 2009.
analyses identify multiple loci associated with central corneal [223] W. Han, M. K. H. Yap, J. Wang, and P. Y. Shea, “Family-based
thickness and keratoconus,” Nature Genetics, vol. 45, no. 2, pp. association analysis of hepatocyte growth factor (HGF) gene
155–163, 2013. polymorphisms in high myopia,” Investigative Ophthalmology
[208] X. Gao, W. J. Gauderman, Y. Liu et al., “A genome-wide associa- and Visual Science, vol. 47, no. 6, pp. 2291–2299, 2006.
tion study of central corneal thickness in Latinos,” Investigative [224] T. Hayashi, J. Huang, and S. S. Deeb, “RINX(VSX1), a novel
Ophthalmology & Visual Science, vol. 54, no. 4, pp. 2435–2443, homeobox gene expressed in the inner nuclear layer of the adult
2013. retina,” Genomics, vol. 67, no. 2, pp. 128–139, 2000.
18 BioMed Research International
[225] E. Heon, W. D. Mathers, W. L. M. Alward et al., “Linkage of [241] A. J. Aldave, V. S. Yellore, A. K. Salem et al., “No VSX1 gene
posterior polymorphous corneal dystrophy to 20q11,” Human mutations associated with keratoconus,” Investigative Ophthal-
Molecular Genetics, vol. 4, no. 3, pp. 485–488, 1995. mology and Visual Science, vol. 47, no. 7, pp. 2820–2822, 2006.
[226] E. V. Semina, H. A. Mintz-Hittner, and J. C. Murray, “Isolation [242] S. M. Hosseini, S. Herd, A. L. Vincent, and E. Héon, “Genetic
and characterization of a novel human paired-like homeod- analysis of chromosome 20-related posterior polymorphous
omain-containing transcription factor gene, VSX1, expressed in corneal dystrophy: genetic heterogeneity and exclusion of three
ocular tissues,” Genomics, vol. 63, no. 2, pp. 289–293, 2000. candidate genes,” Molecular Vision, vol. 14, pp. 71–80, 2008.
[227] P. T. Ashwin and P. J. McDonnell, “Collagen cross-linkage: [243] P. Liskova, N. D. Ebenezer, P. Hysi et al., “Molecular analysis of
a comprehensive review and directions for future research,” the VSX1 gene in familial keratoconus,” Molecular Vision, vol.
British Journal of Ophthalmology, vol. 94, no. 8, pp. 965–970, 13, pp. 1887–1891, 2007.
2010. [244] Y. G. Tang, Y. Picornell, X. Su, X. Li, H. Yang, and Y. S.
[228] S. D. Blair, D. Seabrooks, W. J. Shields, S. Pillai, and H. D. Rabinowitz, “Three VSX1 gene mutations, L159M, R166W, and
Cavanagh, “Bilateral progressive essential iris atrophy and ker- H244R, are not associated with keratoconus,” Cornea, vol. 27,
atoconus with coincident features of posterior polymorphous no. 2, pp. 189–192, 2008.
dystrophy: a case report and proposed pathogenesis,” Cornea, [245] H. Y. Lam, J. L. Wiggs, and U. V. Jurkunas, “Unusual presenta-
vol. 11, no. 3, pp. 255–261, 1992. tion of presumed posterior polymorphous dystrophy associated
[229] P. J. Driver, J. W. Reed, and R. M. Davis, “Familial cases of ker- with iris heterochromia, band keratopathy, and keratoconus,”
atoconus associated with posterior polymorphous dystrophy,” Cornea, vol. 29, no. 10, pp. 1180–1185, 2010.
The American Journal of Ophthalmology, vol. 118, no. 2, pp. 256– [246] M. Tanwar, M. Kumar, B. Nayak et al., “VSX1 gene analysis in
257, 1994. keratoconus,” Molecular Vision, vol. 16, pp. 2395–2401, 2010.
[230] C. Mazzotta, S. Baiocchi, O. Caporossi et al., “Confocal [247] L. Bisceglia, M. Ciaschetti, P. de Bonis et al., “VSX1 mutational
microscopy identification of keratoconus associated with poste- analysis in a series of Italian patients affected by keratoconus:
rior polymorphous corneal dystrophy,” Journal of Cataract and detection of a novel mutation,” Investigative Ophthalmology and
Refractive Surgery, vol. 34, no. 2, pp. 318–321, 2008. Visual Science, vol. 46, no. 1, pp. 39–45, 2005.
[231] S. J. Bechara, H. E. Grossniklaus, G. O. Waring III, and J. [248] D. P. Dash, S. George, D. O’prey et al., “Mutational screening of
A. Wells III, “Keratoconus associated with posterior polymor- VSX1 in keratoconus patients from the European population,”
phous dystrophy,” The American Journal of Ophthalmology, vol. Eye, vol. 24, no. 6, pp. 1085–1092, 2010.
112, no. 6, pp. 729–731, 1991. [249] P. de Bonis, A. Laborante, C. Pizzicoli et al., “Mutational screen-
ing of VSX1, SPARC, SOD1, LOX, and TIMP3 in keratoconus,”
[232] A. R. Gasset and T. J. Zimmerman, “Posterior polymorphous
Molecular Vision, vol. 17, pp. 2482–2494, 2011.
dystrophy associated with keratoconus,” The American Journal
of Ophthalmology, vol. 78, no. 3, pp. 535–537, 1974. [250] P. Eran, A. Almogit, Z. David et al., “The D144E substitution in
the VSX1 gene: a non-pathogenic variant or a disease causing
[233] B. A. Weissman, M. Ehrlich, J. E. Levenson, and T. H. Pet-
mutation?” Ophthalmic Genetics, vol. 29, no. 2, pp. 53–59, 2008.
tit, “Four cases of keratoconus and posterior polymorphous
corneal dystrophy,” Optometry and Vision Science, vol. 66, no. [251] H. A. Mintz-Hittner, E. V. Semina, L. J. Frishman, T. C. Prager,
4, pp. 243–246, 1989. and J. C. Murray, “VSX1 (RINX) mutation with craniofacial
anomalies, empty sella, corneal endothelial changes, and abnor-
[234] E. Héon, A. Greenberg, K. K. Kopp et al., “VSX1: a gene for mal retinal and auditory bipolar cells,” Ophthalmology, vol. 111,
posterior polymorphous dystrophy and keratoconus,” Human no. 4, pp. 828–836, 2004.
Molecular Genetics, vol. 11, no. 9, pp. 1029–1036, 2002.
[252] J.-W. Mok, S.-J. Baek, and C.-K. Joo, “VSX1 gene variants
[235] A. Ohtoshi, S. W. Wang, H. Maeda et al., “Regulation of retinal are associated with keratoconus in unrelated Korean patients,”
cone bipolar cell differentiation and photopic vision by the CVC Journal of Human Genetics, vol. 53, no. 9, pp. 842–849, 2008.
homeobox gene Vsx1,” Current Biology, vol. 14, no. 6, pp. 530– [253] P. Paliwal, A. Singh, R. Tandon, J. S. Titiyal, and A. Sharma,
536, 2004. “A novel VSX1 mutation identified in an individual with
[236] T. Watson and R. L. Chow, “Absence of Vsx1 expression in the keratoconus in India,” Molecular Vision, vol. 15, pp. 2475–2479,
normal and damaged mouse cornea,” Molecular Vision, vol. 17, 2009.
pp. 737–744, 2011. [254] P. Paliwal, R. Tandon, D. Dube, P. Kaur, and A. Sharma,
[237] R. L. Chow, B. Volgyi, R. K. Szilard et al., “Control of late off- “Familial segregation of a VSX1 mutation adds a new dimension
center cone bipolar cell differentiation and visual signaling by to its role in the causation of keratoconus,” Molecular Vision, vol.
the homeobox gene Vsx1,” Proceedings of the National Academy 17, pp. 481–485, 2011.
of Sciences of the United States of America, vol. 101, no. 6, pp. [255] S. Saee-Rad, H. Hashemi, M. Miraftab et al., “Mutation analysis
1754–1759, 2004. of VSX1 and SOD1 in Iranian patients with keratoconus,”
[238] K. K. Abu-Amero, H. Kalantan, and A. M. Al-Muammar, Molecular Vision, vol. 17, pp. 3128–3136, 2011.
“Analysis of the VSX1 gene in keratoconus patients from saudi [256] A. J. Aldave, H. Mintz-Hittner, and E. Semina, “VSX1 mutation
arabia,” Molecular Vision, vol. 17, pp. 667–672, 2011. and corneal dystrophies,” Ophthalmology, vol. 112, no. 1, pp. 170–
[239] M. Štabuc-Šilih, M. Stražišar, M. Hawlina, and D. Glavač, 172, 2005.
“Absence of pathogenic mutations in VSX1 and SOD1 genes in [257] R. Noor, S. Mittal, and J. Iqbal, “Superoxide dismutase—
patients with keratoconus,” Cornea, vol. 29, no. 2, pp. 172–176, applications and relevance to human diseases,” Medical Science
2010. Monitor, vol. 8, no. 9, pp. RA210–RA215, 2002.
[240] M. Stabuc-Silih, M. Strazisar, M. Ravnik-Glavac, M. Hawlina, [258] D. R. Rosen, T. Siddique, D. Patterson et al., “Mutations in
and D. Glavac, “Genetics and clinical characteristics of ker- Cu/Zn superoxide dismutase gene are associated with familial
atoconus,” Acta Dermatovenerologica Alpina, Pannonica, et amyotrophic lateral sclerosis,” Nature, vol. 362, no. 6415, pp. 59–
Adriatica, vol. 19, no. 2, pp. 3–10, 2010. 62, 1993.
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