LAB/IN VITRO RESEARCH

e-ISSN 1643-3750
© Med Sci Monit, 2016; 22: 4271-4276
DOI: 10.12659/MSM.897592

Received: 2016.01.15
Accepted: 2016.03.14 Osteoprotegerin Gene (OPG) Polymorphisms
Published: 2016.11.09
Associated with Peri-Implantitis Susceptibility in
a Chinese Han Population
Authors’ Contribution: AG 1,2 Jian Zhou 1 State Key Laboratory of Military Stomatology, Department of Prosthetic Dentistry,
Study Design  A BCDEF 1 Yimin Zhao School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi,
Data Collection  B P.R. China
Statistical Analysis  C 2 Department of Stomatology, 253th Hospital of Chinese PLA, Huhhot, Inner
Data Interpretation  D Mongolia, P.R. China
Manuscript Preparation  E
Literature Search  F
Funds Collection  G

Corresponding Author: Yimin Zhao, e-mail: [email protected]

Background: The aim of this study was to investigate the association between T950C (rs2073617) and G1181C (rs2073618)
polymorphisms of the osteoprotegerin gene (OPG) and the susceptibility of peri-implantitis in the Chinese Han
population.
Material/Methods: 110 patients with peri-implantitis and 116 healthy persons from the Chinese Han population were included
in this study using a case-control design; rs2073617 and rs2073618 in OPG were genotyped by polymerase
chain reaction-restriction fragment length polymorphism (PCR-RFLP). The linkage disequilibrium (LD) and hap-
lotype analysis were performed with Haploview software. Hardy-Weinberg equilibrium (HWE) was assessed in
the control group based on the genotype distributions of OPG polymorphisms. The genotype, allele, and hap-
lotype distribution differences between the case and control groups were analyzed by chi-square test, and the
relative risk of PD was expressed by odds ratio (OR) and 95% confidence interval (CI).
Results: The study results showed that people carrying the CC genotype of rs2073618 were more likely to have peri-
implantitis than GG genotype carriers (OR=2.18, 95% CI=1.03–4.62, p=0.04). In addition, patients with the C
allele had 1.47 times the risk of suffering from peri-implantitis (OR=1.47, 95% CI=1.01–2.13, p=0.04), but not
rs2073617 polymorphism. The G-C haplotype frequency of rs2073618-rs2073617 in OPG was significantly cor-
related to the increased susceptibility of peri-implantitis (OR=2.27, 95% CI=1.20–4.30).
Conclusions: OPG rs2073618 polymorphism may be related to the risk of peri-implantitis, but not rs2073617. Moreover, hap-
lotype is also a non-ignorable risk factor.

MeSH Keywords: Haplotypes • Peri-Implantitis • Polymorphism, Genetic

Full-text PDF: http://www.medscimonit.com/abstract/index/idArt/897592

 2280    3    —    31

Indexed in:  [Current Contents/Clinical Medicine]  [SCI Expanded]  [ISI Alerting System] 
This work is licensed under Creative Common Attribution-
NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) 4271 [ISI Journals Master List]  [Index Medicus/MEDLINE]  [EMBASE/Excerpta Medica] 
[Chemical Abstracts/CAS]  [Index Copernicus]
 Zhou J. et al.:
LAB/IN VITRO RESEARCH Osteoprotegerin gene (OPG) polymorphisms associated with peri-implantitis…
© Med Sci Monit, 2016; 22: 4271-4276

Background Material and Methods

With the development in social economy and the growing ma- The case and control groups
turity of dental implant technology, dental implants have be-
come the preferred solution for people to repair some or all This study aimed to test the correlation between OPG poly-
of their missing teeth. Peri-implantitis is an inflammation oc- morphisms and peri-implantitis. All study participants were in-
curring in osseous tissue surrounding the dental implant and formed of the research process and signed informed consent
can develop as a chronic progressive marginal inflammation, forms. The study was authorized by the Ethics Committee of
which can cause loss of bone tissue and function around the State Key Laboratory of Military Stomatology, Department of
implant [1]. There are similarities in aspects of microbiology Prosthetic Dentistry, School of Stomatology, The Fourth Military
and clinical and pathological manifestations between peri-im- Medical University. Trained epidemiological investigators col-
plantitis and periodontitis, but there are still differences in the lected blood samples and the process of sample collection
rate and extent of inflammation, as well as in cell composi- was conducted according to the national ethics criteria of hu-
tion [2,3]. Studies have shown chronic periodontitis was signif- man genome research.
icantly associated with cytokine gene polymorphisms and en-
vironmental factors [4,5]; therefore, when studying the cause The case group included 110 patients with peri-implantitis who
of peri-implantitis, the role of molecular genetic susceptibility were selected from the clinical inpatients in the Department
and environmental factors should be considered. of Oral Implantology of the State Key Laboratory of Military
Stomatology, Department of Prosthetic Dentistry, School of
Osteoprotegerin (OPG) is a cytokine receptor, as well as a new Stomatology, The Fourth Military Medical University, and who
member of the tumor necrosis factor (TNF) receptor superfam- were diagnosed by pathobiology between December 2014 to
ily, also known as osteoclastogenesis inhibitory factor (OCIF), January 2015, including 89 males and 21 females. The age
or tumor necrosis factor receptor superfamily member 11B range was 18–67 years, with an average age of 42.85±11.21.
(TNFRSF11B) and belongs to a protein that is encoded by the Inclusion criteria were as follows: IMZ or Frialit-2 (German
TNFRSF11B gene in humans, which was discovered in 1997 by Friadent Corp) implants for the repair of dental implants within
Simonet [6]. It is also a secretory glycoprotein that regulates the oral cavity; no loosening of implants; swelling of the mu-
the function of bone resorption, comprising 401 amino acid cosa around the implant, bleeding on probing, x-ray exami-
residues arranged into seven structural domains. It is found nation of implant crown has bone resorption through shad-
as either a 60-kDa monomer or 120-kDa dimer linked by di- ow; and the absorption of alveolar bone around implants was
sulfide bonds [7]. Its main function is to inhibit osteoclast for- greater than 3 mm. The exclusion criterion was peri-implanti-
mation. OPG is expressed in various tissues and organs, in- tis caused by mechanical overload.
cluding the heart and blood vessels [8].
The control group included 116 persons who had a suc-
Animal tests have shown that OPG gene knockout mice mani- cessful implant, also at the State Key Laboratory of Military
fest severe bone loss and artery calcification [9,10]. OPG gene Stomatology, Department of Prosthetic Dentistry, School of
knockout mice studies suggest that the OPG gene can prevent Stomatology, The Fourth Military Medical University, during
the occurrence of arterial calcification [11,12]. Current studies the same period, and included 94 men and 22 women. The age
indicate that OPG gene promoter and intron polymorphism loci range was 17-69 years, with an average age of 43.02±10.94.
include T950C, T149C, T245G, C889T, G1181C, A163G, G209A, The patients were all from the Chinese Han population, but
A6890C, and C1217T [13]. Reports found that OPG gene poly- they had no blood relationship to one another.
morphism was related to the decrease in bone mineral density
and bone fracture in postmenopausal or elderly patients with DNA extraction
osteoporosis. However, there are few research studies about
OPG gene polymorphism and peri-implantitis. Therefore, in For all participants, 3 mL peripheral venous blood was collect-
this study we investigated the association of OPG rs2073617 ed after a 12-hour fast; the blood sample was placed in a tube
and rs2073618 polymorphisms with genetic susceptibility to containing disodium ethylene diamine tetraacetic acid (EDTA-
peri-implantitis in the Chinese Han population, in order to in- 2Na) as an anticoagulation, and then stored at -80°C. DNA was
vestigate the theoretical foundation for the mechanism of extracted according to the manufacturer’s instructions; periph-
peri-implantitis. eral blood leucocyte genome DNA of all samples was extract-
ed using Beijing TIANGEN biochemical blood genome DNA ex-
traction kit, and then stored at –20°C.

Indexed in:  [Current Contents/Clinical Medicine]  [SCI Expanded]  [ISI Alerting System] 
This work is licensed under Creative Common Attribution-
NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) 4272 [ISI Journals Master List]  [Index Medicus/MEDLINE]  [EMBASE/Excerpta Medica] 
[Chemical Abstracts/CAS]  [Index Copernicus]
Zhou J. et al.:
Osteoprotegerin gene (OPG) polymorphisms associated with peri-implantitis…
© Med Sci Monit, 2016; 22: 4271-4276
LAB/IN VITRO RESEARCH

Table 1. Primer sequences of OPG rs2073617, rs2073618.

SNP Primer sequence Tm (°C)

For. 5’-CCAAGCCCCTGAGGTTT-3’
rs2073618 68°C
Rev. 5’-GGAGACCAGGTGGCAGC-3’

For. 5’-CCTGGGGGATCCTTTCC-3’
rs2073617 54°C
Rev. 5’-AAGTATCGCCTGCCTTTGA-3’

The determination of genotypes in OPG polymorphisms Results

The genotypes of OPG were determined by polymerase chain General characteristics of study objects
reaction-restriction fragment length polymorphism (PCR-RFLP).
Primer design (Genebank database of NCBI) was adopted to This study included 110 patients with peri-implantitis (case
find the complete sequence of OPG and the sequences of group) and 116 controls (control group). In the case group,
rs2073618 and rs2073617 polymorphisms. Complying with women accounted for 19.09%, and the sex (male/female) ra-
general primer design principles, we designed the PCR primers tio was 4.24: 1; the sex ratio for the control group was sim-
using Primer Premier 5.0 software, and synthesized in Shanghai ilar, 4.27: 1. Hence, there was no significant difference be-
Sangon Biotech Co., Ltd. The primer sequences are listed in tween the two groups by sex (p>0.05). The case group mean
Table 1. The PCR reaction mixture was 25 µL, including 1.0 µL age was 42.85±11.21, and the control group mean age was
DNA template, 1.0 µL each of forward and reverse primers, 43.02±10.94; there was no significant different between the
1.0 µL Taq DNA enzyme, 2.0 µL dNTPs, 2.5 µL 10× buffer solu- two groups by age (p>0.05).
tion, and 16.5 µL sterilized double distilled water. The ampli-
fication conditions of the PCR were 95°C pre-denaturation for The genotype distributions of OPG polymorphisms in case
5 minutes, followed by 45 cycles of 94°C degeneration for 10 and control groups
seconds, 68°C/54°C annealing for 30 seconds, 72°C extension
for 60 seconds, and finally 72°C extension for 5 minutes. The The genotype distribution of OPG rs2073618 and rs2073617
PCR products were checked using 1% agarose gel electropho- polymorphisms in the control group conformed to HWE (p=0.93,
resis (AGE). The enzyme reaction mixture was 20 µL, includ- p=0.31, respectively). This result suggests that our population
ing 3.0 µL restriction enzyme (ExoI for rs2073618 and HindIII had a similar genetic background to the Mendelian popula-
for rs2073617), 2.0 µL 10 x buffer solution, 7.0 µL PCR prod- tion. The genotype and allele distributions of two SNPs in OPG
ucts, and 8.0 µL double distilled water. The mixture was digest- are shown in Table 2. GG, GC, and CC genotype frequencies in
ed for 16 hours in a water bath at 37°C. The enzyme-digested rs2073618 were 28.18%, 45.46%, and 26.36% respectively in
products were separated using 3% agarose gel electrophoresis the case group and 36.20%, 48.28%, and 15.52% respective-
(AGE); the final outcome was observed in an imaging system. ly in the control group. The GC allele frequency was 50.91%
and 49.09% in the case group and 60.34% and 39.66% in the
Statistical analysis control group. Thus, the CC genotype and C allele distributions
showed statistically significant differences between the two
Hardy-Weinberg equilibrium (HWE) was used to detect group groups (p=0.04, p=0.04, respectively), and their carriers were
differences. The frequencies of genotype, allele, and haplo- more likely to develop infection compared with those carry-
type in OPG polymorphisms were determined by the direct ing the TT genotype and T allele (CC vs. GG: OR=2.18, 95%
counting method. Linkage disequilibrium (LD) and its corre- CI=1.03–4.62; C vs. G: OR=1.47, 95% CI=1.01–2.13).
lation coefficient (D` value) were calculated using Haploview
software. The comparison of genotypes, alleles, and haplo- The GG, GC, and CC genotypes frequencies of rs2073617 were
types between the two groups was tested by chi-square test. 32.14%, 45.24%, and 22.62% respectively in the case control
_
Measurement data was expressed by c ±s and%. The effects group and 39.66%, 50.00%, and 10.34% respectively in the
of different genotypes, alleles, and haplotypes on peri-implan- control group. There were no significant differences between
titis were estimated through odds ratio (OR) and 95% confi- the two groups based on genotypes and alleles (P>0.05), which
dence interval (CI). All statistical analysis was accomplished demonstrated that this polymorphism was not correlated with
by PASW Statistics 18.0 software; p<0.05 was considered sta- the susceptibility to peri-implantitis.
tistically significant.

Indexed in:  [Current Contents/Clinical Medicine]  [SCI Expanded]  [ISI Alerting System] 
This work is licensed under Creative Common Attribution-
NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) 4273 [ISI Journals Master List]  [Index Medicus/MEDLINE]  [EMBASE/Excerpta Medica] 
[Chemical Abstracts/CAS]  [Index Copernicus]
 Zhou J. et al.:
LAB/IN VITRO RESEARCH Osteoprotegerin gene (OPG) polymorphisms associated with peri-implantitis…
© Med Sci Monit, 2016; 22: 4271-4276

Table 2. Frequency comparisons of genotypes and alleles in OPG gene polymorphisms.

Genotype/allele Case, n=110 (%) Control, n=116 (%) c2 P OR (95% CI) PHWE

rs2073618 0.93

GG 31 (28.18) 42 (36.20) – – 1.00

GC 50 (45.46) 56 (48.28) 0.39 0.53 1.21 (0.66–2.21)

CC 29 (26.36) 18 (15.52) 4.23 0.04 2.18 (1.03–4.62)

G 112 (50.91) 140 (60.34) – – 1.00

C 108 (49.09) 92 (39.66) 4.08 0.04 1.47 (1.01–2.13)

rs2073617 0.31

TT 40 (32.14) 46 (39.66) – – 1.00

CT 51 (45.24) 58 (50.00) 0.01 0.97 1.01 (0.57–1.78)

CC 19 (22.62) 12 (10.34) 1.99 0.16 1.82 (0.79–4.21)

T 131 (54.76) 150 (64.66) – – 1.00

C 89 (45.24) 82 (35.34) 1.25 0.26 1.24 (0.85–1.82)

HWE – Hardy-Weinberg equilibrium.

Table 3. Analyses of LD and haplotypes in OPG rs2073618, rs2073617 polymorphisms.

Haplotype SNP1-SNP2 Case 2n=220 (%) Control 2n=232 (%) c2 P OR (95% CI)

G-T 100 (45.45) 132 (56.90) – – 1.00

C-C 77 (35.00) 74 (31.90) 2.29 0.13 1.37 (0.91–2.07)

G-C 31 (14.09) 18 (7.76) 6.61 0.01 2.27 (1.20–4.30)

C-T 12 (5.46) 8 (3.44) 2.13 0.15 1.98 (0.78–5.03)

SNP1 – rs2073617; SNP2 – rs2073618.

Haplotype analysis of OPG rs2073618, rs2073617 failure of the bone union. It is similar to chronic adult peri-
polymorphisms odontitis. The incidence rate is 5% to 8% [3]. General symp-
toms are bleeding around the implant on probing, festering
The LD and haplotype analysis of OPG rs2073618 and rs2073617 around implant, probing depth increase, sinus formation, gin-
was performed by Haploview software. Strong LD was discov- gival recession, gingival swelling, and on radiological exam-
ered between them (D’=0.93), and four haplotypes were found: ination appearance around the implant of bone resorption.
G-T, C-C, G-C, C-T (rs2073618-rs2073617) (Table 3). The data Peri-implantitis is most often found during a return follow-up
show distributions of G-C haplotype, with obvious differenc- visit, and requires timely, correct diagnosis and treatment to
es between the two groups (p=0.01) compared with G-T hap- avoid complete loss of synostosis, which can lead to failure
lotype, which indicates this haplotype could increase the risk of the implant [14]. In addition, persistent inflammation can
of peri-implantitis (OR=2.27, 95% CI=1.20–4.30). lead to the destruction of the periodontal and peri-implant tis-
sues [15]. At present, genetic differences are not a common
factor known to affect the immune response of periodonto-
Discussion pathogens [16]. The etiology and pathogenesis is not yet fully
understood. Therefore, in this study we investigated the rela-
Peri-implantitis is the most common complication after im- tionship between genetic susceptibility and peri-implantitis.
plantation of support dentures; moreover, it is the main rea-
son for failure of dental implant restoration. Peri-implantitis OPG is a secreted glycoprotein that has the function of pro-
is the inflammation of the hard and soft tissue around the tecting bone and preventing bone resorption [6]. The hu-
implant. It can result in supporting bone loss, which leads to man OPG gene (TNFRSF11B) is located on chromosome 8q24,

Indexed in:  [Current Contents/Clinical Medicine]  [SCI Expanded]  [ISI Alerting System] 
This work is licensed under Creative Common Attribution-
NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) 4274 [ISI Journals Master List]  [Index Medicus/MEDLINE]  [EMBASE/Excerpta Medica] 
[Chemical Abstracts/CAS]  [Index Copernicus]
Zhou J. et al.:
Osteoprotegerin gene (OPG) polymorphisms associated with peri-implantitis…
© Med Sci Monit, 2016; 22: 4271-4276
LAB/IN VITRO RESEARCH

which is a single-copy gene. It contains five exons, and the In our study, the genotype and allele distributions of OPG
total length of the sequence is 29kb. It consists of 401 amino rs2073618 polymorphism were correlated with the suscepti-
acid residues, including a signal peptide composed of 21 ami- bility to peri-implantitis in patients from the Chinese Han pop-
no acids and seven structural domains (D1-D7). OPG mRNA is ulation. The data indicated that CC genotype and C allele fre-
expressed in all tissues of the body, including lung, heart, kid- quencies were much higher in peri-implantitis patients than
ney, liver, gastrointestinal tract, spinal cord, thyroid, and bone in controls, and people carrying the CC genotype and C allele
tissue; it is also expressed in fibroblasts, aortic smooth mus- was more likely to develop peri-implantitis than GG genotype
cle cells, B lymphocytes, and other cells. Cardiovascular stud- and G allele carriers. The C allele of rs2073618 has been asso-
ies have shown that plasma osteoprotegerin could be used ciated with lower bone mineral density (BMD) [26,27], which
for prognosis of patients with cardiovascular disease [17–19]. might contribute to the occurrence of peri-implantitis. This poly-
However, little research has investigated the correlation be- morphism did not have a significant association with the risk
tween it and peri-implantitis. of rheumatoid arthritis (RA) and premenopausal SLE (system-
ic lupus erythematosus) [28,29]. In our study, for rs2073617,
The eleventh member of the OPG ligand family is a recep- we did not find any significant difference between the case
tor activator of nuclear factor k ligand (RANKL), also known group and the control group based on either genotypes or al-
as TNFSF11, a protein related to the TNF ligand super-family leles. One study found OPG rs2073617 polymorphism had no
and which is the stimulating factor for osteoclasts. The RANK/ significant association with BMD and bone metabolism [30];
RANKL/OPG pathway plays an important role in osteoclast for- these study findings may support our results. However, Zavala-
mation, activation, and regulation of bone resorption [20,21]. Cerna et al. showed that C allele carriers had a high preva-
The RANKL gene is closely related to the occurrence of bone lence for RA [31]. In addition, the correlation between the hap-
resorption in other diseases, such as periodontitis, so it is ap- lotypes in OPG rs2073618 and rs2073617 polymorphisms and
propriate to speculate that it is one of the major determining peri-implantitis in G-C haplotype was discovered to obvious-
genes in peri-implantitis [22]. One study showed that RANKL ly increase the risk of developing peri-implantitis. Interactions
gene polymorphism was significantly associated with bone between the SNPs altered the role of every SNP in the devel-
resorption, and for the person carrying RANKL gene polymor- opment of peri-implantitis.
phic locus, metabolism increased and bone mineral density
decreased [23]. By analysis of allele linkage through human
venous blood, Kadkhodazadeh et al. confirmed the correla- Conclusions
tion between RANKL gene polymorphism and peri-implanti-
tis [24]. In addition, Kadkhodazadeh et al. [25] found that an- Our study supported the correlation between OPG polymor-
other major OPG gene in the RANK/OPG/RANKL pathway was phisms and peri-implantitis in patients from a Chinese Han
also associated with the occurrence of peri-implantitis. The population. There are many limitations to our study, such as
single nucleotide polymorphism (SNP) of the gene had T950C small sample size and environmental factors. To confirm our
and G1181C, but only the genetic polymorphism of G1181C study results and achieve the goals of early diagnosis and
was related to the occurrence of peri-implantitis. This result timely treatment of peri-implantitis, further research should
is in agreement with the results of our study. be conducted using well designed larger studies that include
various populations.

References:
1. Xu L, Sun X, Bai J et al: Reosseointegration following regenerative therapy 6. Simonet WS, Lacey DL, Dunstan CR et al: Osteoprotegerin: A novel secret-
of tissue-engineered bone in a canine model of experimental peri-implan- ed protein involved in the regulation of bone density. Cell, 1997; 89(2):
titis. Clin Implant Dent Relat Res, 2016; 18(2): 379–91 309–19
2. Vargas-Reus MA, Memarzadeh K, Huang J et al: Antimicrobial activity of 7. Schoppet M, Preissner KT, Hofbauer LC: RANK ligand and osteoprotegerin:
nanoparticulate metal oxides against peri-implantitis pathogens. Int J paracrine regulators of bone metabolism and vascular function. Arterioscler
Antimicrob Agents, 2012; 40(2): 135–39 Thromb Vasc Biol, 2002; 22(4): 549–53
3. Takamori Y, Atsuta I, Nakamura H et al: Histopathological comparison of 8. Otero L, Garcia DA, Wilches-Buitrago L: Expression and presence of OPG
the onset of peri-implantitis and periodontitis in rats. Clin Oral Implants and RANKL mRNA and protein in human periodontal ligament with orth-
Res, 2016 [Epub ahead of print] odontic force. Gene Regul Syst Bio, 2016; 10: 15–20
4. Chaudhari HL, Warad S, Ashok N et al: Association of Interleukin-17 poly- 9. Kang YH, Jin JS, Yi DW, Son SM: Bone morphogenetic protein-7 inhibits vas-
morphism (-197G/A) in chronic and localized aggressive periodontitis. Braz cular calcification induced by high vitamin D in mice. Tohoku J Exp Med,
Oral Res, 2016; 30(1). pii:S1806-83242016000100219 2010; 221(4): 299–307
5. García-Delaney C, Sánchez-Garcés MÁ, Figueiredo R et al: Clinical signifi- 10. Mizuno, M., et al., Reveromycin A administration prevents alveolar bone
cance of interleukin-1 genotype in smoking patients as a predictor of peri- loss in osteoprotegerin knockout mice with periodontal disease. Sci Rep,
implantitis: A case-control study. Med Oral Patol Oral Cir Bucal, 2015; 20(6): 2015; 5: 16510
e737–43

Indexed in:  [Current Contents/Clinical Medicine]  [SCI Expanded]  [ISI Alerting System] 
This work is licensed under Creative Common Attribution-
NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) 4275 [ISI Journals Master List]  [Index Medicus/MEDLINE]  [EMBASE/Excerpta Medica] 
[Chemical Abstracts/CAS]  [Index Copernicus]
 Zhou J. et al.:
LAB/IN VITRO RESEARCH Osteoprotegerin gene (OPG) polymorphisms associated with peri-implantitis…
© Med Sci Monit, 2016; 22: 4271-4276

11. Xie H, Xie PL, Wu XP et al: Omentin-1 attenuates arterial calcification and 22. Yu XJ, Xiao CJ, Du YM et al: Effect of hypoxia on the expression of RANKL/
bone loss in osteoprotegerin-deficient mice by inhibition of RANKL expres- OPG in human periodontal ligament cells in vitro. Int J Clin Exp Pathol, 2015;
sion. Cardiovasc Res, 2011; 92(2): 296–306 8(10): 12929–35
12. Makarović S, Makarović Z, Steiner R et al: Osteoprotegerin and vascular 23. Rhee EJ, Yun EJ, Oh KW et al: The relationship between Receptor Activator
calcification: Clinical and prognostic relevance. Coll Antropol, 2015; 39(2): of Nuclear Factor-kappaB Ligand (RANKL) gene polymorphism and aortic
461–68 calcification in Korean women. Endocr J, 2010; 57(6): 541–49
13. Ohmori R, Momiyama Y, Taniguchi H et al: Association between osteopro- 24. Kadkhodazadeh M, Ebadian AR, Gholami GA et al: Analysis of RANKL gene
tegerin gene polymorphism and coronary artery disease in Japanese men. polymorphism (rs9533156 and rs2277438) in Iranian patients with chron-
Atherosclerosis, 2006; 187(1): 215–17 ic periodontitis and periimplantitis. Arch Oral Biol, 2013; 58(5): 530–36
14. Trullenque-Eriksson A, Guisado Moya B: Retrospective long-term evalua- 25. Kadkhodazadeh M, Tabari ZA, Ardakani MR et al: Analysis of osteoproteger-
tion of dental implants in totally and partially edentulous patients: Part II: in (OPG) gene polymorphism in Iranian patients with chronic periodonti-
Periimplant disease. Implant Dent, 2015; 24(2): 217–21 tis and peri-implantitis. A cross-sectional study. Eur J Oral Implantol, 2012;
15. Mandzhavidze N, Vadachkoriia N, Gumberidze N: [Prophylaxis and treatment 5(4): 381–88
of periimpalntitis]. Georgian Med News, 2013; (222): 17–23 [in Russian] 26. Roshandel D, Holliday KL, Pye SR et al: Genetic variation in the RANKL/
16. Papathanasiou E, Finkelman M, Hanley J, Parashis AO et al: Prevalence, eti- RANK/OPG signaling pathway is associated with bone turnover and bone
ology and treatment of peri-implant mucositis and peri-implantitis: A sur- mineral density in men. J Bone Miner Res, 2010; 25(8): 1830–38
vey of us periodontists. J Periodontol, 2015 [Epub ahead of print] 27. Shang M, Lin L, Cui H: Association of genetic polymorphisms of RANK, RANKL
17. Ueland T, Dahl CP, Kjekshus J et al: Osteoprotegerin predicts progression and OPG with bone mineral density in Chinese peri- and postmenopausal
of chronic heart failure: Results from CORONA. Circ Heart Fail, 2011; 4(2): women. Clin Biochem, 2013; 46(15): 1493–501
145–52 28. Xu S, Ma XX, Hu LW et al: Single nucleotide polymorphism of RANKL and
18. Røysland R, Bonaca MP, Omland T et al: Osteoprotegerin and cardiovascu- OPG genes may play a role in bone and joint injury in rheumatoid arthri-
lar mortality in patients with non-ST elevation acute coronary syndromes. tis. Clin Exp Rheumatol, 2014; 32(5): 697–704
Heart, 2012; 98(10): 786–91 29. Bonfá AC, Seguro LP, Caparbo V et al: RANKL and OPG gene polymorphisms:
19. Yang Q, Lu S, Chen Y et al: Plasma osteoprotegerin levels and long-term Associations with vertebral fractures and bone mineral density in premeno-
prognosis in patients with intermediate coronary artery lesions. Clin Cardiol, pausal systemic lupus erythematosus. Osteoporos Int, 2015; 26(5): 1563–71
2011; 34(7): 447–53 30. Park SE, Oh KW, Lee WY et al: Association of osteoporosis susceptibility
20. Assmann G, Koenig J, Pfreundschuh M et al: Genetic variations in genes genes with bone mineral density and bone metabolism related markers
encoding RANK, RANKL, and OPG in rheumatoid arthritis: A case-control in Koreans: The Chungju Metabolic Disease Cohort (CMC) study. Endocr J,
study. J Rheumatol, 2010; 37(5): 900–4 2014; 61(11): 1069–78
21. Rakic M, Lekovic V, Nikolic-Jakoba N et al: Bone loss biomarkers associated 31. Zavala-Cerna MG, Moran-Moguel MC, Cornejo-Toledo JA et al: Osteoprotegerin
with peri-implantitis. A cross-sectional study. Clin Oral Implants Res, 2013; polymorphisms in a Mexican population with rheumatoid arthritis and gen-
24(10): 1110–16 eralized osteoporosis: A preliminary report. J Immunol Res, 2015; 2015:
376197

Indexed in:  [Current Contents/Clinical Medicine]  [SCI Expanded]  [ISI Alerting System] 
This work is licensed under Creative Common Attribution-
NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) 4276 [ISI Journals Master List]  [Index Medicus/MEDLINE]  [EMBASE/Excerpta Medica] 
[Chemical Abstracts/CAS]  [Index Copernicus]