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Associations of osteoprotegerin (OPG) TNFRSF11B gene polymorphisms with risk of fractures in older adult populations: meta-analysis of genetic and genome-wide association studies

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Abstract

Summary

The meta-analysis of osteoprotegerin (OPG) (TNFRSF11B) polymorphisms from genetic association studies and genome-wide association studies was performed in order to test the hypothesis of association between OPG polymorphisms and fracture. The findings showed a significant 13% to 37% protective effect of OPG on fractures in postmenopausal women (PSM) (rs2073618), overall, ≥ 60y and Western subjects (rs3134069 and rs3134070).

Purpose

Fractures in older people usually result from compromised bone integrity. The multifactorial aetiology of fractures includes both genetic and environmental factors. Inconsistency of reported associations of osteoprotegerin (OPG) (TNFRSF11B) polymorphisms with fracture in the older adult population warranted a meta-analysis to determine more precise estimates.

Methods

We searched for all available literature on OPG (TNFRSF11B) and fracture. Four polymorphisms were examined, one exonic (rs2073618) and three intronic (rs3134069, rs3134070 and rs3102735). The first two intron polymorphisms were combined (OPGI: osteoprotegerin intron) on account of complete linkage disequilibrium. Risks were estimated with odds ratios (ORs) and 95% confidence intervals (CIs) using the allele-genotype model that included variant (var), wild-type (wt) and heterozygote (het). Multiple comparisons were Bonferroni-corrected. We used meta-regression to examine sources of heterogeneity. Zero heterogeneity (homogeneity: I2 = 0%) and high significance (Pa < 0.00001) were the criteria for strength of evidence. Significant outcomes were subjected to sensitivity analysis and publication bias assessment.

Results

From 13 articles (11 genetic association and two genome-wide), this meta-analysis generated five significant pooled ORs, all indicating reduced risks (ORs 0.44–0.87). Of the five, four highly significant comparisons (Pa ≤ 0.00001–0.002) survived the Bonferroni correction, one in rs2073618 het model of the postmenopausal women (OR 0.87, 95% CI 0.81–0.92, I2 = 0%) and the other three in OPGI wt model of the overall analysis, ≥ 60 y and Western subjects (ORs 0.63–0.71, 95% CI 0.47–0.86, I2 = 97–99%). These findings were consistent, had high significance and high statistical power and were robust and without evidence of publication bias. Four covariates (year of publication, study quality, fracture type/site and sample size) were the sources of heterogeneity in the OPGI overall outcomes (Pa = 0.0001–0.03).

Conclusion

Evidence showed that the OPG (TNFRSF11B) polymorphisms reduced the risk for fracture in older adults, particularly protective among postmenopausal women, ≥ 60 y and Western subjects.

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Data availability

All relevant data are within the paper and its supporting information files.

Abbreviations

A:

Adenine

AES:

Adjusted effect size

BMD:

Bone mineral density

CI:

Confidence interval

C:

Cytosine

d:

Duplicate

GAS:

Genetic association study

G:

Guanine

GWAS:

Genome-wide association study

het :

var + wt (Heterozygous)

HWE:

Hardy-Weinberg equilibrium

I 2 :

Measure of variability

IV:

Inverse variance

L:

Laplace-corrected data

LD:

Linkage disequilibrium

Log:

Logarithm

n:

Number of studies

NOS:

Newcastle-Ottawa Scale

OPG :

osteoprotegerin Gene

OPG:

Osteoprotegerin protein

OPGI:

osteoprotegerin Intron

OR:

Odds ratio

OR^:

Boolean descriptor

P a :

P Value for association

P HET :

P Value for heterogeneity

P HWE :

P Value for HWE

PRS:

Polygenic risk score

PSM:

Postmenopausal

RANK:

Receptor activator of nuclear factor-κB

RANKL:

Ligand of RANK

SD:

Standard deviation

SE:

Standard error

SNP:

Single-nucleotide polymorphism

TNFRSF11B :

Tumour necrosis factor receptor superfamily member 11B

T:

Thymine

var :

Variant

wt :

Wild-type

y:

Year

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Author information

Authors and Affiliations

  1. Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, 12120, Thailand

    P. Tharabenjasin & N. Pabalan

  2. Environmental Monitoring and Reporting Branch, Ontario Ministry of the Environment, Conservation and Parks, 125 Resources Road, Toronto, ON, Canada

    H. Jarjanazi

  3. Integrative Computational Bioscience Center (ICBS), Mahidol University, Nakhon Pathom, 73170, Thailand

    N. Jinawath

  4. Program in Translational Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand

    N. Jinawath

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  1. P. Tharabenjasin
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  4. N. Jinawath
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Contributions

Conceived the topic: NP, PT. Conceived the study design: NP. Data extraction: PT, NP, HJ. Data analysis: PT, NP, HJ. Writing—original draft: PT, NP. Writing—review and editing: PT, NP, HJ, NJ. All authors reviewed the manuscript.

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Correspondence to N. Pabalan.

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Tharabenjasin, P., Pabalan, N., Jarjanazi, H. et al. Associations of osteoprotegerin (OPG) TNFRSF11B gene polymorphisms with risk of fractures in older adult populations: meta-analysis of genetic and genome-wide association studies. Osteoporos Int 33, 563–575 (2022). https://doi.org/10.1007/s00198-021-06161-5

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