Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, 12120, Thailand.
Environmental Monitoring and Reporting Branch, Ontario Ministry of the Environment, Conservation and Parks, 125 Resources Road, Toronto, ON, Canada.
Osteoporos Int. 2022 Mar;33(3):563-575. doi: 10.1007/s00198-021-06161-5. Epub 2021 Oct 30.
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).
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.
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: I = 0%) and high significance (P < 0.00001) were the criteria for strength of evidence. Significant outcomes were subjected to sensitivity analysis and publication bias assessment.
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 (P ≤ 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, I = 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, I = 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 (P = 0.0001-0.03).
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.
老年人的骨折通常是由于骨完整性受损所致。骨折的多因素病因包括遗传和环境因素。在老年人群中，骨保护素（OPG）（TNFRSF11B）多态性与骨折的相关性报道不一致，因此需要进行荟萃分析以确定更准确的估计值。
我们搜索了所有关于 OPG（TNFRSF11B）和骨折的可用文献。共检测了 4 种多态性，其中 1 种位于外显子（rs2073618），3 种位于内含子（rs3134069、rs3134070 和 rs3102735）。前两个内含子多态性由于完全连锁不平衡而合并（OPGI：骨保护素内含子）。使用包含变体（var）、野生型（wt）和杂合子（het）的等位基因-基因型模型估计风险，风险估计值为比值比（OR）和 95%置信区间（CI）。使用 Bonferroni 校正进行多重比较。我们使用荟萃回归来检查异质性的来源。零异质性（同质性：I=0%）和高度显著性（P<0.00001）是证据强度的标准。显著的结果进行了敏感性分析和发表偏倚评估。
从 13 篇文章（11 篇遗传关联研究和 2 篇全基因组研究）中，这项荟萃分析产生了 5 个具有统计学意义的汇总 OR，均表明风险降低（OR 0.44-0.87）。其中，5 个高度显著的比较（P≤0.00001-0.002）在 Bonferroni 校正后仍然存在，一个是绝经后妇女 rs2073618 杂合模型（OR 0.87，95%CI 0.81-0.92，I=0%），另外三个是 OPGI wt 模型在总体分析、≥60 岁和西方人群中的比较（ORs 0.63-0.71，95%CI 0.47-0.86，I=97-99%）。这些发现具有一致性、高度显著性和高统计学功效，并且稳健，没有发表偏倚的证据。在 OPGI 总体结果中，4 个协变量（发表年份、研究质量、骨折类型/部位和样本量）是异质性的来源（P=0.0001-0.03）。
证据表明，OPG（TNFRSF11B）多态性降低了老年人骨折的风险，尤其是绝经后妇女、≥60 岁和西方人群的骨折风险降低。
