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Systematic Review and Meta-Analysis of Candidate Gene Association Studies With Fracture Risk in Physically Active Participants

体力活动参与者骨折风险候选基因关联研究的系统评价和荟萃分析

  • 影响因子:3.60
  • DOI:10.3389/fgene.2020.00551
  • 作者列表:"Edward Ryan-Moore","Edward Ryan-Moore","Yiannis Mavrommatis","Yiannis Mavrommatis","Mark Waldron","Mark Waldron
  • 发表时间:2020-06-16
Abstract

Background: Fractures are common in physically active populations and genetic differences may mediate injury risk.Objective: To meta-analyse the pooled results of candidate gene association studies with non-osteoporotic fracture risk in physically active humans.Methods: Systematic searching of databases returned 11 eligible studies published in English. Pooled odds ratios (ORs) with 95% confidence intervals (CI) were produced using allele contrast, recessive and homozygote contrast meta-analysis models to evaluate associations of risk alleles in the COL1A1 (rs1800012), COL2A1 (rs412777), CTR (rs1801197), ESR1 (rs2234693 and rs9340799) LRP5 (rs3736228), VDR (rs10735810, rs7975232, rs1544410, and rs731236) genes with fracture incidence.Results: Eligible study quality was generally low (7/11) and no significant overall effect was found for any genetic variant with any comparison model (p > 0.05). A trivial reduction in fracture risk was found for female participants with the COL1A1 Sp1 (rs1800012) T allele (OR = 0.48, 95% CI = 0.25–0.91, p = 0.03, d = –0.18).Conclusions: No overall effect was found from the pooled results of included genetic variants on fracture risk in physically active participants. The COL1A1 Sp1 rs1800012 T allele may reduce fracture risk in physically active females but further high-quality research with sex-specific analysis is required.Trial Registration: (PROSPERO; CRD42018115008).

摘要

背景: 骨折在体力活动人群中很常见,遗传差异可能介导损伤风险。目的: 荟萃分析体力活动人群非骨质疏松性骨折风险的候选基因关联研究的汇总结果。方法: 系统检索数据库,返回以英文发表的 11 项合格研究。使用等位基因对比、隐性和纯合子对比荟萃分析模型产生 95% 置信区间 (CI) 的合并比值比 (ORs),以评估 COL1A1 (rs1800012) 中风险等位基因的相关性。COL2A1 (rs412777) 、 CTR (rs1801197) 、 ESR1 (rs2234693 和 rs9340799) LRP5 (rs3736228) 、 VDR (rs10735810 、Rs7975232 、 rs1544410 和 rs731236) 基因与骨折发生率。结果: 符合条件的研究质量普遍较低 (7/11),与任何比较模型相比,未发现任何遗传变异的显著总体效应 (p> 0.05)。COL1A1 Sp1 (rs1800012) T 等位基因的女性受试者骨折风险略有降低 (OR = 0.48,95% CI = 0.25-0.91,p = 0.03, d = -0.18)。结论: 从纳入的遗传变异对体力活动参与者骨折风险的汇总结果中没有发现总体影响。COL1A1 Sp1 rs1800012 T 等位基因可能降低体力活动女性的骨折风险,但需要进一步的具有性别特异性分析的高质量研究。试验注册 :( PROSPERO; CRD42018115008)。

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DOI:10.1080/15592294.2020.1716491
作者列表:["Zhang X","Ehrlich KC","Yu F","Hu X","Meng XH","Deng HW","Shen H","Ehrlich M"]

METHODS::A major challenge in translating findings from genome-wide association studies (GWAS) to biological mechanisms is pinpointing functional variants because only a very small percentage of variants associated with a given trait actually impact the trait. We used an extensive epigenetics, transcriptomics, and genetics analysis of the TBX15/WARS2 neighbourhood to prioritize this region's best-candidate causal variants for the genetic risk of osteoporosis (estimated bone density, eBMD) and obesity (waist-hip ratio or waist circumference adjusted for body mass index). TBX15 encodes a transcription factor that is important in bone development and adipose biology. Manual curation of 692 GWAS-derived variants gave eight strong candidates for causal SNPs that modulate TBX15 transcription in subcutaneous adipose tissue (SAT) or osteoblasts, which highly and specifically express this gene. None of these SNPs were prioritized by Bayesian fine-mapping. The eight regulatory causal SNPs were in enhancer or promoter chromatin seen preferentially in SAT or osteoblasts at TBX15 intron-1 or upstream. They overlap strongly predicted, allele-specific transcription factor binding sites. Our analysis suggests that these SNPs act independently of two missense SNPs in TBX15. Remarkably, five of the regulatory SNPs were associated with eBMD and obesity and had the same trait-increasing allele for both. We found that WARS2 obesity-related SNPs can be ascribed to high linkage disequilibrium with TBX15 intron-1 SNPs. Our findings from GWAS index, proxy, and imputed SNPs suggest that a few SNPs, including three in a 0.7-kb cluster, act as causal regulatory variants to fine-tune TBX15 expression and, thereby, affect both obesity and osteoporosis risk.

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