载脂蛋白相关 LPA 和 9p21 基因座对主动脉瓣狭窄风险的影响。
Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis.
机构信息
Klinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum München, Technical University Munich, Munich, Germany.
Department of Cardiovascular Sciences, Cardiovascular Research Centre, NIHR Leicester Biomedical Research Centre University of Leicester, Leicester, United Kingdom.
出版信息
Int J Cardiol. 2019 Feb 1;276:212-217. doi: 10.1016/j.ijcard.2018.11.094. Epub 2018 Nov 17.
BACKGROUND
Aortic valve stenosis (AVS) and coronary artery disease (CAD) have a significant genetic contribution and commonly co-exist. To compare and contrast genetic determinants of the two diseases, we investigated associations of the LPA and 9p21 loci, i.e. the two strongest CAD risk loci, with risk of AVS.
METHODS
We genotyped the CAD-associated variants at the LPA (rs10455872) and 9p21 loci (rs1333049) in the GeneCAST (Genetics of Calcific Aortic STenosis) Consortium and conducted a meta-analysis for their association with AVS. Cases and controls were stratified by CAD status. External validation of findings was undertaken in five cohorts including 7880 cases and 851,152 controls.
RESULTS
In the meta-analysis including 4651 cases and 8231 controls the CAD-associated allele at the LPA locus was associated with increased risk of AVS (OR 1.37; 95%CI 1.24-1.52, p = 6.9 × 10) with a larger effect size in those without CAD (OR 1.53; 95%CI 1.31-1.79) compared to those with CAD (OR 1.27; 95%CI 1.12-1.45). The CAD-associated allele at 9p21 was associated with a trend towards lower risk of AVS (OR 0.93; 95%CI 0.88-0.99, p = 0.014). External validation confirmed the association of the LPA risk allele with risk of AVS (OR 1.37; 95%CI 1.27-1.47), again with a higher effect size in those without CAD. The small protective effect of the 9p21 CAD risk allele could not be replicated (OR 0.98; 95%CI 0.95-1.02).
CONCLUSIONS
Our study confirms the association of the LPA locus with risk of AVS, with a higher effect in those without concomitant CAD. Overall, 9p21 was not associated with AVS.
背景
主动脉瓣狭窄（AVS）和冠状动脉疾病（CAD）具有显著的遗传贡献，并且通常同时存在。为了比较和对比这两种疾病的遗传决定因素，我们研究了 LPA 和 9p21 位点（即两个最强的 CAD 风险位点）与 AVS 风险的关联。
方法
我们在 GeneCAST（Genetics of Calcific Aortic STenosis）联盟中对 LPA（rs10455872）和 9p21 位点（rs1333049）的 CAD 相关变体进行了基因分型，并对其与 AVS 的关联进行了荟萃分析。病例和对照按 CAD 状态分层。在包括 7880 例病例和 851152 例对照的五个队列中进行了发现的外部验证。
结果
在包括 4651 例病例和 8231 例对照的荟萃分析中，LPA 位点的 CAD 相关等位基因与 AVS 风险增加相关（OR 1.37；95%CI 1.24-1.52，p=6.9×10），在无 CAD 的患者中效应更大（OR 1.53；95%CI 1.31-1.79）与 CAD 患者相比（OR 1.27；95%CI 1.12-1.45）。9p21 的 CAD 相关等位基因与 AVS 风险降低呈趋势相关（OR 0.93；95%CI 0.88-0.99，p=0.014）。外部验证证实了 LPA 风险等位基因与 AVS 风险的关联（OR 1.37；95%CI 1.27-1.47），在无 CAD 的患者中，其效应更大。9p21 CAD 风险等位基因的微小保护作用无法复制（OR 0.98；95%CI 0.95-1.02）。
结论
我们的研究证实了 LPA 位点与 AVS 风险的关联，在无合并 CAD 的患者中，其效应更高。总体而言，9p21 与 AVS 无关。
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