Genome-Wide Association Study of Peripheral Artery Disease.
Genome-Wide Association Study of Peripheral Artery Disease.
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DOI：
10.1161/circgen.119.002862
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发表时间：
2021-10
期刊：
影响因子：
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通讯作者：
GoLEAD Consortium, SUMMIT Consortium†
中科院分区：
文献类型：
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作者：
van Zuydam NR;Stiby A;Abdalla M;Austin E;Dahlström EH;McLachlan S;Vlachopoulou E;Ahlqvist E;Di Liao C;Sandholm N;Forsblom C;Mahajan A;Robertson NR;Rayner NW;Lindholm E;Sinisalo J;Perola M;Kallio M;Weiss E;Price J;Paterson A;Klein B;Salomaa V;Palmer CNA;Groop PH;Groop L;McCarthy MI;de Andrade M;Morris AP;Hopewell JC;Colhoun HM;Kullo IJ;GoLEAD Consortium, SUMMIT Consortium†
补充数字内容可在文本中找到。外周动脉疾病（PAD）影响全世界超过2亿人，并且与高死亡率和发病率相关。我们试图确定与PAD相关的基因组变异，以及在糖尿病和吸烟状态的背景下。我们确定了与PAD相关的遗传变异，然后用百万退伍军人计划和英国生物银行发表的汇总统计数据进行荟萃分析，以复制他们的发现。接下来，我们对曾经吸烟者、从不吸烟者、糖尿病患者和无糖尿病史的个体进行了分层全基因组关联分析，并进行了相应的相互作用分析，以确定通过糖尿病或吸烟状态改变PAD风险的变异。我们发现了5个全基因组显著的（Passociation ≤5×10−8）与PAD相关，449 548（Ncases=12 086）LPA附近的欧洲血统个体（脂蛋白[a]），CDKN 2BAS 1（CDKN 2B反义RNA 1），SH 2B 3（SH 2B衔接蛋白3）-PTPN 11（蛋白酪氨酸磷酸酶非受体11型），HDAC 9（组蛋白脱乙酰酶9）和CHRNA 3（胆碱能受体烟碱α 3亚基）基因座（与先前报道的关联重叠）。先前与PAD相关的变异的荟萃分析显示，19个已发表的变异中有18个仍然具有全基因组意义。在糖尿病患者中，CCSER 1（卷曲螺旋富含丝氨酸蛋白1）位点的rs 116405693与PAD相关（比值比[95% CI]，1.51 [1.32-1.74]，P糖尿病=2.5×10−9，P与糖尿病的相互作用=5.3×10−7）。此外，在吸烟者中，CHRNA 3基因座上的rs 12910984与PAD相关（比值比[95% CI]，1.15 [1.11-1.19]，P吸烟者=9.3×10−10，P与吸烟的相互作用=3.9×10−5）。我们的分析证实了已发表的与PAD的遗传相关性，并确定了在糖尿病或吸烟状态下可能影响PAD易感性的新变异。
Supplemental Digital Content is available in the text. Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status. We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status. We identified 5 genome-wide significant (Passociation ≤5×10−8) associations with PAD in 449 548 (Ncases=12 086) individuals of European ancestry near LPA (lipoprotein [a]), CDKN2BAS1 (CDKN2B antisense RNA 1), SH2B3 (SH2B adaptor protein 3) - PTPN11 (protein tyrosine phosphatase non-receptor type 11), HDAC9 (histone deacetylase 9), and CHRNA3 (cholinergic receptor nicotinic alpha 3 subunit) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the CCSER1 (coiled-coil serine rich protein 1) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32–1.74], Pdiabetes=2.5×10−9, Pinteractionwithdiabetes=5.3×10−7). Furthermore, in smokers, rs12910984 at the CHRNA3 locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11–1.19], Psmokers=9.3×10−10, Pinteractionwithsmoking=3.9×10−5). Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.