Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden (N.R.v.Z.).
Wellcome Centre for Human Genetics, Nuffield Department of Medicine (N.R.v.Z., M.A., A.M., N.R.R., N.W.R., M.I.M., A.P.M.), University of Oxford, United Kingdom.
Circ Genom Precis Med. 2021 Oct;14(5):e002862. doi: 10.1161/CIRCGEN.119.002862. Epub 2021 Oct 4.
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 ( ≤5×10) associations with PAD in 449 548 (N=12 086) individuals of European ancestry near ) 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 ) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32-1.74], =2.5×10, =5.3×10). Furthermore, in smokers, rs12910984 at the locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11-1.19], =9.3×10, =3.9×10).
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.
外周动脉疾病（PAD）影响全球超过 2 亿人，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的相关变异。
我们确定了与 PAD 相关的遗传变异，然后与来自百万退伍军人计划和英国生物库的已发表的汇总统计数据进行元分析，以复制他们的发现。接下来，我们在曾经吸烟者、从不吸烟者、糖尿病患者和没有糖尿病史的个体中进行分层全基因组关联分析，并进行相应的交互分析，以确定通过糖尿病或吸烟状态改变 PAD 风险的变异。
我们在 449548 名（N=12086）欧洲血统个体中发现了 5 个与 PAD 相关的全基因组显著关联（≤5×10）位于 ) 个基因座附近（与先前报道的关联重叠）。与先前与 PAD 相关的变异进行元分析显示，19 个已发表的变异中有 18 个仍然具有全基因组显著性。在糖尿病患者中， ) 基因座的 rs116405693 与 PAD 相关（优势比[95%CI]，1.51[1.32-1.74]，=2.5×10，=5.3×10）。此外，在吸烟者中， ) 基因座的 rs12910984 与 PAD 相关（优势比[95%CI]，1.15[1.11-1.19]，=9.3×10，=3.9×10）。
我们的分析证实了与 PAD 相关的已发表遗传关联，并确定了可能影响糖尿病或吸烟状态下 PAD 易感性的新变异。
