The genetic factors of stroke in South Asians are largely unexplored. Exome-wide sequencing and association analysis (ExWAS) in 75 K Pakistanis identified NM_000435.3(NOTCH3):c.3691C>T, encoding the missense amino acid substitution p.Arg1231Cys, enriched in South Asians (alternate allele frequency = 0.58% compared to 0.019% in Western Europeans), and associated with subcortical hemorrhagic stroke [odds ratio (OR) = 3.39, 95% confidence interval (CI) = [2.26, 5.10], p value = 3.87x10^-9), and all strokes (OR [CI] = 2.30 [3.01, 1.77], p value = 7.79x10^-10). NOTCH3 p.Arg231Cys was strongly associated with white matter hyperintensity on MRI in United Kingdom Biobank (UKB) participants (effect [95% CI] in SD units = 1.1 [0.61, 1.5], p value = 3.0x10^-6). The variant is attributable for approximately 5.5% of hemorrhagic strokes and 1% of all strokes in South Asians. These findings highlight the value of diversity in genetic studies and have major implications for genomic medicine and therapeutic development in South Asian populations.

中文翻译：

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NOTCH3 p.Arg1231Cys 在南亚人中显着丰富并与中风相关

南亚人中风的遗传因素在很大程度上尚未被探索。在 75 K 巴基斯坦人中进行全外显子组测序和关联分析 (ExWAS)，鉴定出 NM_000435.3( NOTCH3 ):c.3691C>T，编码错义氨基酸取代 p.Arg1231Cys，在南亚人中富集（替代等位基因频率 = 0.58%）西欧人为 0.019%），并且与皮质下出血性中风相关 [比值比 (OR) = 3.39，95% 置信区间 (CI) = [2.26, 5.10]，p 值 = 3.87x10 ^-9），以及所有中风（或 [CI] = 2.30 [3.01, 1.77]，p 值 = 7.79x10 ^-10 )。在英国生物银行 (UKB) 参与者中， NOTCH3 p.Arg231Cys 与 MRI 上的白质高信号密切相关（SD 单位中的效应 [95% CI] = 1.1 [0.61, 1.5]，p 值 = 3.0x10 ^-6）。在南亚人中，大约 5.5% 的出血性中风和 1% 的中风是由这种变异引起的。这些发现凸显了遗传研究多样性的价值，并对南亚人群的基因组医学和治疗发展具有重大影响。