Coronary artery disease (CAD), the most prevalent cardiovascular disease, is the leading cause of death worldwide. Heritable factors play a significant role in the pathogenesis of CAD. It has been proposed that approximately one-third of patients with CAD have a positive family history, and individuals with such history are at ~1.5-fold increased risk of CAD in their lifespans. Accordingly, the long-recognized familial clustering of CAD is a strong risk factor for this disease. Our study aimed to identify candidate genetic variants contributing to CAD by studying a cohort of 60 large Iranian families with at least two members in different generations afflicted with premature CAD (PCAD), defined as established disease at ≤45 years in men and ≤55 years in women. Exome sequencing was performed for a subset of the affected individuals, followed by prioritization and Sanger sequencing of candidate variants in all available family members. Subsequently, apparently healthy carriers of potential risk variants underwent coronary computed tomography angiography (CCTA), followed by co-segregation analysis of the combined data. Putative causal variants were identified in seven genes, ABCG8, CD36, CYP27A1, PIK3C2G, RASSF9, RYR2, and ZFYVE21, co-segregating with familial PCAD in seven unrelated families. Among these, PIK3C2G, RASSF9, and ZFYVE21 are novel candidate CAD susceptibility genes. Our findings indicate that rare variants in genes identified in this study are involved in CAD development.

中文翻译：

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遗传变异在心脏病患者家族性早发冠状动脉疾病发展中的作用

冠状动脉疾病（CAD）是最常见的心血管疾病，是全世界死亡的主要原因。遗传因素在 CAD 的发病机制中发挥着重要作用。有人提出，大约三分之一的 CAD 患者有阳性家族史，有此类病史的个体一生中患 CAD 的风险增加约 1.5 倍。因此，长期以来公认的 CAD 家族聚集性是该疾病的一个重要危险因素。我们的研究旨在通过研究 60 个伊朗大家庭组成的队列来确定导致 CAD 的候选遗传变异，这些家庭的不同世代中至少有两名成员患有早发 CAD (PCAD)，定义为男性 ≤ 45 岁和 ≤ 55 岁时患病在女性中。对受影响个体的子集进行外显子组测序，然后对所有可用家庭成员中的候选变异进行优先级排序和桑格测序。随后，潜在风险变异的表面健康携带者接受了冠状动脉计算机断层扫描血管造影（CCTA），然后对组合数据进行共分离分析。在七个基因（ ABCG8、CD36、CYP27A1、PIK3C2G、RASSF9、RYR2和ZFYVE21）中鉴定出假定的因果变异，与七个不相关家族中的家族性 PCAD 共分离。其中，PIK3C2G、RASSF9和ZFYVE21是新的候选CAD易感基因。我们的研究结果表明，本研究中发现的基因中的罕见变异与 CAD 的发展有关。