美国斯坦福大学医学院Themistocles L. Assimes和Catherine Tcheandjieu共同合作近期取得重要工作进展，他们针对基因多样性人群中的冠状动脉疾病进行了大规模全基因组关联研究。这一研究成果2022年8月1日在线发表于《自然—医学》杂志上。

研究人员报告了一项冠状动脉疾病（CAD）的全基因组关联研究（GWAS），纳入了近25万例病例，其中现有研究与来自百万老兵计划（million Veteran Program）的白人、黑人和西班牙裔人群的数据相结合。研究人员记录了CAD在多个祖先群体中几乎相等的遗传力，确定了95个新基因座，包括X染色体上的9个，在黑人和西班牙裔个体中检测到8个具有全基因组意义的基因座，并证明9p21基因座上的两个常见单倍型在所有人群中负责风险分层，但非洲裔的人群除外，这些单倍型在这些人群中几乎没有。

此外，在迄今为止对血管造影衍生的冠状动脉粥样硬化进行的最大GWAS中，研究人员发现15个具有全基因组意义的基因座与临床CAD的已建立基因座完全重叠。新基因座和多基因风险评分（PRSs）的全表型关联分析增强了与胰岛素抵抗相关的信号，将这些基因座的多效性关联扩展到包括吸烟和家族史，并准确记录现有PRSs对黑人个体的可转移性显著降低。下游综合分析强化了血管内皮细胞、成纤维细胞和平滑肌细胞在CAD易感性中的关键作用，但也指出了动脉粥样硬化和肿瘤发生之间的共同生物学。这项研究强调了不同人群在进一步表征CAD遗传结构方面的价值。

附：英文原文

Title: Large-scale genome-wide association study of coronary artery disease in genetically diverse populations

Author: Tcheandjieu, Catherine, Zhu, Xiang, Hilliard, Austin T., Clarke, Shoa L., Napolioni, Valerio, Ma, Shining, Lee, Kyung Min, Fang, Huaying, Chen, Fei, Lu, Yingchang, Tsao, Noah L., Raghavan, Sridharan, Koyama, Satoshi, Gorman, Bryan R., Vujkovic, Marijana, Klarin, Derek, Levin, Michael G., Sinnott-Armstrong, Nasa, Wojcik, Genevieve L., Plomondon, Mary E., Maddox, Thomas M., Waldo, Stephen W., Bick, Alexander G., Pyarajan, Saiju, Huang, Jie, Song, Rebecca, Ho, Yuk-Lam, Buyske, Steven, Kooperberg, Charles, Haessler, Jeffrey, Loos, Ruth J. F., Do, Ron, Verbanck, Marie, Chaudhary, Kumardeep, North, Kari E., Avery, Christy L., Graff, Mariaelisa, Haiman, Christopher A., Le Marchand, Loc, Wilkens, Lynne R., Bis, Joshua C., Leonard, Hampton, Shen, Botong, Lange, Leslie A., Giri, Ayush, Dikilitas, Ozan, Kullo, Iftikhar J., Stanaway, Ian B., Jarvik, Gail P., Gordon, Adam S., Hebbring, Scott, Namjou, Bahram, Kaufman, Kenneth M., Ito, Kaoru, Ishigaki, Kazuyoshi, Kamatani, Yoichiro, Verma, Shefali S.

Issue&Volume: 2022-08-01

Abstract: We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD. To overcome limitations of previous genome-wide association studies of coronary artery disease, this study incorporates a cohort of individuals containing large fractions of Black and Hispanic individuals to provide a wider view of the genetic landscape of this disease.

DOI: 10.1038/s41591-022-01891-3

Source: https://www.nature.com/articles/s41591-022-01891-3