Background:Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants.Methods:Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics).Results:We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10^-11. These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P=3.27×10^-30) and MMP-3 (β=-0.60±0.05, P=1.67×10^-32), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P=1.34×10^-17) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure.Conclusions:Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

中文翻译：

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黑人成年人血浆蛋白质组的全基因组序列分析为心血管疾病提供了新的见解

背景：血浆蛋白是心血管过程的关键介质，也是许多药物的靶标。先前描述血浆蛋白质组遗传结构的努力受到对欧洲血统个体的关注以及利用基因分型阵列和插补的限制。在这里，我们描述了对具有更大非洲血统的个体血浆蛋白质组的全基因组序列分析，增加了我们识别新遗传决定因素的能力。方法：使用基于适体的蛋白质组学对 1852 年杰克逊心脏研究中的黑人成年人进行了 1301 种蛋白质的蛋白质组学分析（索玛扫描）。对次要等位基因计数≥5的所有变异进行了全基因组测序关联分析。结果使用替代的基于抗体的蛋白质组学平台 (Olink) 进行了验证，并在动脉粥样硬化多种族研究和 HERITAGE 家庭研究（健康、风险因素、运动训练和遗传学）中进行了复制。结果：我们确定了 569 479 个蛋白质和 438 个独特遗传区域之间的遗传关联，Bonferroni 调整的显着性水平为 3.8×10 ^-11。这些关联包括 114 个新的基因座-蛋白质关系和另外 217 个新的前哨变异-蛋白质关系。新的心血管发现包括APOE基因位点的新蛋白质关联，包括 ZAP70（前哨单核苷酸多态性 [SNP] rs7412-T，β=0.61±0.05，P =3.27×10 ^-30）和 MMP-3 (β=-0.60± 0.05，P =1.67×10 ^-32），以及HPX基因上一个全新的多效性基因座，与 9 个蛋白质相关。此外，这些关联表明遗传介导的心血管疾病的新机制与非洲血统有关。我们确定了与 APOL1 相关的慢性肾脏和心脏病相关的变异与蛋白质 CKAP2 之间的新关联（rs73885319-G，β=0.34±0.04，P = 1.34 ×10 ^-17）以及 ATTR 淀粉样变性与 RBP4 之间的关联结论：总而言之，这些结果为非欧洲人群中变异的功能重要性提供了证据，并提出了血脂、凝血和心肌功能的祖先特异性决定因素的新生物学机制。