Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA (D.H.K., U.A.T., D.N., M.D.B., J.M.R., Z.-Z.C., D.E.C., S.D., L.F., S.S., A.A.S., D.S., J.G.W., R.E.G.).
Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge (A.G.B., A.P., Z.Y., P.N., R.E.G.).
Circulation. 2022 Feb;145(5):357-370. doi: 10.1161/CIRCULATIONAHA.121.055117. Epub 2021 Nov 24.
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.
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).
We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10. 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 gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, =3.27×10) and MMP-3 (β=-0.60±0.05, =1.67×10), as well as a completely novel pleiotropic locus at the 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, =1.34×10) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure.
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.
血浆蛋白是心血管过程的关键介质，也是许多药物的靶点。以前对血浆蛋白质组遗传结构的特征描述研究受到限制，因为研究主要集中在欧洲血统的个体上，并且利用了基因分型阵列和推测。在这里，我们描述了对具有更大非洲血统个体的血浆蛋白质组进行全基因组序列分析，从而提高了我们识别新遗传决定因素的能力。
使用基于适体的蛋白质组学（SomaScan）在 1852 名来自 Jackson 心脏研究的黑人成年人中对 1301 种蛋白质进行蛋白质组学分析。对所有次要等位基因数≥5 的变体进行全基因组测序关联分析。使用替代的基于抗体的蛋白质组学平台（Olink）进行验证，并在多民族动脉粥样硬化研究和 HERITAGE 家族研究（健康，风险因素，运动训练和遗传学）中进行复制。
我们在 479 个蛋白质和 438 个独特的遗传区域之间鉴定出 569 个遗传关联，达到了 Bonferroni 调整后的显著性水平为 3.8×10。这些关联包括 114 个新的基因座-蛋白质关系和另外 217 个新的哨兵单核苷酸多态性-蛋白质关系。新的心血管发现包括在基因座中的新蛋白质关联，包括 ZAP70（哨兵单核苷酸多态性 SNP rs7412-T，β=0.61±0.05，=3.27×10）和 MMP-3（β=-0.60±0.05，=1.67×10），以及一个全新的多效性基因座，与 9 种蛋白质相关。此外，这些关联表明与非洲血统有关的遗传介导的心血管疾病的新机制；我们发现与 APOL1 相关的慢性肾脏和心脏病相关的变体与 CKAP2 蛋白（rs73885319-G，β=0.34±0.04，=1.34×10）之间存在新的关联，以及在没有心力衰竭的社区居住个体中，ATTR 淀粉样变性与 RBP4 水平之间的关联。
总而言之，这些结果为非欧洲人群中变体的功能重要性提供了证据，并为脂质，凝血和心肌功能的特定祖先决定因素的新生物学机制提供了依据。
