Investigations into the causal underpinnings of disease processes can be aided by the incorporation of genetic information. Genetic studies require populations varied in both ancestry and prevalent disease in order to optimize discovery and ensure generalizability of findings to the global population. Here, we report the genetic determinants of the serum proteome in 466 African Americans with chronic kidney disease attributed to hypertension from the richly phenotyped African American Study of Kidney Disease and Hypertension (AASK) study. Using the largest aptamer-based protein profiling platform to date (6,790 proteins or protein complexes), we identified 969 genetic associations with 900 unique proteins; including 52 novel cis (local) associations and 379 novel trans (distant) associations. The genetic effects of previously published cis-protein quantitative trait loci (pQTLs) were found to be highly reproducible, and we found evidence that our novel genetic signals colocalize with gene expression and disease processes. Many trans- pQTLs were found to reflect associations mediated by the circulating cis protein, and the common trans-pQTLs are enriched for processes involving extracellular vesicles, highlighting a plausible mechanism for distal regulation of the levels of secreted proteins. Thus, our study generates a valuable resource of genetic associations linking variants to protein levels and disease in an understudied patient population to inform future studies of drug targets and physiology.

结合遗传信息可以帮助调查疾病过程的因果基础。遗传研究需要不同血统和流行疾病的人群，以优化发现并确保研究结果对全球人群的普遍性。在这里，我们报告了 466 名患有高血压的慢性肾病的非洲裔美国人血清蛋白质组的遗传决定因素，这些疾病来自表型丰富的非洲裔美国人肾脏疾病和高血压研究 (AASK) 研究。使用迄今为止最大的基于适体的蛋白质分析平台（6,790 种蛋白质或蛋白质复合物），我们确定了 969 种与 900 种独特蛋白质的遗传关联；包括 52 个新的顺式（本地）关联和 379 个新的反式（远距离）关联。这发现先前发表的顺式蛋白质数量性状位点 (pQTL) 的遗传效应具有高度可重复性，并且我们发现证据表明我们的新遗传信号与基因表达和疾病过程共定位。许多反式 pQTL 被发现反映了由循环顺式蛋白介导的关联，并且常见的反式 pQTL 富集了涉及细胞外囊泡的过程，突出了分泌蛋白水平远端调节的似是而非的机制。因此，我们的研究产生了宝贵的遗传关联资源，将变异与未被充分研究的患者群体中的蛋白质水平和疾病联系起来，为未来的药物靶点和生理学研究提供信息。