de Vries Paul S, Yu Bing, Feofanova Elena V, Metcalf Ginger A, Brown Michael R, Zeighami Atefeh L, Liu Xiaoming, Muzny Donna M, Gibbs Richard A, Boerwinkle Eric, Morrison Alanna C
Department of Epidemiology, Human Genetics, and Environmental Sciences, Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, 77030 TX, USA.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, 77030 TX, USA.
Hum Mol Genet. 2017 Sep 1;26(17):3442-3450. doi: 10.1093/hmg/ddx266.
Oligopeptides are important markers of protein metabolism, as they are cleaved from larger polypeptides and proteins. Genetic association studies may help elucidate their origin and function. In 1,552 European Americans and 1,872 African Americans of the Atherosclerosis Risk in Communities study, we performed whole-genome and whole-exome sequencing and measured serum levels of 25 peptides. Common variants (minor allele frequency > 5%) were analysed individually. We grouped low-frequency variants (minor allele frequency ≤ 5%) by a genome-wide sliding window using region-based aggregate tests. Furthermore, low-frequency regulatory variants were grouped by gene, as were functional coding variants. All analyses were performed separately in each ancestry group and then meta-analysed. We identified 22 common variant associations with peptide levels (P-value < 4.2 × 10-10), including 16 novel gene-peptide pairs. Notably, variants in kinin-kallikrein genes KNG1, F12, KLKB1, and ACE were associated with several different peptides. Variants in KLKB1 and ACE were associated with a fragment of complement component 3f. Both common variants and low-frequency coding variants in CPN1 were associated with a fibrinogen cleavage peptide. Four sliding windows were significantly associated with peptide levels (P-value < 4.2 × 10-10). Our results highlight the importance of the kinin-kallikrein system in the regulation of serum peptide levels, strengthen the evidence for a broad link between the kinin-kallikrein and complement systems, and suggest a role of CPN1 in the conversion of fibrinogen to fibrin.
寡肽是蛋白质代谢的重要标志物，因为它们是从较大的多肽和蛋白质中裂解而来的。基因关联研究可能有助于阐明它们的起源和功能。在社区动脉粥样硬化风险研究中的1552名欧洲裔美国人和1872名非洲裔美国人中，我们进行了全基因组和全外显子组测序，并测量了25种肽的血清水平。对常见变异（次要等位基因频率>5%）进行了单独分析。我们使用基于区域的汇总检验，通过全基因组滑动窗口对低频变异（次要等位基因频率≤5%）进行分组。此外，低频调控变异按基因分组，功能性编码变异也按基因分组。所有分析均在每个祖先群体中单独进行，然后进行荟萃分析。我们鉴定出22个与肽水平相关的常见变异关联（P值<4.2×10-10），包括16对新的基因-肽对。值得注意的是，激肽-激肽释放酶基因KNG1、F12、KLKB1和ACE中的变异与几种不同的肽相关。KLKB1和ACE中的变异与补体成分3f的一个片段相关。CPN1中的常见变异和低频编码变异均与纤维蛋白原裂解肽相关。四个滑动窗口与肽水平显著相关（P值<4.2×10-10）。我们的结果突出了激肽-激肽释放酶系统在调节血清肽水平中的重要性，加强了激肽-激肽释放酶系统与补体系统之间广泛联系的证据，并提示CPN1在纤维蛋白原转化为纤维蛋白过程中的作用。
