Whole-genome sequencing study of serum peptide levels: the Atherosclerosis Risk in Communities study

Abstract

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.

Figure 1

Overlap between the peptides associated with KLKB1, F12, KNG1, and ACE.

Figure 2

Interactions among proteins within the kinin-kallikrein system (shown in green) and their interactions with other pathways. Kininogen, kallikrein, and coagulation factor XII participate in the coagulation cascade by initiating the contact activation (intrinsic) pathway. CPN may play a role in coagulation through its interaction with fibrinogen. CPN interacts with the complement system by inactivating anaphylatoxins, which are derived from complement components. Our study suggests that kallikrein and ACE also interact with complement components. Finally, bradykinin and ACE play important roles in the regulation of blood pressure through their roles in the renin-angiotensin system and vasodilation.