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.

Genomic atlas of the human plasma proteome

“…5b), including well-known pleiotropic loci (for example, ABO , CFH , APOE and KLKB1 ) and loci associated with many correlated proteins (for example, the ZFPM2 locus, which encodes the transcription factor FOG2). Similar pleiotropy at these loci has been seen in other plasma pQTL studies 3–5 , albeit with fewer proteins owing to limited assay breadth. A missense variant (rs28929474:T) in SERPINA1 was associated with 13 proteins at P < 1.5 × 10 −11 and a further six at P < 5 × 10 −8 (Fig.…”

“…Identifying factors that determine inter-individual protein variability should, therefore, furnish biological and medical insights 1 . Despite evidence for the heritability of plasma protein abundance 2 , however, systematic assessment of how genetic variation influences plasma protein levels has been limited 3–5 . Studies have examined intra-cellular protein quantitative trait loci (pQTLs) 6,7 , but these studies have tended to be small and involved cell lines rather than primary human tissues.…”

Sequence-Based Analysis of Lipid-Related Metabolites in a Multiethnic Study

“…For WGS, genomic DNA samples were made into Illumina pairedend libraries according to the manufacturer's recommendation (Illumina Multiplexing_SamplePrep_Guide_1005361_D) and sequenced on a Hisequation 2000 (Illumina, San Diego, CA) in a pooled format to generate a minimum of 18 unique aligned giga-basepairs per sample. As previously reported, variant calling was completed using the Atlas2 (Challis et al 2012) suite for WES, and goSNAP (https://sourceforge.net/p/gosnap/git/ci/ master/tree/) for WGS (Yu et al 2016a;de Vries et al 2017). Detailed methods for the sequencing, variant calling and variant quality control for both WES and WGS are provided in the Supplemental Methods.…”

Profile of genetic variations in severely calcified carotid plaques by whole-exome sequencing

“…Plasma kallikrein encoded by KLKB1 – variations of which we observed more commonly in the low-calcified plaque group – cleaves high-molecular-weight kininogen to release bradykinin, which plays crucial roles in the vascular regulation of atherosclerosis by vasodilation and in the prevention of cell proliferation through the kinin-kallikrein system. [ 4 ] Plasma kallikrein also functions in the blood coagulation pathway as well as in the regulation of blood pressure. In addition to plasma prekallikrein deficiency,[ 14 ] SNPs of KLKB1 are significantly associated with venous thromboembolism[ 1 , 10 ] and with the levels of serum metabolomes such as lipids, carbohydrates, and peptides related to atherosclerosis.…”