Genome-wide association reveals that common genetic variation in the kallikrein-kinin system is associated with serum L-arginine levels

Abstract

Summary L-arginine is the essential precursor of nitric oxide, and is involved in multiple key physiological processes, including vascular and immune function. The genetic regulation of blood L-arginine levels is largely unknown. We performed a genome-wide association study (GWAS) to identify genetic factors determining serum L-arginine levels, amongst 901 Europeans and 1,394 Indian Asians. We show that common genetic variations at the KLKB1 and F12 loci are strongly associated with serum L-arginine levels. The G allele of SNP rs71640036 (T/G) in KLKB1 is associated with lower serum L-arginine concentrations (10 μmol/L per allele copy, p=1×10-24), while allele T of rs2545801 (T/C) near the F12 gene is associated with lower serum L-arginine levels (7 μmol/L per allele copy, p=7×10-12). Together these two loci explain 7% of the total variance in serum L-arginine concentrations. The associations at both loci were replicated in independent cohorts with plasma L-arginine measurements (p<0.004). The two sentinel SNPs are in nearly complete LD with the nonsynonymous SNP rs3733402 at KLKB1 and the 5’-UTR SNP rs1801020 at F12, respectively. SNPs at both loci are associated with blood pressure. Our findings provide new insight into the genetic regulation of L-arginine and its potential relationship with cardiovascular risk.

Cardiac Troponin T and Troponin I in the General Population

“…For cTnI, the KLKB1 and F12 genes are both part of the kallikrein-kinin axis and loci have been associated with biomarkers of endothelin-1, proadrenomedullin, 34 B-type natriuretic peptide, 35 and l -arginine, as well. 36 Given this broad association with vasoactive peptides, it is interesting that the loci are associated with cTnI, but no association is seen for cTnT. Plasma prokallikrein is activated by active factor XII (encoded by F12 ) and colocalizes to endothelial cells.…”

Plasma Prekallikrein: Its Role in Hereditary Angioedema and Health and Disease

“…There is an exonic N142S polymorphism (rs3733402) in Apple domain 2 of plasma PK that results in reduced HK binding in the intravascular compartment ( 26 ). This polymorphism is associated with reduced BK formation, lower plasma l -arginine concentrations, and reduced plasma renin ( 27 – 29 ). PK is a plasma prorenin activator.…”