Association of Variability in the DDAH1, DDAH2, AGXT2 and PRMT1 Genes with Circulating ADMA Concentration in Human Whole Blood

Abstract

Asymmetric dimethylarginine is an endogenous inhibitor of nitric oxide synthesis and a cardiovascular risk factor. Its regulation has been studied extensively in experimental models, but less in humans. We studied common single-nucleotide polymorphisms (SNPs) in genes encoding for enzymes involved in ADMA biosynthesis and metabolism, i.e., PRMT1, DDAH1, DDAH2, and AGXT2, and assessed their associations with blood ADMA concentration in 377 unselected humans. The minor allele of DDAH1 SNP rs233112 was significantly more frequent in individuals with ADMA in the highest tertile or in the highest quartile, as was the major allele of DDAH2 rs805304. A combined genotype comprising both SNPs showed a significant genotype–phenotype association, with increasing ADMA concentration by an increasing number of inactive alleles. SNPs in the AGXT2 and PRMT1 genes showed no significant associations with blood ADMA concentration. Our study provides comprehensive evidence that DDAH1 and DDAH2 are the major enzymes regulating blood ADMA concentration, whilst PRMT1 indirectly affects ADMA, and AGXT2 may act as a back-up enzyme in ADMA metabolism under pathophysiological conditions only.