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.

Vascular nitrosative stress in hypertension induced by fetal undernutrition in rats

“…In the present study, we aimed to evaluate the role of NO alterations in fetal programming of hypertension induced by maternal undernutrition during gestation, which we have previously demonstrated in adult male offspring [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34],…”

“…ADMA and SDMA are released from tissues during physiological turnover of di-methylated proteins [21]. ADMA is enzymatically inactivated by dimethylarginine dimethylaminohydrolase (DDAH) [22] whilst SDMA is cleared by the kidneys. It was previously reported that dysfunction of the placental ADMA metabolism by DDAH contributes to high ADMA concentration in the late phase of pregnancy and may be one common cause of preeclampsia and FGR [2,9].…”

“…It was previously reported that dysfunction of the placental ADMA metabolism by DDAH contributes to high ADMA concentration in the late phase of pregnancy and may be one common cause of preeclampsia and FGR [2,9]. Dysfunction of DDAH may be caused by genetic polymorphisms [22] or by oxidative inactivation of the enzyme [21]. It is possible that the higher ADMA levels observed at weaning could be related to oxidative inactivation of DDAH, as we have previously demonstrated a lower degree of antioxidants in MUN rats at this age, particularly in males [33].…”

Asymmetric and symmetric dimethylarginine in high altitude pulmonary hypertension (HAPH) and high altitude pulmonary edema (HAPE)

“…We have previously analysed the associations of single nucleotide polymorphisms in genes encoding for major enzymes involved in the L-arginine/dimethylarginine/NO pathway with the circulating concentrations of L-arginine-related biomarkers. The major gene linked to ADMA plasma concentration is DDAH1, i.e., the gene encoding for one of two variants of the enzyme that converts ADMA to L-citrulline ( Leiper et al, 1999 ; Hannemann et al, 2022 ). SNPs in the DDAH2 gene are inversely associated with ADMA concentrations ( Hannemann et al, 2022 ).…”

“…The major gene linked to ADMA plasma concentration is DDAH1, i.e., the gene encoding for one of two variants of the enzyme that converts ADMA to L-citrulline ( Leiper et al, 1999 ; Hannemann et al, 2022 ). SNPs in the DDAH2 gene are inversely associated with ADMA concentrations ( Hannemann et al, 2022 ). By contrast, SNPs in the PRMT genes, which encode for a family of protein L-arginine methyltransferases that are involved in the formation of symmetrically or asymmetrically dimethylated L-arginine residues within proteins, have no associations with ADMA or SDMA concentrations ( Hannemann et al, 2022 ).…”