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

Figures

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  Figure 1. Scheme of enzymatic pathways for biosynthesis and metabolism of asymmetric dimethylarginine (ADMA). L-arginine residues within specific proteins are subject to methylation by protein arginine N-methyltransferases (PRMTs), amongst which PRMT1 has been identified to be the major isoform generating ADMA. Free ADMA is released during physiological protein turnover. ADMA is a competitive inhibitor of nitric oxide (NO) synthase. ADMA is mainly degraded by dimethylarginine dimethylaminohydrolases (DDAH1 and DDAH2) into L-citrulline and dimethylamine (DMA). It may be cleaved by an alternative pathway through alanine glyoxylate aminotransferase 2 (AGXT2), resulting in the formation of asymmetric dimethylguanidinovaleric acid (DMGV). Enzymes of which we have analyzed genetic variance in this study are marked in bold red type within the yellow arrows.

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  Figure 2. (a) Histogram depicting the distribution of circulating ADMA concentrations in the study cohort. Data are shown as absolute frequencies of ADMA concentrations in 377 adult humans split up in 0.1 µmol/L intervals. (b) ADMA concentration in tertiles of ADMA (first tertile, N = 121; second tertile, N = 128; third tertile, N = 128). (c) ADMA concentration in quartiles of ADMA (first quartile, N = 88; second quartile, N = 99; third quartile, N = 96; fourth quartile, N = 94). Data are depicted as mean ± SD. p-values denote statistical significance for two-sided one-way ANOVA.

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  Figure 3. Allele frequencies for the major and minor allele of DDAH1 SNP rs233112 (a,c) and DDAH2 SNP rs805304 (b,d) separated by tertiles (a,b) and quartiles of ADMA (b,d), respectively. p-values denote statistical significance in χ2 test for trend.

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  Figure 4. ADMA concentration according to the number of inactive alleles in the combined genotype of DDAH1 rs2331112 and DDAH2 rs805304. Data are mean ± S.E.M. p denotes statistical significance in linear regression analysis.