Genetic variation in the dimethylarginine dimethylaminohydrolase 1 gene (DDAH1) is related to asymmetric dimethylarginine (ADMA) levels, but not to endothelium-dependent vasodilation

Abstract

Objectives: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. The breakdown of ADMA is mainly governed by the activity of dimethylarginine dimethylaminohydrolases (DDAHs). We investigated if genetic variation in the DDAH1 and DDAH2 genes were related to ADMA and l-arginine levels, as well as measures of endothelium-dependent vasodilation. Methods: In 1016 70-year-old participants of the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (50% women), we measured endothelium-dependent vasodilation (EDV) using the invasive forearm technique with acetylcholine given in the brachial artery and the brachial artery ultrasound technique with measurement of flow-mediated dilatation (FMD). Plasma l-arginine and ADMA levels were measured by high-performance liquid chromatography and 55 single nucleotide polymorphisms (SNPs) in the DDAH1 and DDAH2 genes were genotyped. Results: Several of the genotypes in the DDAH1 gene were highly significantly related to ADMA levels (p = 10 −7 at best), but not to the l-arginine levels. No relationships between the genotypes in the DDAH2 gene and ADMA or l-arginine levels were found. None of the DDAH1 genotypes being closely related to ADMA levels were significantly related to EDV or FMD. Neither were any of the DDAH2 genotypes closely related to any of the measurements of vasoreactivity. Conclusion: A close relationship was seen between SNPs in the DDAH1, but not DDAH2, gene and ADMA levels. However, variation in those genes was not related to measures of EDV in this elderly population.

Asymmetric Dimethylarginine versus Proton Pump Inhibitors Usage in Patients with Stable Coronary Artery Disease: A Cross-Sectional Study

“…Our salient finding was a similar plasma level of ADMA in PPI users and non-users. This observation appears inconsistent with the previously reported ability of PPI to augment ADMA accumulation in vitro and in an animal model through a direct inhibition of DDAH-1 [ 1 ], an enzyme influencing circulating ADMA [ 16 , 17 , 18 , 19 ]. On the other hand, in subjects with a history of vascular disease, Ghebremariam et al [ 15 ] observed a more pronounced trend towards higher ADMA while on PPI compared to placebo in an interventional cross-over study, nevertheless the differences did not reach the statistical significance, which is in agreement with our cross-sectional retrospective analysis.…”

Genetics of NO Deficiency

“…In 70-year-old Swedish participants in the Vasculature in Uppsala Seniors study (n = 1016), several DDAH1 SNPs were shown to be associated with ADMA levels (p <0.00005): rs11161606, rs12132677, rs13373844, rs233099, rs233109, rs376822qwoo7, rs11161614, rs12140935, rs3768226, rs527762, rs582145, rs6669293, rs669173, and rs7521189; no DDAH2 SNPs were significantly associated with ADMA levels. 39 In a study of 343 Australian patients with type 2 diabetes, the SNPs with the most highly significant association with ADMA levels were rs669173 (p = 2.96 × 10 −7 ; genotypic model), rs7521189 (p = 6.40 × 10 −7 ; additive model), rs2474123 (p = 0.00082; additive model), rs13373844 (p = 0.00027; dominant model), and rs986639 (p = 0.0015; genotypic model) in DDAH1 and rs3131383 (p = 0.0029; dominant model) in DDAH2. 40 In a combined analysis of the most strongly associated SNPs in DDAH1 and DDAH2 (rs669173 and rs3131383, respectively), there was a significant additive effect (p = 1.37 × 10 −8 ) on ADMA levels.…”

Antiepileptic Drugs and Risk Factors of Vascular Diseases

“…Isoform 1 of DDAH is highly expressed in brain. Lind et al [58] showed that several polymorphisms in DDAH1 gene are related to ADMA level, but not to endothelium-dependent vasodilatation. Another group identified 4-nucleotide deletion/ insertion variant in the promoter region that leads to reduction of DDAH1 transcription activity and mRNA level, which increase the ADMA concentration and is a risk factor for thrombosis stroke and coronary heart disease [59].…”