Abstract
BackgroundAsymmetric dimethylarginine (ADMA), present in human serum, is an endogenous inhibitor of nitric oxide synthase and contributes to vascular disease. Dimethylarginine dimethylaminohydrolase (DDAH) is an ADMA degrading enzyme that has two isoforms: DDAHI and DDAHII. We sought to determine whether serum ADMA levels in type 2 diabetes are influenced by common polymorphisms in the DDAH1 and DDAH2 genes.Methodology/Principal FindingsRelevant clinical parameters were measured and peripheral whole blood obtained for serum and genetic analysis on 343 participants with type 2 diabetes. Serum ADMA concentrations were determined by mass spectroscopy. Twenty six tag SNPs in the DDAH1 and 10 in the DDAH2 gene were genotyped in all subjects and tested for association with serum ADMA levels. Several SNPs and haplotypes in the DDAH genes were strongly associated with ADMA levels. Most significantly in the DDAH1 gene, rs669173 (p = 2.96×10−7), rs7521189 (p = 6.40×10−7), rs2474123 (p = 0.00082) and rs13373844 (p = 0.00027), and in the DDAH2 gene, rs3131383 (p = 0.0029) and the TGCCCAGGAG haplotype (p = 0.0012) were significantly associated with ADMA levels. Sub-analysis by diabetic retinopathy (DR) status revealed these variants were associated with ADMA levels predominantly in participants without DR. Combined analysis of the most strongly associated SNPs in DDAH1 (rs669173) and DDAH2 (rs3131383) revealed an additive effect (p = 1.37×10−8) on ADMA levels.Conclusions/SignificanceGenetic variation in the DDAH1 and 2 genes is significantly associated with serum ADMA levels. Further studies are required to determine the pathophysiological significance of elevated serum ADMA in type 2 diabetes and to better understand how DDAH gene variation influences ADMA levels.
Highlights
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), the key endothelial enzyme that converts L-arginine to L-citrulline and nitric oxide (NO)
Several single nucleotide polymorphisms (SNPs) in the Dimethylarginine dimethylaminohydrolase (DDAH) genes were significantly associated with serum ADMA levels after adjusting for associated variables in the multivariate analyses (Table 2 and Figure 1), with the most significant in DDAH1 being rs669173 [p = 2.9661027 in the genotypic model, Beta coefficient (B): 20.03, 95% CI: 20.04 to 20.02], rs7521189 (p = 6.4061027 in the additive model, B: 20.03, 95% CI: 20.04 to 20.01), rs2474123 (p = 0.00082 in the additive model, B: 0.02, 95%CI: 0.01–0.04), rs13373844 (p = 0.00027 in the dominant model, B: 20.03, 95% CI: 20.05 to 20.02) and rs986639 (p = 0.0015 in the genotypic model, B: 0.03, 95% CI: 0.01–0.05)
The SNPSpD method for multiple testing correction in SNP association studies estimated a total of 17 independent tests for DDAH1 analyses and after correcting for multiple testing, the SNPs listed above remained significantly associated with serum ADMA levels (p,0.03, Table 2)
Summary
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), the key endothelial enzyme that converts L-arginine to L-citrulline and nitric oxide (NO). ADMA levels have been shown to be increased in individuals with diabetes mellitus [5]. Endothelial dysfunction, such as occurs in hyperglycemia, is associated with decreased NOS activity and NO bioavailability resulting in vasoconstriction and increased reactive oxygen species. This leads to impaired ocular hemodynamics [6]. Asymmetric dimethylarginine (ADMA), present in human serum, is an endogenous inhibitor of nitric oxide synthase and contributes to vascular disease. We sought to determine whether serum ADMA levels in type 2 diabetes are influenced by common polymorphisms in the DDAH1 and DDAH2 genes
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