A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with chronic kidney disease

Abstract

Objective: Studies reported a relationship between elevated asymmetric dimethylarginine (ADMA) concentrations and adverse renal outcomes. There is evidence that the rs9267551 variant in the DDAH2 gene has a functional impact with the C allele having a higher transcriptional activity resulting in increased expression of DDAH2 in endothelial cells and lower plasma ADMA levels in C allele carriers.

Methods: To address whether this variant is associated with chronic kidney disease (CDK), 2852 White European were studied. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2).

Results: The proportion of subjects with CKD was significantly lower in C allele carriers than in GG genotype carriers (OR 0.49, 95%CI 0.25-0.97; P = 0.03). In a logistic regression model adjusted for age, gender, BMI, blood pressure, total and HDL cholesterol, triglyceride, and fasting plasma glucose, C allele carriers have a lower risk of CKD compared with GG genotype carriers (OR 0.38, 95%CI 0.18-0.78; P = 0.008). This association was maintained after addition to the logistic regression model of other confounders including glucose tolerance status, presence of dyslipidemia, anti-hypertensive and antidiabetic drugs (OR 0.35, 95%CI 0.15-0.80; P = 0.01).

Conclusion: The rs9267551 functional variant of the DDAH2 gene is associated with CKD with carriers of the C allele having a lower risk of renal dysfunction independently from several confounders. Because ADMA predicted progression of renal disease, it is possible that, in GG carriers, ADMA may accumulate at the renal level causing endothelial dysfunction as a consequence of reduced nitric oxide availability and potentiating micro-vascular damage.

Keywords: Asymmetric dimethylarginine; Chronic kidney disease; Dimethylarginine dimethylaminohydrolase.