A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with myocardial infarction in type 2 diabetic patients

Background: Myocardial infarction is the main mortality cause in patients with type 2 diabetes (T2DM). Endothelial dysfunction due to reduced bioavailability of nitric oxide (NO) is an early step of atherogenesis. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and it is metabolized by the enzymes dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2. The functional variant rs9267551 C, in the promoter region of DDAH2, has been linked to increased DDAH2 expression, and lower ADMA plasma levels, and was associated with lower risk of coronary artery disease in large-scale genome-wide association studies (GWAS) performed in the general population. However, it is unknown whether this association holds true in T2DM patients. To address this issue, we investigated whether rs9267551 is associated with risk of myocardial infarction in two cohorts of T2DM patients. Methods: SNP rs9267551 was genotyped in 1839 White T2DM patients from the Catanzaro Study (CZ, n=1060) and the Gargano Heart Study-cross sectional design (GHS, n=779). Cases were patients with a previous myocardial infarction, controls were asymptomatic patients with neither previous myocardial ischemia nor signs of it at resting and during a maximal symptom limited stress electrocardiogram. Results: Carriers of allele rs9267551 C showed a dose dependent reduction in the risk of myocardial infarction [(CZ=OR 0.380, 95% CI 0.175–0.823, p=0.014), (GHS=0.497, 0.267–0.923, p=0.027), (Pooled=0.458, 0.283–0.739, p=0.001)] which remained signifcant after adjusting for sex, age, BMI, smoking, HbA1c, total cholesterol HDL, and triglyceride levels [(CZ=0.307, 0.106–0.885, p=0.029), (GHS=0.512, 0.270–0.970, p=0.040), (Pooled=0.458, 0.266– 0.787, p=0.005)]. Conclusions: We found that rs9267551 polymorphism is signifcantly associated with myocardial infarction in T2DM patients of European ancestry from two independent cohorts. It is possible that in subjects carrying the protective C allele less ADMA accumulates in endothelial cells causing vascular protection as a consequence of higher nitric oxide availability.