The effect of haptoglobin genotype on the association of asymmetric dimethylarginine and DDAH 1 polymorphism with diabetic macroangiopathy

Background: Dimethylarginine dimethylaminohydrolase (DDAH) 1 maintains the bioavailability of nitric oxide by degrading asymmetric dimethylarginine (ADMA). Here, we aimed to investigate the effect of haptoglobin (Hp) genotype on the association of ADMA and DDAH 1 polymorphism with diabetic macroangiopathy.

Methods: In stage 1, 90 Chinese participants with type 2 diabetes were enrolled to measure a panel of targeted metabolites, including ADMA, using tandem mass spectrometry (BIOCRATES AbsoluteIDQ™ p180 kit). In stage 2, an independent cohort of 2965 Chinese patients with type 2 diabetes was recruited to analyze the effect of Hp genotype on the association between DDAH 1 rs233109 and diabetic macroangiopathy. Hp genotypes were detected using a validated assay based on the TaqMan method. DDAH 1 rs233109 was genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy using the MassARRAY platform.

Results: In stage 1, serum ADMA levels correlated with common Hp genotypes (β ± SE = - 0.049 ± 0.023, P = 0.035), but not with diabetic macroangiopathy (P = 0.316). In stage 2, the distribution of DDAH 1 rs233109 genotype frequencies was 15% (CC), 47% (TC), and 38% (TT), which was in Hardy-Weinberg equilibrium (P = 0.948). A significant Hp genotype by rs 233109 genotype interaction effect on diabetic macroangiopathy was found (P = 0.017). After adjusting for confounders, patients homozygous for rs233109 CC were more likely to develop diabetic macroangiopathy than those carrying TT homozygotes in the Hp 2-2 subgroup [odds ratio = 1.750 (95% confidence interval, 1.101-2.783), P = 0.018].

Conclusion: Hp genotype affects the association between DDAH 1 rs233109 and diabetic macroangiopathy in Chinese patients with type 2 diabetes.