Interaction between endothelial nitric oxide synthase rs1799983, cholesteryl ester-transfer protein rs708272 and angiopoietin-like protein 8 rs2278426 gene variants highly elevates the risk of type 2 diabetes mellitus and cardiovascular disease

Background The aim of the present study was to examine the association of angiopoietin-like proteins-8 (ANGPTL8) rs2278426, cholesteryl ester-transfer protein (CETP) rs708272 and endothelial nitric oxide synthase (NOS3) rs1799983 variants with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD), and to investigate the effect of the potential interaction between these variants on disease risk. Methods Our study included 272 subjects classified into 68 patients with T2DM, 68 patients with T2DM complicated with CVD and 136 control subjects. ANGPTL8 c194C>T, CETP Taq1B and NOS3 G894T polymorphisms were genotyped using TaqMan® SNP Genotyping Assay. Results The presence of NOS3, ANGPTL8, and homozygous CETP B1 variants were associated with increased risk of T2DM by 3.07-, 2.33- and 1.75-fold, respectively. NOS3 variant was associated with 3.08-fold increased risk of CVD (95% CI 1.70–5.60), while ANGPTL8 C allele was associated with 2.8-fold increased risk of CVD in T2DM patients (95% CI 1.13–6.97). Concomitant presence of both, CETP B1 and NOS3 T allele, associated with increased risk of T2DM, CVD and CVD in T2DM by 8.36-, 6.33- and 7.87-fold, respectively, while concomitant presence of ANGPTL8 variant with either CETP B1 or NOS3 T allele was not associated with increased risk of T2DM or CVD. However, concomitant presence of the three variants together elevated the risk of T2DM by 13.22-fold (p = 0.004), CVD risk by 8.86-fold (p = 0.03) and highly elevated the risk of CVD in T2DM patients by 13.8-fold (p = 0.008). Conclusions Concomitant presence of CETP B1, NOS3 T and ANGPTL8 T alleles augments the risk of CVD and T2DM. Further studies to clarify the mechanism of gene–gene interaction in the pathogenesis of CVD and T2DM are needed.