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 (R) 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.