Interaction between the rs9356744 polymorphism and metabolic risk factors in relation to type 2 diabetes mellitus: The Cardiometabolic Risk in Chinese (CRC) Study

Abstract

The understanding of the genetic basis of type 2 diabetes mellitus (T2DM) has progressed rapidly, but the interactions among common genetic variants and metabolic risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and metabolic environments on the risk of T2DM. Obesity is emerging as an independent risk factor for T2DM and arterial stiffness. Here, we examined the effect of the rs9356744 polymorphism in the body mass index (BMI) gene CDKAL1 on the risk of T2DM in East Asians and particularly assessed the interactions between this polymorphism and other metabolic risk factors. A total of 1975 subjects in whom the rs9356744 polymorphism had been detected in the CDKAL1 gene were enrolled in this study. The height, weight, blood pressure and relevant markers, including glucose, lipids, liver and renal function, of the participants were successfully measured. Pulse wave velocity (PWV) was measured using an automatic wave form analyzer. At baseline, we found a significant association between BMI and rs9356744 genotypes (CC, CT, TT) (P = 0.048). After adjusting for confounding factors, including sex, age and BMI, participants carrying the T allele of rs9356744 showed a lower incidence of T2DM. Further adjustment for blood pressure and lipids did not appreciably change the results (P = 0.019, 0.009, 0.015, respectively). We found significant interactions between the rs9356744 polymorphism and high-density lipoprotein (HDL), serum uric acid (SUA) and carotid-femoral pulse wave velocity (cf-PWV) in relation to T2DM incidence (P for interaction = 0.007, 0.002, 0.004, respectively), especially in the group with the lowest SUA level and the group with the highest HDL and cf-PWV levels (P for trend = 0.006, 0.008, 0.018, respectively). Furthermore, we found a significant interaction between the rs9356744 polymorphism and cf-PWV in relation to the level of 2-h plasma glucose in the oral glucose tolerance test (OGTT) (P for interaction = 0.0341). In summary, the T allele of rs9356744 was an independent protective factor for T2DM. There were significant interactions between rs9356744 and HDL, SUA, and cf-PWV in relation to T2DM risk.

Keywords: CDKAL1; Interaction; Metabolic risk factors; Type 2 diabetes mellitus; rs9356744 polymorphism.