Protective Effects of an Obesity-Associated Polymorphism (CDKAL1 rs9356744) on Prediabetes: The Cardiometabolic Risk in Chinese (CRC) Study.

ABSTRACT

BACKGROUND: Obesity is strongly associated with insulin resistance and elevated plasma glucose levels. The rs9356744 polymorphism in the CDKAL1 gene is associated with body mass index (BMI) only in East Asians. Here, we examined the effect of the rs9356744 polymorphism on glucose-related traits and prediabetes in Chinese adults. METHODS: A total of 2 357 participants were enrolled from the Cardiometabolic Risk in Chinese (CRC) Study, including 499 persons with prediabetes, 204 persons with type 2 diabetes, and 1 654 normoglycemic controls. The rs9356744 polymorphism in CDKAL1 was genotyped and analyzed in all participants. RESULTS: Despite the positive relationship between obesity and glucose traits, the T allele of rs9356744, which is associated with a predisposition to obesity, was correlated with lower levels of 2-h oral glucose tolerance test (OGTT) plasma glucose (2hPG) (ß=- 0.2104 and P=0.0233), glycated hemoglobin (HbA1c) (ß=- 0.0551 and P=0.0298) and higher levels of homeostasis model of assessment ß-cell function (HOMA-B) (ß=5.282 and P=0.0424). After further adjustment for BMI, the levels of HOMA-B maintained a similar increased trend across rs9356744 genotype (ß=3.277 and P=0.1958). In stratified analyses, the associations of rs9356744 with 2hPG and HbA1c were significant for individuals with a low BMI. Moreover, an antagonism action of BMI and rs9356744 on 2hPG (P for interaction=0.0055) was observed. In addition, we found a protective effect of rs9356744 on prediabetes. CONCLUSIONS: The CDKAL1 rs9356744 T allele associated with a predisposition to obesity showed a protective effect on HbA1c, 2hPG, and prediabetes. BMI was mediator of the association between the genetic variant and HbA1c, 2hPG, and prediabetes.