The FTO Gene Is Associated With an Atherogenic Lipid Profile and Myocardial Infarction in Patients With Type 2 Diabetes

Abstract

Background— Common variation in the fat mass and obesity ( FTO )–related gene is associated with increased body fat and susceptibility to type 2 diabetes. We hypothesized that this would also associate with metabolic phenotypes of insulin resistance and increased risk of cardiovascular morbidity and mortality. Methods and Results— FTO rs9939609 genotype was determined in 4897 patients with type 2 diabetes in the prospective Genetics of Diabetes Audit and Research Study in Tayside Scotland study. The A allele was associated with lower plasma high-density lipoprotein cholesterol (mean difference, 0.03 mmol/L; P =0.008), higher triglycerides (0.1 mmol/L, P =0.007), higher atherogenic index of plasma (0.03, P =0.003), and, as expected, increased body mass index (0.77 kg/m 2 , P =8.8�10 −6 ). During a mean follow-up of 3.6 years, the A allele was also associated with increased risk (hazard ratio, 2.36; CI, 1.49 to 3.74; P =0.0002) of fatal and nonfatal myocardial infarction (total of 324 events) in a model, including baseline age, gender, prevalent myocardial infarction, smoking status, statin, and insulin use. This association diminished but remained significant when obesity-related traits, such as body mass index, glycohemoglobin, and lipid parameters, were also included (hazard ratio, 2.01; CI, 1.18 to 3.45, P =0.011). There was a strong interaction of FTO genotype and statin use and cardiovascular outcome ( P =0.001), such that cardiovascular morbidity and mortality was completely abrogated in individuals who were prescribed statins. Conclusion— The increased fat mass in carriers of the A allele of rs9939609 of FTO is associated not only with increased risk of type 2 diabetes, but also with an increase in atherogenic lipid profile and myocardial infarction in these patients. This variant may, therefore, in the future contribute to more effective targeting of specific preventative therapy.