Doney Alex S F, Dannfald Jennifer, Kimber Charlotte H, Donnelly Louise A, Pearson Ewan, Morris Andrew D, Palmer Colin N A
Diabetes Research Group, Biomedical Research Institute, University of Dundee, Dundee, United Kingdom.
Circ Cardiovasc Genet. 2009 Jun;2(3):255-9. doi: 10.1161/CIRCGENETICS.108.822320. Epub 2009 Mar 30.
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.
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 x 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.
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.
脂肪量与肥胖相关基因（FTO）的常见变异与体脂增加及2型糖尿病易感性有关。我们推测，这也与胰岛素抵抗的代谢表型以及心血管疾病发病率和死亡率增加的风险有关。
在苏格兰泰赛德地区糖尿病审计与研究前瞻性基因研究中，对4897例2型糖尿病患者测定了FTO rs9939609基因型。A等位基因与较低的血浆高密度脂蛋白胆固醇水平（平均差异为0.03 mmol/L；P = 0.008）、较高的甘油三酯水平（0.1 mmol/L，P = 0.007）、较高的血浆致动脉粥样硬化指数（0.03，P = 0.003）相关，并且正如预期的那样，与体重指数增加（0.77 kg/m²，P = 8.8×10⁻⁶）相关。在平均3.6年的随访期间，在一个包含基线年龄、性别、既往心肌梗死、吸烟状况、他汀类药物使用和胰岛素使用情况的模型中，A等位基因还与致命和非致命性心肌梗死风险增加（风险比为2.36；可信区间为1.49至3.74；P = 0.0002）相关（共324例事件）。当纳入与肥胖相关的特征，如体重指数、糖化血红蛋白和血脂参数时，这种关联减弱但仍具有显著性（风险比为2.01；可信区间为1.18至3.45，P = 0.011）。FTO基因型与他汀类药物使用和心血管结局之间存在强烈的相互作用（P = 0.001），即使用他汀类药物的个体心血管疾病发病率和死亡率完全消除。
FTO rs9939609的A等位基因携带者体脂增加不仅与2型糖尿病风险增加有关，还与这些患者动脉粥样硬化性血脂异常和心肌梗死增加有关。因此，这种变异未来可能有助于更有效地针对特定的预防性治疗。
