General Medicine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Atherosclerosis. 2013 Jul;229(1):149-54. doi: 10.1016/j.atherosclerosis.2013.03.037. Epub 2013 Apr 22.
Common variants at the 2q36.3-IRS1 locus are associated with insulin resistance (IR), type 2 diabetes (T2D) and coronary artery disease (CAD) in large-scale association studies. We tested the hypothesis that variants at this locus are associated with subclinical atherosclerosis traits.
We studied 2740 Framingham Heart Study participants (54.9% women; mean age 57.8 years) with measures of coronary artery or abdominal aortic calcium, internal and common carotid intima-media thickness, and ankle-brachial index (ABI). We tested 1) four SNPs previously shown to be associated with IR (rs2972146, rs2943650), T2D (rs2943641) or CAD (rs2943634) and 2) any SNP at 2q36.3-IRS1, for association with subclinical atherosclerosis traits, adjusting for atherosclerosis risk factors. We set type 1 error rate for test 1) as 0.05/5 traits = P < 0.01, and for test 2) as 0.05 divided by the effective number of independent tests, divided by 5 for the number of traits analyzed.
We found no association between the four known SNPs and subclinical atherosclerosis, but identified one SNP (rs10167219, r(2) with rs2943634 = 0.07) at 2q36.3 that was significantly associated with ABI (corrected P = 0.009). However, rs10167219 was not associated with ABI (P = 0.70) in 35,404 participants in a published ABI association study.
Common variants at the 2q36.3-IRS1 locus were not associated with subclinical atherosclerosis traits in this study which was adequately powered to find associations with moderate effect size. Although IR and T2D may be mechanistically linked to CAD via subclinical atherosclerosis, an alternate mechanism for the IR-T2D-CAD associations at 2q36.3-IRS1 must be postulated.
在大规模的关联研究中，位于 2q36.3-IRS1 位置的常见变异与胰岛素抵抗（IR）、2 型糖尿病（T2D）和冠状动脉疾病（CAD）有关。我们检验了这样一个假设，即该位置的变异与亚临床动脉粥样硬化特征有关。
我们研究了 2740 名弗雷明汉心脏研究参与者（54.9%为女性；平均年龄 57.8 岁），他们的冠状动脉或腹主动脉钙、内颈动脉和颈总动脉内膜中层厚度以及踝臂指数（ABI）。我们检验了 1）四个先前与 IR（rs2972146、rs2943650）、T2D（rs2943641）或 CAD（rs2943634）相关的 SNPs，2）2q36.3-IRS1 上的任何 SNP，与亚临床动脉粥样硬化特征相关，调整了动脉粥样硬化危险因素。我们将检验 1）的Ⅰ型错误率设定为 0.05/5 个特征=P<0.01，检验 2）的Ⅰ型错误率设定为 0.05 除以有效独立检验的数量，除以 5 个分析的特征数量。
我们发现四个已知的 SNPs 与亚临床动脉粥样硬化之间没有关联，但在 2q36.3 上发现了一个 SNP（rs10167219，与 rs2943634 的 r(2)为 0.07）与 ABI 显著相关（校正后的 P=0.009）。然而，在一项已发表的 ABI 关联研究中，rs10167219 与 ABI 无关（P=0.70），涉及 35404 名参与者。
在这项研究中，2q36.3-IRS1 位置的常见变异与亚临床动脉粥样硬化特征没有关联，该研究有足够的效力发现与中等效应大小相关的关联。尽管胰岛素抵抗和 2 型糖尿病可能通过亚临床动脉粥样硬化与 CAD 在机制上相关，但 2q36.3-IRS1 的胰岛素抵抗-2 型糖尿病-CAD 关联需要假设另一种机制。
