Department of Clinical Biochemistry, Herlev Hospital, Denmark.
J Am Coll Cardiol. 2012 Jun 19;59(25):2356-65. doi: 10.1016/j.jacc.2012.02.043.
The purpose of this study was to test whether elevated nonfasting glucose levels associate with and cause ischemic heart disease (IHD) and myocardial infarction (MI).
Elevated fasting plasma glucose levels associate with increased risk of IHD, but whether this is also true for nonfasting levels and whether this is a causal relationship is unknown.
Using a Mendelian randomization approach, we studied 80,522 persons from Copenhagen, Denmark. Of those, IHD developed in 14,155, and MI developed in 6,257. Subjects were genotyped for variants in GCK (rs4607517), G6PC2 (rs560887), ADCY5 (rs11708067), DGKB (rs2191349), and ADRA2A (rs10885122) associated with elevated fasting glucose levels in genome-wide association studies.
Risk of IHD and MI increased stepwise with increasing nonfasting glucose levels. The hazard ratio for IHD in subjects with nonfasting glucose levels ≥11 mmol/l (≥198 mg/dl) versus <5 mmol/l (<90 mg/dl) was 6.9 (95% confidence interval [CI]: 4.2 to 11.2) adjusted for age and sex, and 2.3 (95% CI: 1.3 to 4.2) adjusted multifactorially; corresponding values for MI were 9.2 (95% CI: 4.6 to 18.2) and 4.8 (95% CI: 2.1 to 11.2). Increasing number of glucose-increasing alleles was associated with increasing nonfasting glucose levels and with increased risk of IHD and MI. The estimated causal odds ratio for IHD and MI by instrumental variable analysis for a 1-mmol/l (18-mg/dl) increase in nonfasting glucose levels due to genotypes combined were 1.25 (95% CI: 1.03 to 1.52) and 1.69 (95% CI: 1.28 to 2.23), and the corresponding observed hazard ratio for IHD and MI by Cox regression was 1.18 (95% CI: 1.15 to 1.22) and 1.09 (95% CI: 1.07 to 1.11), respectively.
Like common nonfasting glucose elevation, plasma glucose-increasing polymorphisms associate with increased risk of IHD and MI. These data are compatible with a causal association.
本研究旨在检验非空腹血糖升高是否与缺血性心脏病（IHD）和心肌梗死（MI）相关，并导致这些疾病。
空腹血糖升高与 IHD 风险增加相关，但非空腹血糖升高是否也如此，以及这是否存在因果关系尚不清楚。
我们使用孟德尔随机化方法，对来自丹麦哥本哈根的 80522 人进行了研究。其中，14155 人发生了 IHD，6257 人发生了 MI。对与全基因组关联研究中空腹血糖升高相关的 GCK（rs4607517）、G6PC2（rs560887）、ADCY5（rs11708067）、DGKB（rs2191349）和 ADRA2A（rs10885122）的变体进行了基因分型。
非空腹血糖水平升高与 IHD 和 MI 的风险呈逐步增加。与非空腹血糖水平<5mmol/l（<90mg/dl）相比，非空腹血糖水平≥11mmol/l（≥198mg/dl）的受试者发生 IHD 的风险比为 6.9（95%置信区间[CI]：4.2 至 11.2），经年龄和性别调整后为 2.3（95%CI：1.3 至 4.2），经多因素调整后为 4.8（95%CI：2.1 至 11.2）。与 MI 对应的数值分别为 9.2（95%CI：4.6 至 18.2）和 4.8（95%CI：2.1 至 11.2）。与增加的葡萄糖升高等位基因数量相关的非空腹血糖水平升高与 IHD 和 MI 风险增加相关。通过基于工具变量的分析，对于由于基因型组合引起的 1mmol/l（18mg/dl）非空腹血糖升高，IHD 和 MI 的估计因果比值比分别为 1.25（95%CI：1.03 至 1.52）和 1.69（95%CI：1.28 至 2.23），而 Cox 回归分析中观察到的 IHD 和 MI 的相应风险比分别为 1.18（95%CI：1.15 至 1.22）和 1.09（95%CI：1.07 至 1.11）。
与常见的非空腹血糖升高一样，升高的血浆葡萄糖多态性与 IHD 和 MI 风险增加相关。这些数据与因果关系相一致。
