Overall, evidence for or against a causal contribution of glucose to the pathogenesis of macrovascular disease, including IHD and MI, can come from 5 types of evidence; that is, conventional epidemiology, mechanistic studies, animal models, randomized intervention trials, and Mendelian randomization studies like the present (22- 23). 1) Previous prospective epidemiologic studies showed that elevated fasting glucose levels associate with increased IHD and MI risk even at nondiabetic glucose levels (1- 2). Our results using nonfasting glucose levels are in agreement with this, and confirm that even after adjustment for obesity, dyslipidemia, and hypertension, elevated IHD and MI risk remain. 2) Results from in vitro and animal studies have suggested several mechanisms by which glucose may contribute to macrovascular disease: increased glucose levels, free fatty acids, and insulin resistance together leads to oxidative stress, activation of protein kinase C isoforms, formation of advanced glycation end product, and nonenzymatic glycation of low-density lipoprotein, apolipoproteins, and clotting factors, collectively resulting in vasoconstriction, inflammation, and thrombosis (2,24- 25). 3) In animal models with experimental hypercholesterolemia or genetic predisposition for atherosclerosis, elevated glucose levels may directly cause macrovascular disease (24,26). 4) A meta-analysis of randomized intervention trials (27- 32) showed that intensive glycemic control in patients with diabetes mellitus was associated with a 15% reduction in risk of IHD (3). However, in all included studies, intensive glycemic control also had beneficial effects on obesity, dyslipidemia, and/or hypertension, obscuring the isolated effect of reduced glucose levels, and this issue remains unresolved. 5) Using a Mendelian randomization approach free from reverse causation and unconfounded by obesity, dyslipidemia, and hypertension, we here found that both observational and genetic lifelong elevated nonfasting or fasting glucose levels associate with increased risk of IHD and MI. In the present study, we use genotypes associated with glucose levels in the nondiabetic range and not associated with diabetes mellitus in our general population samples, suggesting that the increased risk of IHD is more likely due to glucose per se, rather than mediated through diabetes mellitus. A recent Mendelian randomization study support that elevated fasting plasma glucose levels may also be causally related to increased intima-media thickness (33). Therefore, these 5 different types of evidence collectively suggest that elevated plasma glucose per se might be causally related to the development of IHD and MI.