Nonfasting glucose, ischemic heart disease, and myocardial infarction: a Mendelian randomization study

Abstract

Objectives: 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).

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Figure 1. Cumulative Incidence Using Kaplan-Meier Estimates of IHD and MI

Cumulative incidence using Kaplan-Meier estimates of (A) ischemic heart disease (IHD) and (B) myocardial infarction (MI) in percent as a function of age at event. Subjects with IHD or MI before study enrollment were excluded, resulting in 16,318 subjects followed up for as long as 35 years with respect to incident events. Solid line indicates <5 mmol/l; long-dashed line indicates 5 to 6.9 mmol/l; shorter-dashed line indicates 7 to 8.9 mmol/l; shortest-dashed line indicates 9 to 10.9 mmol/l; and dotted line indicates ≥11 mmol/l.

Figure 2. Risk of IHD and MI as a Function of Baseline Nonfasting Plasma Glucose Levels in General Population

Nonfasting plasma glucose levels were measured in 16,568 subjects who participated in the 1976 to 1978, 1981 to 1983, 1991 to 1994, and/or 2001 to 2003 examinations of the Copenhagen City Heart Study. Results are shown for (A) ischemic heart disease (IHD) and (B) myocardial infarction (MI). Participants with IHD or MI before study enrollment were excluded, resulting in 16,318 subjects followed up for as long as 35 years with respect to incident events. Basic multifactorial adjustment was for age, sex, current smoking, menopause, and statin use. The fully multifactorially adjusted model additionally included body mass index, total cholesterol, high-density lipoprotein (HDL) cholesterol, and hypertension. CI = confidence interval; HR = hazard ratio.

Figure 2. Risk of IHD and MI as a Function of Baseline Nonfasting Plasma Glucose Levels in General Population

Nonfasting plasma glucose levels were measured in 16,568 subjects who participated in the 1976 to 1978, 1981 to 1983, 1991 to 1994, and/or 2001 to 2003 examinations of the Copenhagen City Heart Study. Results are shown for (A) ischemic heart disease (IHD) and (B) myocardial infarction (MI). Participants with IHD or MI before study enrollment were excluded, resulting in 16,318 subjects followed up for as long as 35 years with respect to incident events. Basic multifactorial adjustment was for age, sex, current smoking, menopause, and statin use. The fully multifactorially adjusted model additionally included body mass index, total cholesterol, high-density lipoprotein (HDL) cholesterol, and hypertension. CI = confidence interval; HR = hazard ratio.

Figure 3. Nonfasting Plasma Glucose Levels as a Function of Genotype in General Population

Glucose-increasing alleles were combinations of genotypes with glucose-increasing effects; the most common genotype combinations are shown, whereas the rarer combinations were excluded because of reduced statistical power. This was examined in 67,914 participants from the Copenhagen City Heart Study and the Copenhagen General Population Study combined, irrespective of other cardiovascular risk factors or treatment for diabetes mellitus. Estimates of effect on fasting plasma glucose levels reported from genome-wide association studies (GWAS) using plasma glucose level as the phenotype are reported in the right column. To convert mmol/l glucose to mg/dl, multiply by 18.

Figure 4. Summary of Causal Effects of Increased Nonfasting Glucose on Increased Risk of IHD and MI

Studies’ summary of the causal effect of increased nonfasting glucose on increased risk of ischemic heart disease (IHD) and myocardial infarction (MI). This was tested in the Copenhagen City Heart Study, the Copenhagen General Population Study, and the Copenhagen Ischemic Heart Disease Study combined; 6,448 participants were not genotyped for lack of deoxyribonucleic acid; and for participants genotyped, numbers vary slightly from genotype to genotype. The causal effect of increased nonfasting glucose levels on risk of IHD and MI was estimated by the association between a 1-mmol/l (18-mg/dl) genetic increase in nonfasting glucose levels and risk of IHD and MI, using instrumental variable analysis by 2-stage least-squares regression and given as an odds ratio (OR) with a 95% confidence interval (CI). This risk is compared to the observational prospective increased risk of IHD and MI, respectively, associated with a 1-mmol/l (18-mg/dl) increase in nonfasting glucose in the general population, the Copenhagen City Heart Study, given as a multifactorially adjusted Cox regression hazard ratio (HR) with a 95% CI. Odds ratios for a 1-mmol/l (18-mg/dl) genetic increase in nonfasting glucose levels are also given for individual and combined genotypes. F-statistics (evaluation of strength of instrument) and R² (contribution of genotype to variation in plasma glucose levels in percent) are from the first-stage regression analysis. In the second-stage regression analysis studying the association between genotype and risk, imputed glucose values were included in part of the cases in the Copenhagen Ischemic Heart Disease Study. The causal effect of a 1-mmol/l (18-mg/dl) genetic increase in nonfasting glucose levels on risk of IHD and MI was also estimated using effect sizes for genotypes previously reported from genome-wide association studies specifically aimed at identifying genes associated with plasma glucose levels. The p value is for significance of hazard ratio/odds ratio. The p value comparison is between the estimate from observational epidemiology and the causal estimate from instrumental variable analysis. To convert mmol/l glucose to mg/dl, multiply by 18.