Nonfasting glucose, ischemic heart disease, and myocardial infarction: a Mendelian randomization study.
OBJECTIVE
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.
Department of Clinical Biochemistry, Herlev Hospital, Denmark.
Marianne
M
Benn
Anne
A
Tybjaerg-Hansen
Mark I
MI
McCarthy
Gorm B
GB
Jensen
Peer
P
Grande
Børge G
BG
Nordestgaard
D000328:Adult; D000368:Aged; D000483:Alleles; D001786:Blood Glucose / Q000378:metabolism*; D015992:Body Mass Index; D008076:Cholesterol, HDL / Q000097:blood; D003718:Denmark / Q000453:epidemiology; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000150:complications; D053208:Kaplan-Meier Estimate; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics; D017202:Myocardial Ischemia / Q000097:blood* / Q000453:epidemiology / Q000235:genetics*; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors
D001786:Blood Glucose; D008076:Cholesterol, HDL