Author + information
- Received January 25, 2012
- Accepted February 15, 2012
- Published online June 19, 2012.
- Marianne Benn, MD, PhD, DMSc⁎,†,‡,
- Anne Tybjærg-Hansen, MD, DMSc†,‡,§∥,
- Mark I. McCarthy, MD¶,#,⁎⁎,
- Gorm B. Jensen, MD, DMSc‡,§,
- Peer Grande, MD, DMSc‡,§ and
- Børge G. Nordestgaard, MD, DMSc⁎,†,‡∥,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Børge G. Nordestgaard, Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, Herlev DK-2730, Denmark
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.
This work was supported by Chief Physician Johan Boserup and Lise Boserup's Foundation and the Danish Heart Foundation, both nonprofit organizations with no right to approve or disapprove of the manuscript. The authors have reported they have no relationships relevant to the contents of this paper to disclose.
- Received January 25, 2012.
- Accepted February 15, 2012.
- American College of Cardiology Foundation