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

ABSTRACT: 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.

SUBMITTER: Benn M

PROVIDER: S-EPMC4606982 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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

Benn Marianne M Tybjaerg-Hansen Anne A McCarthy Mark I MI Jensen Gorm B GB Grande Peer P Nordestgaard Børge G BG

Journal of the American College of Cardiology 20120601 25

<h4>Objectives</h4>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).<h4>Background</h4>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.<h4>Methods</h4>Using a Mendelian randomization approach, we studied 80,522 persons from Copenhagen, Denmark. Of t ...[more]

PMID: 22698489

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Project description:Background: Although earlier menarche age has been associated with ischemic heart disease in previous observational studies, the relationship's causation has not been shown. Through two-sample Mendelian randomization (MR), we were able to define the causal connection. Methods: We performed Mendelian Randomization (MR) analysis to explore the associations between genetically predicted AAM and IHD. Summary-level databases for exposure and outcome were selected from the MR-Base database (https://gwas.mrcieu.ac.uk/). Single-nucleotide polymorphisms (SNPs) connected to AAM at genome-wide significance level (p < 5 × 10-8) were considered as instrumental variables (IVs). We used four methods to pool MR estimates, including fixed-effects inverse variance weighting (fe-IVW), multiplicative random-effects inverse variance weighting (mre-IVW), weighted median (WM), and MR-Egger regression methods. Sensitivity analyses were performed to evaluate the robustness of the results. PhenoScanner searches and Multivariable Mendelian randomization (MVMR) analysis was used for assessing confounders. Results: 117 SNPs significantly correlated with AAM were screened as instruments, the results of three main methods showed that genetically earlier AAM may have a causal effect on the higher risk of IHD (fe-IVW: OR = 0.80, 95% CI: 0.72-0.88, p < 0.001; mre-IVW: OR = 0.80, 95% CI: 0.70-0.90, p < 0.001; WE: OR = 0.79, 95% CI: 0.66-0.93, p = 0.006). These results were consistent across sensitivity analyses. MR analysis revealed that there was still a relationship between AAM and IHD even when pleiotropic SNPs of confounders were removed employing PhenoScanner searches. In MVMR, the significant association remained after adjusting for biological sex, but it was attenuated with adjustment of body mass index including childhood and adult. Conclusion: Our MR analysis revealed a substantial genetically determined confounder-mediated relationship between an increase in genetically predicted AAM and a lower risk of IHD. By addressing the intervention of body mass index, the risk of IHD may be lowered.

Project description:BackgroundAn imbalance of innate and acquired immune responses is significantly involved in the pathophysiology of coronary atherosclerosis and the occurrence of ischemic heart disease (IHD). Regulatory T cells (Tregs) play an essential regulatory role in atherosclerotic plaque formation and maintenance; therefore, dysfunction of Tregs triggers the formation of atherosclerotic plaques and accelerates their progression. However, due to the inherent limitations of observational research, clinical evidence is limited concerning the relationship between the variation in peripheral Tregs and the risk of IHD, and the cause-and-effect relationship between these factors is unclear. Mendelian randomization (MR) uses genetic variation as a proxy for exposure and can be used to inferentially determine the causal effect of exposure on outcomes. We thus used MR analysis to investigate whether there is a causal relationship between the biomarkers of Tregs and IHD.MethodsSelected genetic variants (P<5.00E-08) from the summary data of a genome-wide association study (GWAS) were used to conduct a two-sample bidirectional MR analysis. The analysis included 51 extensive Treg subtypes involving 3,757 individuals from the general population. Summary statistics of IHD were obtained from the IEU open GWAS project, which contains 30,952 cases and 187,845 controls. The populations in both GWAS studies were of European ancestry.ResultsWe identified a set of 197 single-nucleotide polymorphisms (SNPs) that served as instrumental variables (IVs) for evaluating 51 Treg subtypes. Thirteen significant variables were found to be potentially associated with IHD. After false-discovery rate (FDR) adjustment, we identified four Treg subtypes to be causally protective for IHD risk: CD28 on activated & secreting CD4 Tregs [odds ratio (OR) =0.89; 95% confidence interval (CI): 0.82-0.96; P=3.10E-03; adjusted P=0.04], CD28 on activated CD4 Tregs (OR =0.87; 95% CI: 0.80-0.95; P=3.10E-03; adjusted P=0.04), CD28 on CD4 Tregs (OR =0.87; 95% CI: 0.80-0.96; P=3.41E-03; adjusted P=0.04), and CD28 on resting CD4 Treg cell (OR =0.91; 95% CI: 0.85-0.97; P=3.48E-03; adjusted P=0.04). Reverse MR analysis found eight potential causal variables, but these associations were nonsignificant after FDR correction (all adjusted P values >0.05).ConclusionsThis study identified the significance of elevated CD28 expression on CD4 Tregs as a novel molecular modifier that may influence IHD occurrence, suggesting that targeting CD28 expression on CD4 Tregs could offer a promising therapeutic approach for IHD.

Dataset Information

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

Publications

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

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