Thyroid function and ischemic heart disease: a Mendelian randomization study

Background: Observationally plasma apolipoprotein E (apoE) is positively associated with ischemic heart disease (IHD). A Mendelian randomization (MR) study suggesting apoE is unrelated to cardiovascular mortality did not consider specific isoforms. We used MR to obtain estimates of plasma apoE2, apoE3 and apoE4 on IHD, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides and apolipoprotein B (apoB). Methods: We obtained independent genetic instruments from proteome genome-wide association studies (GWAS) and applied them to large outcome GWAS. We used univariable MR to assess the role of each isoform and multivariable MR to assess direct effects. Results: In univariable MR, apoE4 was positively associated with IHD (odds ratio (OR) 1.05, 95% confidence interval (CI) 1.01 to 1.09), but apoE2 and apoE3 were less clearly associated. Using multivariable MR an association of apoE2 with IHD (OR 1.16, 95% CI 0.98 to 1.38) could not be excluded, and associations of apoE3 and apoE4 with IHD were not obvious. In univariable MR, apoE2 and apoE4 were positively associated with apoB, and a positive association of apoE2 with LDL cholesterol could not be excluded. Using multivariable MR apoE2 was positively associated with LDL cholesterol, and associations with apoB could not be excluded. After adjusting for apoB, no direct effects of apoE isoforms on IHD were evident. Conclusions: Plasma apoE2 and apoE4 may play a role in lipid modulation and IHD. Whether apoE could be a potential therapeutic target requires further clarification when larger genetic studies of apoE isoforms are available.

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Effects of copper and zinc on ischemic heart disease and myocardial infarction: a Mendelian randomization study

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqy129 ◽

2018 ◽

Vol 108 (2) ◽

pp. 237-242 ◽

Cited By ~ 11

Author(s):

Hanish P Kodali ◽

Brian T Pavilonis ◽

C Mary Schooling

Keyword(s):

Sensitivity Analysis ◽

Heart Disease ◽

Ischemic Heart Disease ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Dietary Factors ◽

Ischemic Heart ◽

P Value ◽

Copper And Zinc ◽

A Genome

ABSTRACTBackgroundDespite great progress in prevention and control, ischemic heart disease (IHD) remains a leading cause of global morbidity and mortality. Diet plays a key role in IHD, but a comprehensive delineation of the role of dietary factors in IHD is not yet quite complete.ObjectiveThe aim of this study was to test the long-standing hypothesis that copper is protective and zinc harmful in IHD.DesignWe used separate-sample instrumental variable analysis with genetic instruments (Mendelian randomization). We obtained single nucleotide polymorphisms (SNPs) from a genome wide association study, strongly (P value < 5 × 10−8) and independently associated with erythrocyte copper and zinc. We applied these genetic predictors of copper and zinc to the largest, most extensively genotyped IHD case (n ≤ 76014)-control (n ≤ 264785) study, based largely on CARDIoGRAMplusC4D 1000 Genomes and the UK Biobank SOFT CAD, to obtain SNP-specific Wald estimates for the effects of copper and zinc on IHD, which were combined through the use of inverse variance weighting. Sensitivity analysis included use of the MR-Egger method, and reanalysis including SNPs independently associated with erythrocyte copper and zinc at P value < 5 × 10−6.ResultsGenetically instrumented copper was negatively associated with IHD (OR: 0.94; 95% CI: 0.90, 0.98). Genetically instrumented zinc was positively associated with IHD (OR: 1.06; 95% CI: 1.02, 1.11). Sensitivity analysis via MR-Egger gave no indication of unknown pleiotropy; less strongly associated SNPs gave similar results for copper.ConclusionGenetic validation of a long-standing hypothesis suggests that further investigation of the effects, particularly of copper, on IHD may provide a practical means of reducing the leading cause of mortality and morbidity.

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