Introduction and Objective: Hypertriglyceridemia may explain higher atherosclerotic cardiovascular disease (ASCVD) risk in women with type 2 diabetes (T2D) than men. We examined the causal relationship between triglycerides (TG) and ASCVD in men (M) and women (W) with T2D.Methods: We included participants with T2D from the Electronic Medical Records and Genomics (eMERGE) Network, who had ≥1 TG and BMI measurement and ≥1 statin prescription (nM=9740, nw=9266). We conducted sex-specific GWAS for median TG concentration, coronary heart disease (CHD), ischemic stroke (IS), and hemorrhagic stroke (HS), respectively. In our GWAS, we controlled BMI, age, statin use, race, collection site, and genetic principal components. We used the significant single nucleotide polymorphisms (SNPs) from our TG GWAS (p < 5×10-8) to perform inverse variance weighted Mendelian Randomization (MR) with TG value as the exposure and the other ASCVD traits as outcomes. We then calculated sex-stratified odds ratios (ORs) per standard deviation increment (σ=96mg/dL) for our outcomes and tested for differences between ORs using z-tests.Results: Our sex-specific GWAS identified 269 significant SNPs associated with median TG values. Of these, 104 were shared, 129 were males only, and 36 were females only. MRs showed sex differential associations between TG and CHD (OR and 95% CI M: 0.6 [0.2, 1.4], W: 3.2 [1.2, 8.3]), IS (M:0.5 [0.2, 1.2], W: 7.6 [2.9, 20.0]), and HS (M: 1.7 [0.7, 4.0], W: 3.2 [1.2, 8.3]). The ORs were significantly stronger in females (pairwise z-tests for CHD p=2.3×10-13, IS p=1.4×10-57, and HS p=2.3×10-3, respectively).Conclusion: We found sex differential TG SNPs and sex differential associations between TG and ASCVD in people with T2D. TG is associated with greater ASCVD risk in women than men with T2D.
J. Irizarry Ayala: None. Y. Lu: None. D.R. Crosslin: None. Y. Yoshida: None.
American Diabetes Association (7-23-JDFWH-10), National Institute of General Medical Sciences of the National Institutes of Health (1P20GM152305), Administrative Supplement of the Louisiana Clinical & Translational Science Center (U54 GM104940)
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