Genetic Associations of Lipids and Lipid-Modifying Drug Targets With Type 2 Diabetes in the Chinese Population

Figures

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  Figure 1. Association Between Weighted GRSs of Lipid Traits and T2D Risk The association between the weighted genetic risk scores (GRSs) of 3 lipid traits (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides [TGs]) and the risk of type 2 diabetes (T2D). The logistic model adjusted for age, sex, body mass index, smoking and drinking behavior, exercise frequency, education, waist circumference, systolic blood pressure, diastolic blood pressure, history of hypertension, and lipid-modifying and antihypertension medications. The OR with 95% CI represents the risk of T2D per 1 SD increase in the weighted GRS of lipid traits. The results indicate that the weighted GRSs of LDL-C and TGs are significantly associated with an increased risk of T2D. SNP = single nucleotide polymorphism.

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  Figure 2. Univariable Mendelian Randomization Analysis of Lipid Traits and T2D Risk (A) The causal effects of lipid levels on T2D using the 1-sample Mendelian randomization (MR) method with Kunshan community cohort data. (B) The causal effect of lipid levels on T2D using 2-sample MR method with Global Lipids Genetic Consortium (GLGC) and Biobank of Japan (BBJ) data. The OR with 95% CI represents the risk of T2D per 1 mmol/L increase in each lipid trait. The results show that genetically predicted lower levels of LDL-C and TGs were significantly associated with a higher risk of T2D in both the main and replication analyses. Abbreviations as in Figure 1.

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  Figure 3. Multivariable MR Analyses of Lipids and T2D and 3 Lipid Traits (A) This analysis shows that genetically predicted levels of LDL-C and TG are directly associated with an increased risk of T2D. (B) This analysis shows the associations among the genetically predicted lipid traits (LDL-C, HDL-C, and TG). The OR with 95% CI represents the risk of T2D per 1 mmol/L increase in each lipid trait. Abbreviations as in Figures 1 and 2.

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  Figure 4. Associations Between Genetically Proxied Lipid-Modifying Drugs and T2D Risk The associations between genetically proxied effects of 7 lipid-modifying drugs and the risk of T2D. The OR with 95% CI represents the risk of T2D per 1 mmol/L decrease in LDL-C via HMGCR, PCSK9, and APOB; per 1 mmol/L decrease in TG via LPL, APOC3, and ANGPTL3; and per 1 mmol/L increase in HDL-C via CETP. The results indicate that genetic mimicry of APOC3 inhibition is associated with an increased risk of T2D. Abbreviations as in Figure 1.

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  Central Illustration. Relationships Between Lipids, Lipid-Modifying Drugs, and Type 2 Diabetes in the Chinese Population The associations between genetically proxied lipid levels, lipid-modifying drugs, and the risk of type 2 diabetes (T2D) in the Chinese population. Lower genetic risk scores of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs) were associated with increased T2D risk. Mendelian randomization analyses showed that genetically predicted lower LDL-C and TG levels were associated with increased T2D risk. These findings highlight the potential adverse effects of lower LDL-C and TG levels, as well as long-term use of APOC3 inhibitors, on T2D risk in this population. HDL-C = high density lipoprotein cholesterol.