Causal Graph Among Serum Lipids and Glycemic Traits: A Mendelian Randomization Study

We systematically investigated the bidirectional causality among HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides (TGs), fasting insulin (FI), and glycated hemoglobin A(1c) (HbA(1c)) based on genome-wide association summary statistics of Europeans (n = 1,320,016 for lipids, 151,013 for FI, and 344,182 for HbA(1c)). We applied multivariable Mendelian randomization (MR) to account for the correlation among different traits and constructed a causal graph with 13 significant causal effects after adjusting for multiple testing (P < 0.0025). Remarkably, we found that the effects of lipids on glycemic traits were through FI from TGs (beta = 0.06 [95% CI 0.03, 0.08] in units of 1 SD for each trait) and HDL-C (beta = -0.02 [-0.03, -0.01]). On the other hand, FI had a strong negative effect on HDL-C (beta = -0.15 [-0.21, -0.09]) and positive effects on TGs (beta = 0.22 [0.14, 0.31]) and HbA(1c) (beta = 0.15 [0.12, 0.19]), while HbA(1c) could raise LDL-C (beta = 0.06 [0.03, 0.08]) and TGs (beta = 0.08 [0.06, 0.10]). These estimates derived from inverse-variance weighting were robust when using different MR methods. Our results suggest that elevated FI was a strong causal factor of high TGs and low HDL-C, which in turn would further increase FI. Therefore, early control of insulin resistance is critical to reduce the risk of type 2 diabetes, dyslipidemia, and cardiovascular complications.

Automated summary

This study systematically investigated the causal relationships among HDL cholesterol, LDL cholesterol, triglycerides, fasting insulin, and glycated hemoglobin A(1c). The results suggest that insulin resistance is a strong causal factor of high triglycerides and low HDL cholesterol, highlighting the importance of early control of insulin resistance to prevent type 2 diabetes, dyslipidemia, and cardiovascular complications.