Mendelian randomization of blood lipids for coronary heart disease

Abstract

AimsTo investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.Methods and resultsWe developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10−6); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).ConclusionThe genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

“…However, an HDL‐C influence on CHD is itself paradoxical. While observational studies consistently report a protective association of high blood HDL‐C levels with lower CHD risk, previous MR studies show that HDL‐C is not a causal risk factor for CHD 48, 57. Furthermore, a recent study has reported that a loss‐of‐function variant in scavenger receptor BI ( SRB1 ) raises HDL‐C and increases CHD risk 58.…”

High Triglycerides Are Associated With Increased Cardiovascular Events, Medical Costs, and Resource Use: A Real‐World Administrative Claims Analysis of Statin‐Treated Patients With High Residual Cardiovascular Risk

“…Epidemiologic studies have shown that elevated triglycerides correlate with elevated cardiovascular risk,4, 5 and the American Heart Association has long recognized that elevated triglycerides are an important marker of cardiovascular risk 6. More recently, genetic,7, 8, 9, 10, 11, 12, 13 genome‐wide analysis,14, 15, 16, 17 and mendelian randomization18, 19, 20, 21, 22 studies have suggested a causal role for triglycerides as a modifiable risk factor in the development and progression of ASCVD. Analyses from clinical data have demonstrated that lower on‐treatment triglycerides correlate with reduced cardiovascular risk 23, 24…”

Blood Lipids and Type 2 Diabetes Risk: Can Genetics Help Untangle the Web?

“…These variants have been incorporated into so-called allele scores for use as instruments for their levels in Mendelian randomization experiments (10). Allele scores appear to provide more powerful genetic instruments for complex traits than single variants as the combination of variants has a greater effect on lipid levels and has been used effectively to investigate causal links between lipid moieties and cardiovascular disease (11,12). In their analysis, Fall et al minimized potential confounding between lipid fractions by constructing allele scores with maximal specificity for their index trait.…”