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Mendelian randomization of blood lipids for coronary heart disease
Michael V Holmes1, Folkert W Asselbergs2, Tom M Palmer3
1Genetic Epidemiology Group, Institute of Cardiovacular Science, Faculty of Population Healh Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK Division of Transplant Surgery, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104, USA mvholmes@gmail.com.
Insights
Genetic analysis reveals triglycerides causally increase coronary heart disease (CHD) risk. The causal role of high-density lipoprotein cholesterol (HDL-C) in CHD remains less certain, despite initial associations.
Area of Science:
- Cardiovascular Genetics
- Epidemiology
- Biostatistics
Background:
- Coronary heart disease (CHD) is a leading cause of mortality globally.
- Understanding the causal roles of lipid profiles, including high-density lipoprotein cholesterol (HDL-C) and triglycerides, is crucial for effective prevention strategies.
- Mendelian randomization (MR) offers a powerful approach to infer causality using genetic variants as instrumental variables.
Purpose of the Study:
- To investigate the causal relationship between HDL-C and triglycerides with CHD risk.
- To employ a robust MR framework using multiple instrumental variables (weighted allele scores).
- To differentiate the causal impact of HDL-C and triglycerides on CHD, accounting for potential confounding factors.
Main Methods:
- Developed weighted allele scores using single nucleotide polymorphisms (SNPs) associated with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C).
- Constructed both unrestricted and restricted allele scores, with the latter excluding SNPs associated with other lipid traits.
- Conducted MR meta-analyses across 17 studies, encompassing 62,199 participants and 12,099 CHD events.
Main Results:
- Allele scores for LDL-C showed robust associations with CHD.
- Unrestricted HDL-C allele scores indicated a potential association with reduced CHD risk, but this was not consistently observed in restricted models or after adjusting for other lipids.
- Both unrestricted and restricted triglyceride allele scores demonstrated a significant association with increased CHD risk, which attenuated after multivariable adjustment.
Conclusions:
- Genetic evidence strongly supports a causal effect of triglycerides in increasing CHD risk.
- The causal role of HDL-C in CHD is less certain and requires further investigation.
- MR analyses highlight the distinct causal pathways of different lipid fractions in cardiovascular disease etiology.
Aims:
To 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 Results:
We 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).
Conclusion:
The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.
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