Mendelian randomization of blood lipids for coronary heart disease

By Michael Holmes, F. Asselbergs, T. Palmer, F. Drenos, M. Lanktree, C. Nelson, C. Dale, S. Padmanabhan, C. Finan, D. Swerdlow and 58 more. European Heart Journal, 2014

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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.

Subfields: Endocrinology, Diabetes and Metabolism, Genetics, Surgery

View Paper: https://www.semanticscholar.org/paper/c6206ffcba7e8c92b81020223b6bef940b609a11

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Citations in the corpus

Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic (2016, background): “We do not therefore claim that this approach is superior to the more liberal inclusion policy adopted by Holmes et al.(8) in their main analysis, or that any single approach should be relied upon.”
Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel (2017, background): “Indeed, when the effect of each LDL-C variant is plotted against its effect on CHD, there is a continuous, dose-dependent, and log-linear causal association between the magnitude of the absolute change in LDL-C level and the lifetime risk of CHD (Figure 2).(28,30) Furthermore, when adjusted for a st”
2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. (2016, background): “The causative role of HDL-C for protection against CVD has been questioned in several studies utilizing Mendelian randomization.(87,89,91,92) Recent studies suggest that HDL has a complex role in atherogenesis and that the presence of dysfunctional HDL may be more relevant to the ESC/EAS Guidelines ”
Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator (2016, background): “However, a more liberal Mendelian randomization analysis including genetic variants associated with other lipid fractions (in particular, triglycerides) did suggest a causal effect of HDL-c on CAD risk (Holmes et al., 2015).”
Machine learning in cardiovascular medicine: are we there yet? (2018, methodology): “45 MR has recently been used to demonstrate that a biomarker associated with CVD (cystatin C) was not causally related.”
Mendelian randomization: genetic anchors for causal inference in epidemiological studies (2014, methodology): “An initial way of interrogating this problem is to use regression methods to attempt to separate the effects, and two independent studies utilizing this approach have recently suggested that the causal influence of triglycerides was robust, whereas the apparent protective effect of HDL-C was not (81”
2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. (2019, background): “In contrast, Mendelian randomization studies do not provide compelling evidence that HDL-C is causally associated with the risk of ASCVD.(49,61,62) However, this evidence must be interpreted with caution because most genetic variants associated with HDL-C are also associated with directionally oppos”