2 research outputs found
Mendelian randomization of blood lipids for coronary heart disease
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 ร 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 โค 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
Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study
Background High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this
association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent
of non-genetic confounding, and are unmodifi ed by disease processes, mendelian random isation can be used to test
the hypothesis that the association of a plasma biomarker with disease is causal.
Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide
polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies
(20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of
14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of
myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs
exclusively associated with LDL cholesterol.
Findings Carriers of the LIPG 396Ser allele (2ยท6% frequency) had higher HDL cholesterol (0ยท14 mmol/L higher,
p=8ร10โ
ยนยณ) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with noncarriers.
This diff erence in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio
[OR] 0ยท87, 95% CI 0ยท84โ0ยท91). However, we noted that the 396Ser allele was not associated with risk of myocardial
infarction (OR 0ยท99, 95% CI 0ยท88โ1ยท11, p=0ยท85). From observational epidemiology, an increase of 1 SD in HDL
cholesterol was associated with reduced risk of myocardial infarction (OR 0ยท62, 95% CI 0ยท58โ0ยท66). However, a 1 SD
increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0ยท93,
95% CI 0ยท68โ1ยท26, p=0ยท63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in
LDL cholesterol associated with OR 1ยท54, 95% CI 1ยท45โ1ยท63) was concordant with that from genetic score (OR 2ยท13,
95% CI 1ยท69โ2ยท69, p=2ร10โ
ยนโฐ).
Interpretation Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial
infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into
reductions in risk of myocardial infarction.
Funding US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the
German Federal Ministry of Education and Research