2 research outputs found
Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies
Background
Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling.
Methods
In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125โ222 participants. We also compared the frequency of Asp358Ala in 51โ441 patients with coronary heart disease and in 136โ226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6.
Findings
The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele โฅ0ยท04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34ยท3% (95% CI 30ยท4โ38ยท2) and of interleukin 6 by 14ยท6% (10ยท7โ18ยท4), and mean concentration of C-reactive protein was reduced by 7ยท5% (5ยท9โ9ยท1) and of fibrinogen by 1ยท0% (0ยท7โ1ยท3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3ยท4% (1ยท8โ5ยท0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes.
Interpretation
Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.
Funding
British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation
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