2 research outputs found
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 (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher,
p=8Ă10â
ÂčÂł) 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] 0·87, 95% CI 0·84â0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial
infarction (OR 0·99, 95% CI 0·88â1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL
cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58â0·66). However, a 1 SD
increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93,
95% CI 0·68â1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in
LDL cholesterol associated with OR 1·54, 95% CI 1·45â1·63) was concordant with that from genetic score (OR 2·13,
95% CI 1·69â2·69, p=2Ă10â
Âčâ°).
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
Common variants at 10 genomic loci influence hemoglobin Aâ(C) levels via glycemic and nonglycemic pathways.
Glycated hemoglobin (HbAâ(c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbAâ(c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbAâ(c) levels