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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 unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.
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.
In summary, our results showed that polymorphisms related to plasma LDL cholesterol were consistently associated with risk of myocardial infarction, whereas this was not the case for variants related to plasma HDL cholesterol. A polymorphism in the endothelial lipase gene and a genetic score of 14 common SNPs that specifically raised HDL cholesterol were not associated with myocardial infarction, suggesting that some genetic mechanisms that raise HDL cholesterol do not lower risk of myocardial infarction. Hence, interventions (lifestyle or pharmacological) that raise plasma HDL cholesterol cannot be assumed ipso facto to lead to a corresponding benefit with respect to risk of myocardial infarction.