HDL and Cardiovascular Risk
Time to Call the Plumber?
Plasma HDL Cholesterol and Risk of Myocardial Infarction:
A Mendelian Randomisation Study
Voight et al
High-density lipoprotein cholesterol (HDL-C) has been dubbed the good cholesterol because it is thought to reflect the ability of HDL particles to remove excess cholesterol molecules from peripheral cells (including those in atherosclerotic plaques) for return to the liver. Not surprisingly, then, HDL-C has frequently been assumed to be a biomarker of HDL function, consistent with the inverse relationship in observational studies between plasma levels of HDL-C and risk of coronary artery disease. Recently, Voight et al have challenged this assumption by showing that genetically elevated HDL-C did not protect against myocardial infarction. This finding has fueled a lively discussion in the lay, scientific, and medical press about the relationship between HDL-C and HDL function, and the potential effectiveness of various HDL-C raising strategies.
Epidemiological studies clearly show that levels of high-density lipoprotein cholesterol (HDL-C) are inversely associated with the risk of coronary artery disease and its thrombotic complications.1 However, in a recent study, Voight et al2 tested the hypothesis that increased plasma HDL-C is protective for myocardial infarction (MI) by examining the relationship between genetic variations associated with elevated levels of plasma HDL-C and the risk of MI.2 The major approach used was Mendelian randomization, a method developed to infer disease causality of a genetic variation.3 In the first test of the hypothesis, a loss of function single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser; minor allele frequency 2.6%) that is associated with an elevated mean plasma level of HDL-C (but no change in the plasma level of low-density lipoprotein cholesterol [LDL-C] or triglycerides) was evaluated in 20 913 MI cases and 95 407 controls. Although carriers of LIPG Asn396Ser had 0.14 mmol/L (5.5 mg/dL) higher mean plasma levels of HDL-C (with similar levels of other lipid and nonlipid risk factors for …