Abstract 16452: LCAT, HDL Cholesterol and Myocardial Infarction - A Mendelian Randomization Study of HDL Cholesterol in 54,500 Individuals
Background: Epidemiologically, high-density lipoprotein cholesterol (HDL-C) levels relate inversely to risk of ischemic cardiovascular disease. We tested whether genetic variation in lecithin:cholesterol acyltransferase (LCAT), a key enzyme in HDL metabolism, contributes to HDL-C levels and risk of myocardial infarction (MI) in the general population and whether HDL-C levels associate causally with risk of MI.
Methods: We resequenced the regulatory and coding regions of LCAT in 380 individuals from the Copenhagen City Heart Study (CCHS) with the lowest 2% and highest 2% HDL-C levels. All six identified variants were genotyped in the CCHS (n=10,281), and a common genetic variant (S208T, rs4986970), which affected HDL-C levels in the CCHS, was further genotyped in the Copenhagen General Population Study (CGPS, n=50,523). Instrumental variable analysis with MI as endpoint and S208T as the genetic instrument was performed in the combined study (n=54,500).
Results: S208T associated with decreased HDL-C levels of up to 0.2 mmol/L resulting in a predicted increase in risk of 18% for MI. However, S208T did not associate with increased risk of MI. The estimated causal increase in risk of MI by instrumental variable analysis for a 50% reduction in genetically reduced HDL-C levels was -51% (-89%-116%) compared to an observational increase of 111% (70%-162%) for a similar reduction in HDL-C on Cox regression (P-comparison=0.03).
Conclusion: Common genetic variation in LCAT associated with decreased HDL-C levels did not associate with increased risk of MI. Low HDL-C levels robustly associated with increased risk of MI, however genetically decreased HDL-C did not. This suggests that HDL-C levels are not causally related to risk of MI.
- © 2011 by American Heart Association, Inc.