Abstract 17194: Genetically Elevated High-Density Lipoprotein Cholesterol and Unaffected Risk of Symptomatic Gallstone Disease: a Mendelian Randomization Study Challenging Reverse Cholesterol Transport
Background: In observational studies, elevated levels of high-density lipoprotein cholesterol (HDL-C) are associated with a decreased risk of gallstone disease. This is the opposite of what would be expected from the concept of reverse cholesterol transport, namely that elevated HDL-C would increase the risk of gallstones due to an increased transhepatic cholesterol flux into bile. We therefore tested whether there is a causal association between increased plasma levels of HDL-C and risk of gallstone disease.
Methods: Using a Mendelian randomization approach, we studied 47,620 individuals from the general population of Copenhagen, Denmark. Of these, 2,712 developed symptomatic gallstone disease during up to 34 years of follow-up. Subjects were genotyped for nine variants in ABCA1, CETP, LCAT, LIPC, and APOA1, all known to associate with increased plasma levels of HDL-C. A weighted combined genotype score from 1-4 was calculated for each individual.
Results: In observational analyses, mean baseline HDL-C was 123%(1.3 mmol/L) increased in individuals in the fourth versus the first quartile, and the corresponding multifactorially adjusted hazard ratio(HR) for symptomatic gallstone disease was 0.70(95% confidence interval, 0.57-0.85)(P-trend=5х10E-4 across quartiles). The individual genetic variants associated with increases in HDL-C of up to 39%(0.5 mmol/L), but none associated with risk of gallstone disease. Compared to individuals with a combined genotype score of 1, individuals with a genotype score of 4 had a mean 15%(0.2 mmol/L) increase in HDL-C levels (P-trend=3х10E-269 across quartiles), and a corresponding HR for symptomatic gallstone disease of 1.02(0.92-1.13)(P-trend=0.85). Using instrumental variable analysis, the causal odds ratio for a 1 mmol/L genetic increase in HDL-C was 0.92(0.56-1.51; F-statistic=447), with a corresponding observational HR of 0.77(0.67-0.89).
Conclusion: Levels of HDL-C are not likely to be causally associated with the risk of symptomatic gallstone disease, challenging the concept of reverse cholesterol transport.
- © 2013 by American Heart Association, Inc.