Abstract 14243: Genetic Variation in ABCG5/8 Associated with Lower Plasma LDL Cholesterol Protects Against Myocardial Infarction, but Increases the Risk of Gallstone Disease in the General Population

Abstract

Introduction: The sterol transporter ABCG5/8 effluxes sterols from enterocytes and hepatocytes into the intestine and bile, respectively, and may therefore simultaneously both lower plasma cholesterol levels and increase biliary cholesterol excretion. We tested the hypothesis that genetic variation in ABCG5/8, associated with a lowering of plasma cholesterol levels, protects against myocardial infarction (MI), but increases risk of gallstone disease in the general population.

Methods: We genotyped five common nonsynonymous variants and a known functional variant (ABCG5: Q604E; ABCG8: D19H, Y54C, T400K, A632V, IVS3+981 T>C) in 57,663 individuals from the general population, the Copenhagen City Heart Study and the Copenhagen General Population Study, including 2,794 with MI and 3,081 with gallstone disease, and 2,932 MI patients. We measured lipid and lipoprotein levels, and determined risk of MI and gallstone disease as a function of genotypes, individually and combined.

Results: ABCG8 D19H, Y54C, T400K, A632V and IVS3+981 T>C genotypes were individually associated with stepwise reductions in low-density lipoprotein cholesterol (LDL-C) of up to -5% (P-values: 0.02 to <0.001). Combining genotypes with increasing number of LDL-C decreasing alleles versus 0 alleles, associated with a stepwise per allele decrease in LDL-C of up to -6% (P for trend <0.001), and predicted corresponding stepwise reductions in risk of MI, and stepwise increases in risk of gallstone disease, with odds ratios up to 0.8(0.7-0.9) for MI and up to 2.6(2.2-3.1) for gallstone disease (P-values for trend <0.001).

Conclusion: Genetic variation in ABCG5/8 associated with lower plasma LDL-C protects against MI, but increases the risk of gallstone disease in humans. These data suggest that MI and gallstones, two seemingly unrelated diseases, are intrinsically linked through the function of the ABCG5/8 sterol transporter.