Abstract 1341: ATP Binding Cassette Transporter A1 Mutations in the General Population -Impact on HDL Cholesterol and Ischemic Heart Disease
Objectives: HDL cholesterol (HDL-C) is a major risk factor for ischemic heart disease (IHD). We have recently shown that common single nucleotide polymorphisms (SNPs) in ATP Binding Cassette Transporter A1 (ABCA1) contribute to HDL-C levels in the general population. Whether mutations identified in the general population predicts risk of IHD and whether this risk is reflected in HDL-C levels is not known.
Methods: In 9,259 individuals from the general population and during 25 years of follow-up, we determined the predictive value for IHD of mutations previously identified by resequencing 190 individuals with extreme HDL cholesterol levels from the same general population.
Results: Four “rare” mutations (S364C, P1065S, G1216V, R2144X) had frequencies below 0.04% whereas four “common” mutations (V399A, T774P, K776N, N1800H) had frequencies of 0.2– 0.4%. In silico predictions classified S364C, K776N, P1065S, G1216V and N1800H to be of functional significance, whereas the R2144X mutation resulted in a truncation of the 62 C-terminal amino acids. The S364C, P1065S, G1216V, N1800H and R2144X mutations were associated with low HDL-C levels in the general population. The K776N mutation had incidence rates in non-carriers and heterozygotes of 70 and 161 per 10,000 person years, respectively, corresponding to a hazard ratio of 2.1 for heterozygotes versus non-carriers. By the age of 80 years, 48% of heterozygotes and 23% of non-carriers had IHD.
Conclusions: We show that eight ABCA1 mutations are present in the general population with a total frequency of 1.4%. Five mutations were associated with low HDL-C levels whereas one mutation predicted IHD independent of HDL-C levels.