Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes

We and others have recently identified mutations in the ABCA1 gene as the u nderlying cause of Tangier disease (TD) and of a dominantly inherited form of familial hypoalphalipoproteinemia (FHA) associated with reduced choleste rol efflux, We have now identified 13 ABCA1 mutations in 11 families (five TD, six FHA) and have examined the phenotypes of 77 individuals heterozygou s for mutations in the ABCA1 gene. ABCA1 heterozygotes have decreased HDL c holesterol (HDL-C) and increased triglycerides. Age is an important modifie r of the phenotype in heterozygotes, with a higher proportion of heterozygo tes aged 30-70 years having HDL-C greater than the fifth percentile for age and sex compared with carriers less than 30 years of age. Levels of choles terol efflux are highly correlated with HDL-C levels, accounting for 82% of its variation. Each 8% change in ABCA1-mediated efflux is predicted to be associated with a 0.1 mmol/l change in HDL-C. ABCA1 heterozygotes display a greater than threefold increase in the frequency of coronary artery diseas e (CAD), with earlier onset than unaffected family members. CAD is more fre quent in those heterozygotes with lower cholesterol efflux values. These da ta provide direct evidence that impairment of cholesterol efflux and conseq uently reverse cholesterol transport is associated with reduced plasma HDL- C levels and increased risk of CAD.