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Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes
Susanne M. Clee, … , Jacques Genest Jr., Michael R. Hayden
Susanne M. Clee, … , Jacques Genest Jr., Michael R. Hayden
Published November 15, 2000
Citation Information: J Clin Invest. 2000;106(10):1263-1270. https://doi.org/10.1172/JCI10727.
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Article

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

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Abstract

We and others have recently identified mutations in the ABCA1 gene as the underlying cause of Tangier disease (TD) and of a dominantly inherited form of familial hypoalphalipoproteinemia (FHA) associated with reduced cholesterol efflux. We have now identified 13 ABCA1 mutations in 11 families (five TD, six FHA) and have examined the phenotypes of 77 individuals heterozygous for mutations in the ABCA1 gene. ABCA1 heterozygotes have decreased HDL cholesterol (HDL-C) and increased triglycerides. Age is an important modifier of the phenotype in heterozygotes, with a higher proportion of heterozygotes 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 cholesterol 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 disease (CAD), with earlier onset than unaffected family members. CAD is more frequent in those heterozygotes with lower cholesterol efflux values. These data provide direct evidence that impairment of cholesterol efflux and consequently reverse cholesterol transport is associated with reduced plasma HDL-C levels and increased risk of CAD.

Authors

Susanne M. Clee, John J.P. Kastelein, Marjel van Dam, Michel Marcil, Kirsten Roomp, Karin Y. Zwarts, Jennifer A. Collins, Roosje Roelants, Naoki Tamasawa, Tomás Stulc, Toshihiro Suda, Richard Ceska, Betsie Boucher, Colette Rondeau, Christele DeSouich, Angela Brooks-Wilson, Henri O.F. Molhuizen, Jiri Frohlich, Jacques Genest Jr., Michael R. Hayden

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Figure 1

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The percent of heterozygotes or unaffected family members with HDL-C and...
The percent of heterozygotes or unaffected family members with HDL-C and TG within a given range of percentiles for age and sex, based on the Lipid Research Clinics criteria (25), are shown. A broad distribution of HDL-C levels was seen in the heterozygotes, extending up to the 31st percentile for age and sex. There is much overlap in the distribution of TG between heterozygotes and unaffected family members, although a larger portion of heterozygotes have TG greater than or equal to the 80th percentile for age and sex.

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