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 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.

[1]  M. Freeman,et al.  Cellular cholesterol efflux in heterozygotes for tangier disease is markedly reduced and correlates with high density lipoprotein cholesterol concentration and particle size. , 2000, Journal of lipid research.

[2]  M. Hayden,et al.  Cholesterol efflux regulatory protein, Tangier disease and familial high-density lipoprotein deficiency , 2000, Current opinion in lipidology.

[3]  L. M. Thurston,et al.  Novel mutations in the gene encoding ATP-binding cassette 1 in four tangier disease kindreds. , 2000, Journal of lipid research.

[4]  B. Sarkadi,et al.  An inventory of the human ABC proteins. , 1999, Biochimica et biophysica acta.

[5]  P. Denéfle,et al.  Human ATP-binding cassette transporter 1 (ABC1): genomic organization and identification of the genetic defect in the original Tangier disease kindred. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[6]  C. Sensen,et al.  Mutations in the ABC 1 gene in familial HDL deficiency with defective cholesterol efflux , 1999, The Lancet.

[7]  A. Vaughan,et al.  The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. , 1999, The Journal of clinical investigation.

[8]  C. Sensen,et al.  Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency , 1999, Nature Genetics.

[9]  T. Langmann,et al.  The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease , 1999, Nature Genetics.

[10]  J. Piette,et al.  Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1 , 1999, Nature Genetics.

[11]  B. J. Klevering,et al.  ABCR unites what ophthalmologists divide(s) , 1998, Ophthalmic genetics.

[12]  A. von Eckardstein,et al.  Plasma and fibroblasts of Tangier disease patients are disturbed in transferring phospholipids onto apolipoprotein A-I. , 1998, Journal of lipid research.

[13]  P. Duchateau,et al.  Prebeta-1 HDL in plasma of normolipidemic individuals: influences of plasma lipoproteins, age, and gender. , 1998, Journal of lipid research.

[14]  M. McQueen,et al.  Reverse cholesterol transport--a review of the process and its clinical implications. , 1997, Clinical biochemistry.

[15]  R. Krauss,et al.  Predominance of large LDL and reduced HDL2 cholesterol in normolipidemic men with coronary artery disease. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[16]  J. Frohlich,et al.  Severe familial HDL deficiency in French-Canadian kindreds. Clinical, biochemical, and molecular characterization. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[17]  Sudhir Gupta.  P-Glycoprotein Expression and Regulation , 1995 .

[18]  C. Fielding,et al.  Molecular physiology of reverse cholesterol transport. , 1995, Journal of lipid research.

[19]  G. Assmann,et al.  The high density lipoprotein- and apolipoprotein A-I-induced mobilization of cellular cholesterol is impaired in fibroblasts from Tangier disease subjects. , 1994, Biochemical and biophysical research communications.

[20]  P. Wilson,et al.  High density lipoprotein cholesterol and mortality. The Framingham Heart Study. , 1988, Arteriosclerosis.

[21]  K. Anderson,et al.  Longitudinal and secular trends in lipoprotein cholesterol measurements in a general population sample. The Framingham Offspring Study. , 1987, Atherosclerosis.

[22]  G. Heiss,et al.  The Epidemiology of Plasma High‐density Lipoprotein Cholesterol Levels: The Lipid Research Clinics Program Prevalence Study Summary , 1980, Circulation.

[23]  H. Brewer,et al.  Coronary heart disease prevalence and other clinical features in familial high-density lipoprotein deficiency (Tangier disease). , 1980, Annals of internal medicine.

[24]  S. Sasayama,et al.  Contractile Performance of the Hypertrophied Ventricle in Patients with Systemic Hypertension , 1980, Circulation.

[25]  D. Jacobs,et al.  Lipoprotein‐Cholesterol Distributions in Selected North American Populations: The Lipid Research Clinics Program Prevalence Study , 1980, Circulation.

[26]  D. Fredrickson,et al.  Abnormal concentration and anomalous distribution of apolipoprotein A-I in Tangier disease. , 1978, Metabolism: clinical and experimental.

[27]  G. Assmann,et al.  Characterization of high density lipoproteins in patients heterozygous for Tangier disease. , 1977, The Journal of clinical investigation.

[28]  R. Levy,et al.  Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. , 1972, Clinical chemistry.

[29]  J. Seegmiller,et al.  Cystinosis. Combined clinical staff conference at the National Institutes of Health. , 1968, Annals of internal medicine.

[30]  L. Avioli,et al.  Tangier Disease: Combined Clinical Staff Conference at the National Institutes of Health , 1961 .

[31]  J. Genest,et al.  Cellular cholesterol transport and efflux in fibroblasts are abnormal in subjects with familial HDL deficiency. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[32]  G. Cockerill,et al.  High-density lipoprotein: multipotent effects on cells of the vasculature. , 1999, International review of cytology.

[33]  J. Medalie,et al.  Isolated low HDL cholesterol as a risk factor for coronary heart disease mortality. A 21-year follow-up of 8000 men. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[34]  S. Gupta.  P-glycoprotein expression and regulation. Age-related changes and potential effects on drug therapy. , 1995, Drugs & aging.

[35]  P. Allhoff,et al.  The Framingham Offspring Study , 1991 .

[36]  P. Allhoff,et al.  The Lipid Research Clinics Program Prevalence Study. , 1980, Circulation.

[37]  J. Glomset,et al.  The metabolic role of lecithin: cholesterol acyltransferase: perspectives from pathology. , 1973, Advances in lipid research.