Promoter haplotype of a new ABCA1 mutant influences expression of familial hypoalphalipoproteinemia


      Mutations in the ATP-binding cassette A1 (ABCA1) transporter cause the high-density lipoprotein (HDL) deficiency syndromes of Tangier disease and familial hypoalphalipoproteinemia (FHA). Between individuals carrying ABCA1 mutations, the expression of FHA can be highly variable. Using denaturing HPLC (dHPLC) and direct promoter sequencing we screened the ABCA1 gene of a family with Tangier disease and variable expression of FHA. A new mutation (R1068H) within the first ATP-binding domain was identified in homozygous form in the Tangier disease individual and was present in several family members. Haplotyping of both 1068H alleles in the proband showed homozygosity in the coding region, however, the maternal 1068H allele had three single nucleotide polymorphisms (SNPs) in the promoter previously reported to be associated with reduced ABCA1 expression and HDL levels. An analysis of HDL levels based on 1068H allele haplotype showed the paternal 1068H heterozygotes to have the expected low HDL levels (0.67 ± 0.16 mmol/L), while maternal 1068H heterozygotes showed normal HDL levels (1.18 ± 0.14 mmol/L). Haplotype analysis of the wildtype allele amongst heterozygotes showed no haplotype that was common to the paternal or maternal side. We propose that the paternal 1068H ABCA1 allele causes a negative effect on the function of the wildtype allele and is associated with low HDL levels. In contrast, the maternal 1068H allele has less effect and is associated with a relatively normal HDL level. We conclude that haplotypes of mutant ABCA1 alleles may contribute to the phenotypic variance shown between FHA individuals.


      ABCA1 (ATP-binding cassette A1), apoA1 (apolipoprotein A1), CAD (coronary artery disease), dHPLC (denaturing high performance liquid chromatography), FHA (familial hypoalphalipoproteinemia), HDL (high density lipoprotein), HDL-C (high density lipoprotein cholesterol), SNP (single nucleotide polymorphism)


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Assman G.
        • von Eckardstein A.
        • Brewer B.H.
        Familial high density lipoprotein deficiency: Tangier disease.
        in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The metabolic and molecular basis of inherited disease.7th ed. McGraw-Hill, New York1995: 2053-2072
        • Fredrickson D.S.
        • Altrocchi P.H.
        • Avioli L.V.
        • et al.
        Tangier disease. Combined clinical staff conference at the National Institutes of Health.
        Ann Int Med. 1961; 55: 1016-1031
        • Brooks-Wilson A.
        • Marcil M.
        • Clee S.M.
        • et al.
        Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.
        Nat Genet. 1999; 22: 336-345
        • Bodzioch M.
        • Orso E.
        • Klucken J.
        • et al.
        The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease.
        Nat Genet. 1999; 22: 347-351
        • Rust S.
        • Rosier M.
        • Funke H.
        • et al.
        Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1.
        Nat Genet. 1999; 22: 352-355
        • Marcil M.
        • Brooks-Wilson A.
        • Clee S.M.
        • et al.
        Mutations in the ABC1 gene in familial HDL deficiency with defective cholesterol efflux.
        Lancet. 1999; 354: 1341-1346
        • Marcil M.
        • Yu L.
        • Krimbou L.
        • et al.
        Cellular cholesterol transport and efflux in fibroblasts are abnormal in subjects with familial HDL deficiency.
        Arterioscler Thromb Vasc Biol. 1999; 19: 159-169
        • Oram J.F.
        Tangier disease and ABCA1.
        Biochim Biophys Acta. 2000; 1529: 321-330
        • Brousseau M.E.
        • Eberhart G.P.
        • Dupuis J.
        • et al.
        Cellular cholesterol efflux in heterozygotes for tangier disease is markedly reduced and correlates with high density lipoprotein cholesterol concentration and particle size.
        J Lipid Res. 2000; 41: 1125-1135
        • Santamarina-Fojo S.
        • Peterson K.
        • Knapper C.
        • et al.
        Complete genomic sequence of the human ABCA1 gene: analysis of the human and mouse ATP-binding cassette A promoter.
        Proc Natl Acad Sci USA. 2000; 97: 7987-7992
        • Cohen J.C.
        • Kiss R.S.
        • Pertsemlidis A.
        • et al.
        Multiple rare alleles contribute to low plasma levels of HDL cholesterol.
        Science. 2004; 305: 869-872
        • Frikke-Schmidt R.
        • Nordestgaard B.G.
        • Jensen G.B.
        • et al.
        Genetic variation in ABC transporter A1 contributes to HDL cholesterol in the general population.
        J Clin Invest. 2004; 114: 1343-1353
        • Zwarts K.Y.
        • Clee S.M.
        • Zwinderman A.H.
        • et al.
        ABCA1 regulatory variants influence coronary artery disease independent of effects on plasma lipid levels.
        Clin Genet. 2002; 61: 115-125
        • Lutucuta S.
        • Ballantyne C.M.
        • Elghannam H.
        • et al.
        Novel polymorphisms in promoter region of atp binding cassette transporter gene and plasma lipids, severity, progression, and regression of coronary atherosclerosis and response to therapy.
        Circ Res. 2001; 88: 969-973
        • Probst M.C.
        • Thumann H.
        • Aslanidis C.
        • et al.
        Screening for functional sequence variations and mutations in ABCA1.
        Atherosclerosis. 2004; 175: 269-279
        • Kyriakou T.
        • Hodgkinson C.
        • Pontefract D.E.
        • et al.
        Genotypic Effect of the −565C>T polymorphism in the ABCA1 gene promoter on ABCA1 expression and severity of atherosclerosis.
        Arterioscler Thromb Vasc Biol. 2005; 25: 418-423
        • Friedewald W.T.
        • Levy R.I.
        • Fredrickson D.S.
        Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
        Clin Chem. 1972; 18: 499-502
        • Oefner P.J.
        • Underhill P.A.
        DNA mutation detection using denaturing high-performance-liquid chromatography (DHPLC).
        in: Dracopoli N.C. Haines J.L. Korf B.R. Current protocols in human genetics. John Wiley & Sons, New York1999: 7.10.1-7.10.12
        • Tregouet D.A.
        • Ricard S.
        • Nicaud V.
        • et al.
        In-depth haplotype analysis of ABCA1 gene polymorphisms in relation to plasma ApoA1 levels and myocardial infarction.
        Arterioscler Thromb Vasc Biol. 2004; 24: 775-781
        • Singaraja R.R.
        • Brunham L.R.
        • Visscher H.
        • et al.
        Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene.
        Arterioscler Thromb Vasc Biol. 2003; 23: 1322-1332
        • Roosbeek S.
        • Caster H.
        • Liu Q.Z.
        • et al.
        Expression and activity of the nucleotide-binding domains of the human ABCA1 transporter.
        Protein Expr Purif. 2004; 35: 102-110