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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1983.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Common and Rare ABCA1 Variants Affecting Plasma HDL Cholesterol

Jian Wang; John R. Burnett; Susan Near; Kue Young; Bernard Zinman; Anthony J. G. Hanley; Philip W. Connelly; Stewart B. Harris; Robert A. Hegele

From the John P. Robarts Research Institute (J.W., S.N., R.A.H.), London, Ontario, Canada; the Department of Core Clinical Pathology and Biochemistry (J.R.B.), Royal Perth Hospital, Perth, Australia; the Northern Health Research Unit (K.Y.), Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; the Samuel Lunenfeld Research Institute (B.Z., A.J.G.H.), Mount Sinai Hospital, Toronto, Ontario; St. Michael’s Hospital (P.W.C.), University of Toronto, Toronto, Ontario, Canada; and the Thames Valley Family Practice Research Unit (S.B.H.), University of Western Ontario, London, Ontario, Canada.

Correspondence to Robert A. Hegele, MD, Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 406-100 Perth Dr, London, Ontario, Canada N6A 5K8. E-mail robert.hegele{at}rri.on.ca

Abstract—Mutations in ABCA1, a member of the ATP-binding cassette family, have been shown to underlie Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA), which are genetic disorders that are characterized by depressed concentrations of plasma high density lipoprotein (HDL) cholesterol. An important question is whether common variants within the coding sequence of ABCA1 can affect plasma HDL cholesterol in the general population. To address this issue, we developed a screening strategy to find common ABCA1 variants. This strategy involved long-range amplification of genomic DNA by using coding sequences only, followed by deep sequencing into the introns. This method helped us to characterize a new set of amplification primers, which permitted amplification of virtually all of the coding sequence of ABCA1 and its intron-exon boundaries with a single DNA amplification program. With these new sequencing primers, we found 3 novel ABCA1 mutations: a frameshift mutation (4570insA, A1484SX1492), a missense mutation (A986D) in a TD family, and a missense mutation (R170C) in aboriginal subjects with FHA. We also used these sequencing primers to characterize 4 novel common amino acid variants in ABCA1, in addition to 5 novel common silent variants. We tested for association of the ABCA1 I/M823 variant with plasma HDL cholesterol in Canadian Inuit and found that M823/M823 homozygotes had significantly higher plasma HDL cholesterol compared with subjects with the other genotypes. The results provide proof of principle of the effectiveness of this approach to identify both rare and common ABCA1 genomic variants and also suggest that common amino acid variation in ABCA1 is a determinant of plasma HDL cholesterol in the general population.

Key Words: DNA • genetics • complex disease • susceptibility • aboriginal

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