© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Common and Rare ABCA1 Variants Affecting Plasma HDL Cholesterol
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,
A1484S
X1492), 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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