Common and Rare ABCA1 Variants Affecting Plasma HDL Cholesterol

Abstract

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, A1484S3 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. (Arterioscler

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

“…One of the primary weaknesses of prior genetic association studies on ABCA1 has been that sample sizes have been relatively small. The results of the present investigation suggest that variants of ABCA1 primarily affect APOB levels given that there was no evidence for effects upon HDL-C or APOA1 levels, the two principal phenotypes for which several prior studies suggest association (Wang et al 2000;Srinivasan et al 2003;Tregouet et al 2004). Studies in animal models point to several phenotypes that are affected by ABCA1 modification, including plasma APOB levels, which has been shown both in transgenic mice (Vaisman et al 2001) and more recently in studies exploiting RNA interference (Ragozin et al 2005).…”

“…This will be necessary in order to corroborate findings across phenotypes (for example, earlier observations of modest effects on senile plaque load in the AD brain) (Katzov et al 2004). The extent of local sequence variation in ABCA1 is fairly well resolved after a number of exhaustive DNA sequencing efforts (Wang et al 2000;Tregouet et al 2004). Among discovered and examined variable sites, the best evidence for potentially functional polymorphism is for the commonly studied R219K and R1587K variants (Tregouet et al 2004).…”

“…The accumulated literature supports the existence of functionally different alleles of ABCA1 that affect both discrete disease states (Singaraja et al 2003) and quantitative traits (Wang et al 2000;Clee et al 2001;FrikkeSchmidt et al 2004). One of the principal problems has been that the sample sizes of most studies have been small, typically entailing less than 1,000 individuals.…”

ABCC6 gene polymorphism associated with variation in plasma lipoproteins

“…Mutations in the gene encoding ATP-binding cassette transporter 1 (ABCA1) cause Tangier disease (TD) and familial deficiency of high-density lipoprotein (HDL) cholesterol (Bodzioch et al 1999;Brooks-Wilson et al 1999;Rust et al 1999;Remaley et al 1999;Brousseau et al 2000;Wang et al 2000). There is also some evidence that a common variation in ABCA1 may be a determinant of plasma lipoprotein concentration (Wang et al 2000;Clee et al 2001).…”

“…There is also some evidence that a common variation in ABCA1 may be a determinant of plasma lipoprotein concentration (Wang et al 2000;Clee et al 2001). ABCA1 is part of a multigene family comprising more than 40 ABC transporters, many of which transport a variety of lipids, including cholesterol, phospholipids, bile acids, and very long chain fatty acids (Klucken et al 2000).…”