Common polymorphisms of ATP binding cassette transporter A1, including a functional promoter polymorphism, associated with plasma high density lipoprotein cholesterol levels in Turks

Hodoğlugil, Uğur; Williamson, David W.; Huang, Yadong; Mahley, Robert W.

doi:10.1016/j.atherosclerosis.2005.03.004

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Volume 183, Issue 2 , Pages 199-212, December 2005

Common polymorphisms of ATP binding cassette transporter A1, including a functional promoter polymorphism, associated with plasma high density lipoprotein cholesterol levels in Turks

Uğur Hodoğlugil
- Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA
- Cardiovascular Research Institute, University of California, San Francisco, CA, USA
David W. Williamson
- Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA
- Graduate Program in Biological and Medical Informatics, University of California, San Francisco, CA, USA
Yadong Huang
- Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA
- Department of Pathology, University of California, San Francisco, CA, USA
- Cardiovascular Research Institute, University of California, San Francisco, CA, USA
Robert W. Mahley
- Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA
- Department of Pathology, University of California, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, CA, USA
- Cardiovascular Research Institute, University of California, San Francisco, CA, USA
- Corresponding author. Tel.: +1 415 734 2000; fax: +1 415 355 0820.

Received 9 July 2004; received in revised form 7 February 2005; accepted 1 March 2005. published online 03 June 2005.

Abstract

The role of high levels of high density lipoprotein cholesterol (HDL-C) in protection against development of atherosclerosis is generally attributed to its role in reverse cholesterol transport, and the ATP binding cassette transporter A1 (ABCA1) is a key element of this process. We examined polymorphisms in ABCA1 in Turks, a population characterized by very low HDL-C levels. We discovered 36 variations in ABCA1 and genotyped informative polymorphisms in over 2300 subjects. The rare alleles of C–14T and V771M polymorphisms were associated with higher HDL-C levels in men and, in combination with the rare alleles of R219K and I883M, respectively, with higher HDL-C in both sexes. Rare alleles of the C–14T and V771M polymorphisms were more frequent in the high HDL-C (≥40mg/dl) than in the low HDL-C group (≤30mg/dl) in men (P<0.05). Moreover, the T allele of C–14T had more in vitro transcriptional activity than the C allele (20–88%), depending on the cell line (P<0.05), suggesting its functionality. Haplotype construction and haplotype association with phenotype were performed in the promoter and coding region of ABCA1 separately. Analysis of the promoter haplotype block supported the association with the C–14T polymorphism. The C–14T and R219K polymorphisms were on different haplotype blocks. Analysis of the coding region structure revealed that the rare M allele of V771M was distributed predominantly among three common haplotypes, but the sum of their frequencies comprise only two-thirds of the frequency of the M allele. The rare alleles of the V771M and the I883M polymorphisms do not exist together on any of the common haplotypes. In conclusion, we describe a functional promoter polymorphism (C–14T) and a coding sequence variant (V771M) of ABCA1 and their interactions with two other variants (R219K and I883M) on plasma HDL-C levels in Turks.