Elsevier

Atherosclerosis

Volume 154, Issue 3, 15 February 2001, Pages 607-611
Atherosclerosis

Common variants in the gene encoding ATP-binding cassette transporter 1 in men with low HDL cholesterol levels and coronary heart disease

https://doi.org/10.1016/S0021-9150(00)00722-XGet rights and content

Abstract

HDL cholesterol (HDL-C) deficiency is the most common lipid abnormality observed in patients with premature coronary heart disease (CHD). Recently, our laboratory and others demonstrated that mutations in the ATP-binding cassette transporter 1 (ABCA1) gene are responsible for Tangier disease, a rare genetic disorder characterized by severely diminished plasma HDL-C concentrations and a predisposition for CHD. To address the question of whether common variants within the coding sequence of ABCA1 may affect plasma HDL-C levels and CHD risk in the general population, we determined the frequencies of three common ABCA1 variants (G596A, A2589G and G3456C) in men participating in the Veterans Affairs Cooperative HDL Cholesterol Intervention Trial (VA-HIT), a study designed to examine the benefits of HDL raising in men having low HDL-C (≤40 mg/dl) and established CHD, as well as in CHD-free men from the Framingham Offspring Study (FOS). Allele frequencies (%) in VA-HIT were 31, 16, and 4 for the G596A, A2589G, and G3456C variants, respectively, versus 27, 12, and 2 in FOS (P<0.03). None of the variants were significantly associated with plasma HDL-C concentrations in either population; however, in VA-HIT, the G3456C variant was associated with a significantly increased risk for CHD end points, suggesting a role for this variant in the premature CHD observed in this population.

Introduction

A number of laboratories [1], [2], [3], [4], [5], [6] have demonstrated that mutations in the ATP-binding cassette transporter 1 (ABCA1) gene are responsible for a rare form of genetic HDL deficiency known as Tangier disease (TD). TD is characterized by severely diminished plasma HDL-C concentrations, reduced levels of low density lipoprotein cholesterol (LDL-C), the deposition of cholesteryl esters in tissues throughout the body, and a predisposition to neuropathy and CHD [7], [8]. Although mutations in ABCA1 cause TD, the precise molecular mechanism by which they do so remains unknown. Investigations on the function of ABCA1 have revealed its role in: (1) engulfment of apoptotic cells by macrophages [9]; (2) macrophage interleukin-1β secretion [10]; (3) modulation of apolipoprotein-mediated cellular lipid efflux [11]; and (4) caveolar processing [12]. Due to its diverse functions, ABCA1 is an attractive candidate gene for the modulation of plasma HDL-C levels in the general population as well.

With this concept in mind, we determined the frequencies of three common variants within the coding sequence of ABCA1 (G596A, A2589G and G3456C) in men participating in the Veterans Affairs Cooperative HDL Cholesterol Intervention Trial (VA-HIT), a population comprised of men having low HDL-C and CHD [13]. Because CHD-free control subjects were not included in VA-HIT, we also assessed the frequencies of these three ABCA1 variants in men from the Framingham Offspring Study (FOS) [14]. In view of the subject composition of VA-HIT, we believed that this would be an ideal population for the identification of ABCA1 variants and, ultimately, for associations to be made with plasma lipids and/or CHD end points. Although our findings must be interpreted with caution, the greater frequency of each ABCA1 variant in VA-HIT, along with the increased risk for CHD end points associated with the G3456C variant, suggests a role for these ABCA1 variants in the premature CHD observed in this population.

Section snippets

Subjects

Subjects were men participating in either the VA-HIT (n=1014) or Framingham Offspring (n=1014) studies. The design and methods for FOS have been described elsewhere in detail [14], as have the rationale, design, and results of the VA-HIT study [13]. For VA-HIT, men were recruited at 20 Veterans Affairs medical centers throughout the United States. Eligibility for the trial required a documented history of CHD, an age of <74 years, an absence of coexisting conditions, an HDL-C level of ≤40 mg/dl

Results

The biochemical characteristics and ABCA1 genotypes of men from VA-HIT and FOS are provided in Table 1. Men participating in VA-HIT were older, and slightly heavier, than men in FOS. Inherent to the study design of VA-HIT, men in this group had significantly (P<0.01) lower concentrations of plasma total cholesterol (−14%), HDL-C (−27%), and LDL-C (−17%) as compared with men in FOS, with the greatest difference between the groups noted in HDL-C levels. These differences resulted in a TC:HDL-C

Discussion

The recent discovery of the obligatory role of ABCA1 in cellular cholesterol efflux poses several new questions for the field of atherosclerosis research. Of obvious importance is whether or not identification of the molecular defect in TD, a rare inherited disorder, can provide insight into the regulation of HDL-C levels and CHD risk in the general population. To explore this possibility, we designed a study in which the frequencies of three common ABCA1 variants were determined in men

Acknowledgements

The authors are grateful to Tatyana Massov and Judith R. McNamara of New England Medical Center for the plasma lipid analyses, as well as to Alison Kelleher of Tufts University for technical assistance. This work was supported by the Department of Veterans Affairs, Medical Research Services VA Cooperative Program, research grants of the Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany and by NIH grant R01 HL60935 and contract

References (26)

  • A. Brooks-Wilson et al.

    Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency

    Nat. Genet.

    (1999)
  • S. Rust et al.

    Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1

    Nat. Genet.

    (1999)
  • A.T. Remaley et al.

    Human ATP-binding cassette transporter 1 (ABC1): Genomic organization and identification of the genetic defect in the original Tangier disease kindred

    Proc. Natl. Acad. Sci. USA

    (1999)
  • Cited by (86)

    • Genetic and secondary causes of severe HDL deficiency and cardiovascular disease

      2018, Journal of Lipid Research
      Citation Excerpt :

      Heterozygotes were found to have a 50% reduction in cellular cholesterol efflux, very low levels of very large α1 and large α2 HDL particles, and approximately 50% of normal HDL-C levels (53, 54). Population studies indicated that three common ABCA1 variants (p.G596A, p.A2589G, and p.G3456C) were more common in men with low HDL-C (<40 mg/dl) and ASCVD than in control subjects (55). Cohen et al. (56) sequenced the APOA1,ABCA1, and LCAT genes in 284 subjects with HDL-C concentrations below the 5th percentile (<30 mg/dl) and in 236 subjects with HDL-C levels above the 95th percentile (>75 mg/dl).

    View all citing articles on Scopus
    View full text