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To the Editor: In their study of loss-of-function mutations in the ABCA1 gene, Dr Frikke-Schmidt and colleagues¹ reported that heterozygosity for certain ABCA1 variants was not associated with increased risk of ischemic heart disease (IHD) in 3 Danish cohorts and concluded that reduced high-density lipoprotein (HDL) cholesterol levels caused by mutations in ABCA1 do not contribute to atherosclerosis. However, a number of limitations preclude this conclusion.

The variants studied are at most mild mutations, not true loss-of-function mutations. This is clear from the relatively small reductions in HDL cholesterol levels in carriers of these mutations. The N1800H mutation, although known to impair ABCA1-mediated cholesterol efflux,^1-2 was associated with only a 28% reduction in HDL levels in this cohort.¹ Complete loss-of-function mutations in ABCA1 tend to be associated with a 50% reduction in HDL levels, corresponding to a complete loss of function of one ABCA1 allele.³

The mild nature of . . . [Full Text of this Article]

Liam R. Brunham, MD, PhD
Centre for Molecular Medicine and Therapeutics
Department of Medical Genetics and Department of Medicine
University of British Columbia
Vancouver, British Columbia, Canada

John J. P. Kastelein, MD, PhD
Department of Vascular Medicine
Academic Medical Center
Amsterdam, the Netherlands

Michael R. Hayden, MD, PhD
mrh@cmmt.ubc.ca
Centre for Molecular Medicine and Therapeutics
Department of Medical Genetics and Department of Medicine
University of British Columbia

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Association of Loss-of-Function Mutations in the ABCA1 Gene With High-Density Lipoprotein Cholesterol Levels and Risk of Ischemic Heart Disease
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ABCA1 Gene Mutations, HDL Cholesterol Levels, and Risk of Ischemic Heart Disease—Reply
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