ABCA1 Gene Mutations, HDL Cholesterol Levels, and Risk of Ischemic Heart Disease

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 these variants is again indicated by the modest impairment in efflux, especially for the rare variants, reported as 74% to 79% of normal.¹ Such a small reduction in function is of questionable significance given the relatively large variability of this assay. In contrast, many of the pathogenic ABCA1 mutations that have been extensively characterized have less than 20% to 30% of normal efflux activity.²

These findings are also in contrast to reports from the same group on the same cohort that showed that genetic variation in ABCA1 influences IHD in the general population and, in the case of the variants K776N (in men)⁴ and R1587K,⁵ is associated with low HDL cholesterol levels. These prior studies, which also included the Copenhagen City Heart Study (CCHS) cohort, and which reached a different conclusion, are not referenced or mentioned in the current article.

ABCA1 variants are associated with a broad range of biochemical and clinical phenotypes.³ Any specific variant must be considered in relation to its impact on the function of the protein, as different variants will have different effects on HDL levels and susceptibility to atherosclerosis depending on the impact on protein function. Indeed, the rare mutations studied by Frikke-Schmidt and colleagues were associated with a 25% reduction in low-density lipoprotein (LDL) cholesterol levels,¹ which may offset the small reduction in HDL levels.