Absence of ABCA1 mutations in individuals with low serum HDL-cholesterol.
Over the last quarter century, a decreased concentration of serum HDL-cholesterol (HDL-C) has emerged as one of the major risk factors for coronary artery disease (1, 2). The antiatherogenic role of HDL-C has been proposed to be a result of its role in reverse cholesterol transport-removal of excess cholesterol from peripheral tissues to the liver for reuse or excretion as bile acids (3). An important discovery was made recently with regard to the first step in reverse cholesterol transport: the efflux of the intracellular cholesterol and its subsequent uptake by nascent HDL particles is now thought to be catalyzed by an enzyme that is a member of the ATP-binding cassette transporter (ABC) family, known as the ABCA1 enzyme. Deleterious mutations, when present in both alleles in the ABCA1 gene, have been found to be the cause of Tangier disease (TD), which is characterized by an almost complete absence of serum HDL-C (<70 mg/L) (4-6). The carrier state of deleterious mutations in the ABCA1 gene has also been found to be the cause of familial hypoalphalipoproteinemia (FHA), which is characterized by low serum HDL-C (150-350 mg/L) (7).
Many different mutations have been identified in the ABCA1 gene in both TD and FHA patients (4-9). However, the prevalence of these mutations in a general population with low HDL-C remains unknown. We chose seven mutations, two associated with TD (T4369C and A1730G) and five associated with FHA (de12017-2019, C6370T, C2665T, T3212C, and de15618-5623), and screened 257 individuals with serum HDL-C [less than or equal to]300 mg/L [mean (SD), 258 (39) mg/L] and serum triglycerides [less than or equal to]2500 mg/L [1570 (470) mg/L] for these mutations. Of the 257 individuals, 209 were patients with premature coronary artery disease (documented by angiographically confirmed atherosclerosis and/or one or more episodes of myocardial infarction or coronary artery bypass surgery before age of 55 years), including 193 males ranging in age from 19 to 69 years [mean (SD) age, 49.7 (5.7) years], and 16 females ranging in age from 25 to 59 years [47.5 (8.2) years]. The remaining 48 individuals were patients undergoing diagnostic evaluation for cardiovascular disease; of these, 40 were males ranging in age from 19 to 69 years [48.7 (12.2) years], and 8 were females ranging in age from 17 to 59 years [40.5 (14.3) years]. The patients represented individuals seen over a period of 4 years at the Minneapolis Heart Institute and were of mixed ancestry common to the upper Midwestern region of the US, belonging to no particular ethnic group. This study was approved by the Institutional Review Board: Human Subjects Committee of the University of Minnesota, and all participants gave informed consent. Mutations were detected as described previously (4, 7).
None of the seven mutant alleles were found in our population of 257 individuals with low HDL-C (Table 1). To our knowledge, no previous study has reported the prevalence of ABCA1 gene mutations in a population with low HDL-C. Our results may be interpreted to mean that mutations in the ABCA1 gene, which have been found in patients with TD and FHA, are not present to a high degree in the general population with low HDL-C. This has also been suggested previously by Clee and coworkers (10, 11). A weakness of the current study is in limiting the screening to only 7 of the initially described mutations, whereas >30 mutations have now been reported in the ABCA1 gene (4-9). However, the interpretation of our results is indirectly supported by other studies. For example, many segregation studies have been done and failed to detect major gene loci influencing variation of HDL-C in either Caucasian or non-Caucasian populations (12-14). Furthermore, published reports of genome-wide anonymous marker scans have not shown significant linkage of HDL-C to the chromosome region (9822-31) where the ABCA1 gene has been mapped (1517). Because TD is quite rare, we speculate that there are relatively few heterozygous carriers in the general population (1:400 to 1:600) and that they therefore account for only a few of the large number of individuals with low HDL-C. We speculate that genetic influence on HDL-C may result from the combined influence of polymorphisms and rare mutations present in the ABCA1 gene as well as a large number of other genes coding for enzymes and cofactors that are involved in HDL metabolism. Genes coding for cholesteryl ester transfer protein, hepatic lipase, lipoprotein lipase, and apolipoprotein CII and CIII are only some of the examples. Further investigations involving the more deleterious mutations of the ABCA1 gene are needed to confirm our finding. In addition, given that the ABCA1 enzyme has a rapid turnover (18), it may be important to study the regulation of this turnover. These studies, along with more comprehensive studies of the common polymorphisms of the ABCA1 gene, will ultimately determine the extent to which the ABCA1 gene participates as a genetic determinant of serum HDL-C concentrations in the general population.
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Petter S. Woll
Naomi Q. Hanson
Michael Y. Tsai*
Department of Laboratory Medicine and Pathology
University of Minnesota
Minneapolis, MN 55455
* Address correspondence to this author
at: 420 Delaware St. SE, Mayo Mail
Code 609, Minneapolis, MN 55455-0392.
Fax 612-625-5622; e-mail tsaix001@tc.
Table 1. ABCA1 mutations in individuals with serum HDL-C [less than or equal to]300 mg/L and serum triglycerides [less than or equal to]2500 mg/L. Mutation Amino acid change ABCA1 A1730G Q537R ABCA1 del2017-2019 [DELTA]L633 ABCA1 C2665T R849Stop ABCA1 T3212C M1031T ABCA1 T4369C C1417R ABCA1 del5618-5623 [DELTA]E1833, D1834 ABCA1 C6370T R2084Stop Genotype, n Mutation Wild type Heterozygous Mutant ABCA1 A1730G 257 0 0 ABCA1 del2017-2019 257 0 0 ABCA1 C2665T 257 0 0 ABCA1 T3212C 257 0 0 ABCA1 T4369C 243 (a) 0 0 ABCA1 del5618-5623 211 (a) 0 0 ABCA1 C6370T 257 0 0 (a) Not all 257 individuals were screened because some individuals' DNA did not amplify after second repeat.
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|Author:||Woll, Petter S.; Hanson, Naomi Q.; Tsai, Michael Y.|
|Article Type:||Letter to the editor|
|Date:||Mar 1, 2003|
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