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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.
- Source :
-
JAMA [JAMA] 2008 Jun 04; Vol. 299 (21), pp. 2524-32. - Publication Year :
- 2008
-
Abstract
- Context: Low levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Whether this is a causal effect is unclear.<br />Objective: To determine whether genetically reduced HDL cholesterol due to heterozygosity for 4 loss-of-function mutations in ABCA1 cause increased risk of ischemic heart disease (IHD).<br />Design, Setting, and Participants: Three studies of white individuals from Copenhagen, Denmark, were used: the Copenhagen City Heart Study (CCHS), a 31-year prospective general population study (n = 9022; 28 heterozygotes); the Copenhagen General Population Study (CGPS), a cross-sectional general population study (n = 31,241; 76 heterozygotes); and the Copenhagen Ischemic Heart Disease Study (CIHDS), a case-control study (n = 16,623; 44 heterozygotes). End points in all 3 studies were recorded during the period of January 1, 1976, through July 9, 2007.<br />Main Outcome Measures: Levels of HDL cholesterol in the general population, cellular cholesterol efflux, and the association between IHD and HDL cholesterol and genotype.<br />Results: Heterozygotes vs noncarriers for 4 ABCA1 mutations (P1065S, G1216V, N1800H, R2144X) had HDL cholesterol levels of 41 mg/dL (interquartile range, 31-50 mg/dL) vs 58 mg/dL (interquartile range, 46-73 mg/dL), corresponding to a reduction in HDL cholesterol of 17 mg/dL (P < .001). A 17-mg/dL lower HDL cholesterol level in the CCHS was associated with a multifactorially adjusted hazard ratio for IHD of 1.70 (95% confidence interval [CI], 1.57-1.85). However, for IHD in heterozygotes vs noncarriers, the multifactorially adjusted hazard ratio was 0.67 (95% CI, 0.28-1.61; 1741 IHD events) in the CCHS, the multifactorially adjusted odds ratio was 0.82 (95% CI, 0.34-1.96; 2427 IHD events) in the CGPS, and the multifactorially adjusted odds ratio was 0.86 (95% CI, 0.32-2.32; 2498 IHD cases) in the CIHDS. The corresponding odds ratio for IHD in heterozygotes vs noncarriers for the combined studies (n = 41,961; 6666 cases; 109 heterozygotes) was 0.93 (95% CI, 0.53-1.62).<br />Conclusion: Lower plasma levels of HDL cholesterol due to heterozygosity for loss-of-function mutations in ABCA1 were not associated with an increased risk of IHD.
- Subjects :
- ATP Binding Cassette Transporter 1
Aged
Denmark
Female
Genotype
Humans
Loss of Heterozygosity
Male
Middle Aged
Myocardial Ischemia epidemiology
Risk Factors
White People genetics
ATP-Binding Cassette Transporters genetics
Cholesterol, HDL blood
Mutation
Myocardial Ischemia blood
Myocardial Ischemia genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1538-3598
- Volume :
- 299
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- JAMA
- Publication Type :
- Academic Journal
- Accession number :
- 18523221
- Full Text :
- https://doi.org/10.1001/jama.299.21.2524