 |
|
Association of Loss-of-Function Mutations in the ABCA1 Gene With High-Density Lipoprotein Cholesterol Levels and Risk of Ischemic Heart Disease
Ruth Frikke-Schmidt, MD, PhD;
Børge G. Nordestgaard, MD, DMSc;
Maria C. A. Stene, MSc, PhD;
Amar A. Sethi, MD, PhD;
Alan T. Remaley, MD, PhD;
Peter Schnohr, MD;
Peer Grande, MD, DMSc;
Anne Tybjærg-Hansen, MD, DMSc
JAMA. 2008;299(21):2524-2532.
Context Low levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Whether this is a causal effect is unclear.
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).
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.
Main Outcome Measures Levels of HDL cholesterol in the general population, cellular cholesterol efflux, and the association between IHD and HDL cholesterol and genotype.
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).
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.
Author Affiliations: Department of Clinical Biochemistry, Rigshospitalet (Drs Frikke-Schmidt, Stene, and Tybjærg-Hansen), Department of Cardiology, Rigshospitalet (Dr Grande), Department of Clinical Biochemistry, Herlev Hospital (Dr Nordestgaard), Copenhagen City Heart Study, Bispebjerg Hospital (Drs Nordestgaard, Schnohr, and Tybjærg-Hansen), Copenhagen General Population Study, Herlev Hospital (Drs Frikke-Schmidt, Nordestgaard, and Tybjærg-Hansen), Copenhagen University Hospitals, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; and Lipoprotein Metabolism Section, Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland (Drs Sethi and Remaley).
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati
What's this?
RELATED LETTERS
ABCA1 Gene Mutations, HDL Cholesterol Levels, and Risk of Ischemic Heart Disease
, , and
JAMA. ;300():1997-1998.
FULL TEXT
ABCA1 Gene Mutations, HDL Cholesterol Levels, and Risk of Ischemic Heart Disease--Reply
, , and
JAMA. ;300():1998-1998.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Genetically Elevated Lipoprotein(a) and Increased Risk of Myocardial Infarction
Kamstrup et al.
JAMA 2009;301:2331-2339.
ABSTRACT
| FULL TEXT
The year in atherothrombosis.
Sanz et al.
J Am Coll Cardiol 2009;53:1326-1337.
FULL TEXT
Elevated High-Density Lipoprotein (HDL) Levels due to Hepatic Lipase Mutations Do Not Reduce Cardiovascular Disease Risk: Another Strike against the HDL Dogma
Fazio and Linton
J. Clin. Endocrinol. Metab. 2009;94:1081-1083.
FULL TEXT
Hepatic Lipase, Genetically Elevated High-Density Lipoprotein, and Risk of Ischemic Cardiovascular Disease
Johannsen et al.
J. Clin. Endocrinol. Metab. 2009;94:1264-1273.
ABSTRACT
| FULL TEXT
Tissue-Specific Roles of ABCA1 Influence Susceptibility to Atherosclerosis
Brunham et al.
Arterioscler. Thromb. Vasc. Bio. 2009;29:548-554.
ABSTRACT
| FULL TEXT
The ABCs of sterol transport
Baldan et al.
J. Lipid Res. 2009;50:S80-S85.
ABSTRACT
| FULL TEXT
Genomics and cardiovascular drug development.
Plump and Lum
J Am Coll Cardiol 2009;53:1089-1100.
ABSTRACT
| FULL TEXT
Associations of Genetic Variants in ATP-Binding Cassette A1 and Cholesteryl Ester Transfer Protein and Differences in Lipoprotein Subclasses in the Multi-Ethnic Study of Atherosclerosis
Tsai et al.
Clin. Chem. 2009;55:481-488.
ABSTRACT
| FULL TEXT
Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis
Briel et al.
BMJ 2009;338:b92-b92.
ABSTRACT
| FULL TEXT
Nonfasting Triglycerides and Risk of Ischemic Stroke in the General Population
Freiberg et al.
JAMA 2008;300:2142-2152.
ABSTRACT
| FULL TEXT
ABCA1 Gene Mutations, HDL Cholesterol Levels, and Risk of Ischemic Heart Disease
Brunham et al.
JAMA 2008;300:1997-1998.
FULL TEXT
Genetically Elevated C-Reactive Protein and Ischemic Vascular Disease
Zacho et al.
NEJM 2008;359:1897-1908.
ABSTRACT
| FULL TEXT
ABCA1 Mutations Not Associated With Ischemic Heart Disease
Journal Watch Cardiology 2008;2008:2-2.
FULL TEXT
|
