CLINICAL RESEARCH: CORONARY ARTERY DISEASE
Mutation in ABCA1 Predicted Risk of Ischemic Heart Disease in the Copenhagen City Heart Study Population
Ruth Frikke-Schmidt, MD, PhD*,
Børge G. Nordestgaard, MD, DMSc , ,
Peter Schnohr, MD,
Rolf Steffensen, MD and
Anne Tybjærg-Hansen, MD, DMSc,*
* Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Department of Clinical Biochemistry, Herlev University Hospital, Herlev, Denmark
The Copenhagen City Heart Study, Bispebjerg University Hospital, Bispebjerg, Denmark
Department of Medicine B, Hillerød Hospital, Hillerød, Denmark
Manuscript received January 27, 2005;
revised manuscript received June 16, 2005,
accepted June 20, 2005.
* Reprint requests and correspondence: Dr. Anne Tybjaerg-Hansen, Department of Clinical Biochemistry KB 3011, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. (Email: at-h{at}rh.dk).
OBJECTIVES: We tested whether heterozygosity for the K776N mutation (frequency: 0.4%) in ATP-binding cassette transporter A1 (ABCA1) predicted ischemic heart disease (IHD) in the Copenhagen City Heart Study population.
BACKGROUND: In a complex trait like IHD, genetic variation is considered to be conferred by common DNA polymorphisms, although rare mutations may have a larger impact. Tangier disease, a rare high-density lipoprotein cholesterol (HDL-C) deficiency syndrome with IHD, is caused by homozygous ABCA1 mutations.
METHODS: We analyzed blood samples from a large cohort study of 9,076 Danish individuals followed for 24 years (167,287 person-years), during which 1,033 incident IHD events occurred. The hypothesis was retested in an independent case-control study comparing 562 IHD patients with 3,103 controls.
RESULTS: The cumulative incidence of IHD as a function of age was increased in K776N heterozygotes compared with non-carriers (log-rank test: p = 0.005). At the age of 80 years, 48% of heterozygotes and 23% of non-carriers had IHD. Incidence rates in non-carriers and K776N heterozygotes were 61 and 157 per 10,000 person-years. The age-adjusted hazard ratio for IHD in K776N heterozygotes versus non-carriers was 2.4 (95% confidence interval 1.3 to 4.5). Adjusting for HDL-C, or for smoking, diabetes, and hypertension did not change the result, suggesting that genotype predicted risk of IHD beyond that offered by HDL-C, and by other conventional risk factors. Similar trends were obtained in an independent case-control study.
CONCLUSIONS: Heterozygosity for an ABCA1 mutation (K776N) conferred two- to three-fold risk of IHD in 37 participants in the Copenhagen City Heart study.
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Abbreviations and Acronyms
| | apoAI = apolipoprotein AI | | CFTR = cystic fibrosis transmembrane conductance regulator | | HDL-C = high-density lipoprotein cholesterol | | IHD = ischemic heart disease |
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