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Pentanucleotide Repeat Polymorphism, Lipoprotein(a) Levels, and Risk of Ischemic Heart Disease

Department of Clinical Biochemistry (P.R.K., B.G.N.), Herlev Hospital, Copenhagen University Hospital, DK-2730 Copenhagen, Denmark; Department of Clinical Biochemistry (A.T.-H.), Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark; The Copenhagen City Heart Study (B.G.N., A.T.-H.), Bispebjerg Hospital, Copenhagen University Hospital, DK-2400 Copenhagen, Denmark; and Department of Internal Medicine (R.S.), Nordsjællands Hospital-Hillerød, Faculty of Health Sciences, University of Copenhagen, Copenhagen, DK-2200 Denmark

Address all correspondence and requests for reprints to: Børge G. Nordestgaard, M.D., D.MSc., Professor and Chief Physician, Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. E-mail: brno{at}heh.regionh.dk.

Context: Lipoprotein(a) is a cardiovascular risk factor. Levels of lipoprotein(a) are predominantly determined by apolipoprotein(a) gene variation, including a pentanucleotide repeat promoter polymorphism.

Objective: We tested the hypothesis that apolipoprotein(a) pentanucleotide repeat genotype predicts elevated lipoprotein(a) levels and risk of myocardial infarction (MI) and ischemic heart disease (IHD) in the general population.

Design: We used a cohort study of the Danish general population, The Copenhagen City Heart Study, including 10,276 individuals of which 860 and 1,781 developed MI and IHD, respectively, during up to 31 yr of follow-up, and a case-control study including 1,814 IHD patients and 5,076 controls. Follow-up was 100% complete.

Results: Allele frequencies were 0.0018, 0.0018, 0.6750, 0.1596, 0.1465, 0.0146, and 0.0004 for 6, 7, 8, 9, 10, 11, and 12 repeats, respectively. Mean lipoprotein(a) levels were 40, 36, and 27 mg/dl for individuals with 14–15, 16, and 17–22 repeats (sum of repeats on both alleles), respectively (trend, P < 0.001). Cumulative incidence of MI and IHD was increased for individuals with 14–15 vs. at least 16 repeats (log rank, P < 0.001 and P = 0.002). Multifactorially adjusted hazard ratios for 14–15 and 17–22 vs. 16 repeats were 3.1 (95% confidence interval, 1.6–5.8) and 1.0 (0.9–1.2) for MI and 2.2 (1.3–3.6) and 1.0 (0.9–1.1) for IHD. In the case-control study, multifactorially adjusted odds ratios for 14–15 and 17–22 vs. 16 repeats were 2.9 (1.1–7.8) and 0.9 (0.8–1.0) for MI and 2.5 (1.0–6.0) and 0.9 (0.8–1.0) for IHD.

Conclusions: Apolipoprotein(a) 14–15 pentanucleotide repeats predict elevated levels of lipoprotein(a) and a 3- and 2-fold increased risk of MI and IHD in the general population.