Angiotensinogen Mutations and Risk for Ischemic Heart Disease, Myocardial Infarction, and Ischemic Cerebrovascular Disease: Six Case–Control Studies from the Copenhagen City Heart Study
- Amar A. Sethi, MD;
- Anne Tybjærg-Hansen, MD, DMSc;
- Marie-Louise Moes Grønholdt, MD, PhD;
- Rolf Steffensen, MD;
- Peter Schnohr, MD; and
- Børge G. Nordestgaard, MD, DMSc
- From Herlev University Hospital, Copenhagen University Hospital, and Bispebjerg University Hospital, Copenhagen, Denmark.
Abstract
Background: The M235T and T174M angiotensinogen mutations have been linked to increased risk for ischemic heart and cerebrovascular disease.
Objective: To determine whether angiotensinogen mutations are associated with ischemic heart disease, myocardial infarction, and ischemic cerebrovascular disease.
Design: Six case–control studies from the Copenhagen City Heart Study.
Setting: Copenhagen, Denmark.
Participants: Participants in the Copenhagen City Heart Study and patients from the same hospital with ischemic heart disease (n = 866 and n = 943, respectively), myocardial infarction (n = 519 and n = 493, respectively), or ischemic cerebrovascular disease (n = 489 and n = 434, respectively) and 7975 controls without these conditions.
Measurements: Genotypes for the M235T and T174M angiotensinogen mutations were compared between controls and Copenhagen City Heart Study participants with ischemic heart disease, myocardial infarction, and cerebrovascular disease (studies 1a, 1b, and 1c) and patients from Copenhagen University Hospital with the same conditions (studies 2a, 2b, and 2c).
Results: Relative allele frequencies of 235T and 174M in the general population were 0.41 and 0.12, respectively. Genotype was not associated with increased risk for ischemic heart or ischemic cerebrovascular disease in studies of either mutation alone or combined in women or men. Among compound heterozygotes (235MT/174TM), women in case–control study 2a had decreased risk for ischemic heart disease in age-adjusted analysis; however, this decreased risk was not seen in multifactorial-adjusted or matched analyses, in men, or in case–control study 1a. Among double homozygotes (235TT/174MM), women in case–control study 2b had increased risk for myocardial infarction in matched analysis; however, this increased risk was not seen in age- or multifactorial-adjusted analyses, in men, or in case–control study 1b. Among single homozygotes (235TT/174TT), men in case–control study 2b had increased risk for myocardial infarction in multifactorial-adjusted and matched analyses. This risk was not present in age-adjusted analysis, in women, or in case–control study 1b. In addition, male single homozygotes had decreased risk for ischemic cerebrovascular disease in case–control study 2c in age- and multifactorial-adjusted analyses, but this finding was not seen in matched analysis, in women, or in case–control study 1c.
Conclusions: In six large case–control studies, the M235T and T174M angiotensinogen mutations were not consistently associated with increased (or decreased) risk for ischemic heart disease, myocardial infarction, or ischemic cerebrovascular disease. Statistically significant associations may represent chance findings rather than real phenomena.
Article and Author Information
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Grant Support: By the Danish Heart Foundation, the Danish Medical Research Council, University of Copenhagen, the European Organization for the Control of Circulatory Diseases, the Beckett Fund, Manufacturer Frands Køhler Nielsen and Wife's Grant, and King Christian the Xth Fund.
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Acknowledgment: The authors thank Marianne Lodahl for technical assistance and the participants of the Copenhagen City Heart Study for their willingness to participate.
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Requests for Single Reprints: Børge G. Nordestgaard, MD, DMSc, Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark; e-mail, brno{at}herlevhosp.kbhamt.dk.
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Current Author Addresses: Drs. Sethi and Nordestgaard: Department of Clinical Biochemistry 54M1, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
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Dr. Tybjærg-Hansen: Department of Clinical Biochemistry KB3011, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark.
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Dr. Grønholdt: Department of Vascular Surgery, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark.
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Dr. Steffensen: Department of Medicine B, Division of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø , Denmark.
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Dr. Schnohr: The Copenhagen City Heart Study, Bispebjerg University Hospital, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark.
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Author Contributions: Conception and design: A.A. Sethi, A. Tybjærg-Hansen, M.L.M. Grønholdt, R. Steffensen, P. Schnohr, B.G. Nordestgaard.
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Analysis and interpretation of the data: A.A. Sethi, A. Tybjærg-Hansen, B.G. Nordestgaard.
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Drafting of the article: A.A. Sethi.
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Critical revision of the article for important intellectual content: A. Tybjærg-Hansen, B.G. Nordestgaard.
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Final approval of the article: A.A. Sethi, A. Tybjærg-Hansen, M.L.M. Grønholdt, Rolf Steffensen, P. Schnohr, B.G. Nordestgaard.
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Provision of study materials or patients: M.L.M. Grønholdt, R. Steffensen, P. Schnohr.
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Statistical expertise: A. Tybjærg-Hansen, B.G. Nordestgaard.
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Obtaining of funding: A.A. Sethi, A. Tybjærg-Hansen, B.G. Nordestgaard.
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Collection and assembly of data: M.L.M. Grønholdt, R. Steffensen, P. Schnohr.
- Copyright ©2004 by the American College of Physicians
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