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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
[+] Article and Author Information

From Herlev University Hospital, Copenhagen University Hospital, and Bispebjerg University Hospital, Copenhagen, Denmark.


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.

Acknowledgment: The authors thank Marianne Lodahl for technical assistance and the participants of the Copenhagen City Heart Study for their willingness to participate.

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@herlevhosp.kbhamt.dk.

Current Author Addresses: Drs. Sethi and Nordestgaard: Department of Clinical Biochemistry 54M1, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.

Dr. Tybjærg-Hansen: Department of Clinical Biochemistry KB3011, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark.

Dr. Grønholdt: Department of Vascular Surgery, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark.

Dr. Steffensen: Department of Medicine B, Division of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø , Denmark.

Dr. Schnohr: The Copenhagen City Heart Study, Bispebjerg University Hospital, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark.

Author Contributions: Conception and design: A.A. Sethi, A. Tybjærg-Hansen, M.L.M. Grønholdt, R. Steffensen, P. Schnohr, B.G. Nordestgaard.

Analysis and interpretation of the data: A.A. Sethi, A. Tybjærg-Hansen, B.G. Nordestgaard.

Drafting of the article: A.A. Sethi.

Critical revision of the article for important intellectual content: A. Tybjærg-Hansen, B.G. Nordestgaard.

Final approval of the article: A.A. Sethi, A. Tybjærg-Hansen, M.L.M. Grønholdt, Rolf Steffensen, P. Schnohr, B.G. Nordestgaard.

Provision of study materials or patients: M.L.M. Grønholdt, R. Steffensen, P. Schnohr.

Statistical expertise: A. Tybjærg-Hansen, B.G. Nordestgaard.

Obtaining of funding: A.A. Sethi, A. Tybjærg-Hansen, B.G. Nordestgaard.

Collection and assembly of data: M.L.M. Grønholdt, R. Steffensen, P. Schnohr.


Ann Intern Med. 2001;134(10):941-954. doi:10.7326/0003-4819-134-10-200105150-00008
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Angiotensinogen is a key protein in the renin–angiotensin system, which influences vascular tone, renal sodium reabsorption, and blood pressure (1). Huge scientific interest was generated when one of two amino acid–changing mutations in the angiotensinogen gene, M235T but not T174M, was found to be associated with elevated plasma angiotensinogen levels (2), elevated blood pressure (2), ischemic heart disease (3), and ischemic cerebrovascular disease (4). The M235T mutation changes a nonpolar amino acid to a polar amino acid and thus potentially changes the tertiary structure of the protein. Because of this, it is likely that such a mutation may also influence protein function.

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Figure 1.
Study design.

First, Copenhagen City Heart Study controls were compared with patients who had ischemic heart disease, myocardial infarction, or ischemic cerebrovascular disease (case–control studies 2a, 2b, and 2c), ascertained through hospital referrals to the same hospital where the Copenhagen City Heart Study was performed. Second, persons in the Copenhagen City Heart Study who had ischemic heart disease, myocardial infarction, or ischemic cerebrovascular disease (case–control studies 1a, 1b, and 1c) were compared with Copenhagen City Heart Study controls.

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Figure 2.
Risk for ischemic heart disease in women and men according to angiotensinogen genotype.

Odds ratios and 95% CIs were calculated as a function of M235T, T174M, and M235T/T174M genotypes by using logistic regression analysis in three ways: 1) adjusted for age; 2) adjusted for age, body mass index, diabetes mellitus, smoking, hypertension, total cholesterol level, high-density lipoprotein cholesterol level, triglyceride level, apolipoprotein A-I level, lipoprotein[a] level, and, in women, menopausal status and hormone replacement therapy; and 3) matched for age, smoking, hypertension, and cholesterol levels. Double slashes indicate a break in the odds ratio axis. *The number of persons in each genotype subgroup are from the age-adjusted analysis; these numbers were lower in the multifactorial-adjusted and matched analyses.

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Figure 3.
Risk for myocardial infarction in women and men according to angiotensinogen genotype.

Odds ratios and 95% CIs were calculated as a function of M235T, T174M, and M235T/T174M genotypes by using logistic regression analysis in three ways: 1) adjusted for age; 2) adjusted for age, body mass index, diabetes mellitus, smoking, hypertension, total cholesterol level, high-density lipoprotein cholesterol level, triglyceride level, apolipoprotein A-I level, lipoprotein[a] level, and, in women, menopausal status and hormone replacement therapy; and 3) matched for age, smoking, hypertension, and cholesterol levels. Double slashes indicate a break in the odds ratio axis. *Numbers of persons in each genotype subgroup are from the age-adjusted analysis; these numbers were lower in multifactorial-adjusted and matched analyses.

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Figure 4.
Risk for ischemic cerebrovascular disease in women and men according to angiotensinogen genotype.

Odds ratios and 95% CIs were calculated as a function of M235T, T174M, and M235T/T174M genotypes by using logistic regression analysis in three ways: 1) adjusted for age; 2) adjusted for age, body mass index, diabetes mellitus, smoking, hypertension, total cholesterol level, high-density lipoprotein cholesterol level, triglyceride level, and, in women, menopausal status; and 3) matched for age, smoking, hypertension, and cholesterol levels. Double slashes indicate a break in the odds ratio axis. *Numbers of persons in each genotype subgroup are from the age-adjusted analysis; these numbers were lower in multifactorial-adjusted and matched analyses. †No odds ratio could be calculated because no case-patients were included in this genotype subgroup.

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Figure 5.
Relative genotype frequencies of M235T, T174M, and M235T/T174M in three and four age groups of case-patients and controls, respectively.IHDICVDPPP

To increase statistical power, case-patients with ischemic heart disease ( ) from case–control studies 2a and 1a were combined, as were case-patients with ischemic cerebrovascular disease ( ) from case–control studies 2c and 1c. Chi-square tests were used to examine whether genotype frequencies changed as a function of age.  > 0.2 for all comparisons except where indicated by an asterisk. *  = 0.04 (female controls);  = 0.2 (men with ICVD).

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Summary for Patients

Mutations of the Angiotensinogen Gene and the Risk for Heart Disease and Stroke

The summary below is from the full report titled “Angiotensinogen Mutations and Risk for Ischemic Heart Disease, Myocardial Infarction, and Ischemic Cerebrovascular Disease. Six Case–Control Studies from the Copenhagen City Heart Study.” It is in the 15 May 2001 issue of Annals of Internal Medicine (volume 134, pages 941-954). The authors are AA Sethi, A Tybjærg-Hansen, MLM Grønholdt, R Steffensen, P Schnohr, and BG Nordestgaard.

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