Cardiovascular Disease Risk Prediction With and Without Knowledge of Genetic Variation at Chromosome 9p21.3

  1. Nina P. Paynter, PhD;
  2. Daniel I. Chasman, PhD;
  3. Julie E. Buring, ScD;
  4. Dov Shiffman, PhD;
  5. Nancy R. Cook, ScD; and
  6. Paul M. Ridker, MD, MPH
  1. From Brigham and Women's Hospital, Boston, Massachusetts, and Celera, Alameda, California.

    Abstract

    Background: Although genetic variation at chromosome 9p21.3 is associated with incident cardiovascular disease, it is unclear whether screening for this polymorphism improves risk prediction.

    Objective: To determine whether knowledge of variation at chromosome 9p21.3 provides predictive information beyond that from other readily available risk factors.

    Design: Prospective cohort study.

    Setting: United States.

    Patients: 22 129 female white health professionals participating in the Women's Genome Health Study, initially without any major chronic disease, who were prospectively followed over a median of 10.2 years for incident cardiovascular disease.

    Measurements: Polymorphism at rs10757274 in chromosome 9p21.3 and additional cardiovascular disease risk factors (blood pressure, smoking status, diabetes, blood levels of cholesterol, high-sensitivity C-reactive protein, and family history of premature myocardial infarction).

    Results: Polymorphism at rs10757274 was associated with an adjusted hazard ratio for incident cardiovascular disease of 1.25 (95% CI, 1.04 to 1.51) for the AG genotype and 1.32 (CI, 1.07 to 1.63) for the GG genotype. However, the addition of the genotype to a prediction model based on traditional risk factors, high-sensitivity C-reactive protein, and family history of premature myocardial infarction had no effect on model discrimination as measured by the c-index (0.807 to 0.809) and did not improve the Net Reclassification Improvement score (−0.2%; P = 0.59) or the Integrated Discrimination Improvement score (0.0; P = 0.18).

    Limitation: Study participants were all white women.

    Conclusion: In this large prospective cohort of white women, genetic variation in chromosome 9p21.3 was associated with incident cardiovascular disease but did not improve on the discrimination or classification of predicted risk achieved with traditional risk factors, high-sensitivity C-reactive protein, and family history of premature myocardial infarction.

    Funding: National Heart, Lung, and Blood Institute and National Cancer Institute; Donald W. Reynolds Foundation; Leducq Foundation; Celera; Roche Diagnostics; and Amgen.

    Article and Author Information

    • Grant Support: The WHS and the WGHS are supported by grants HL 043851 and HL 080467 from the National Heart, Lung, and Blood Institute and grant CA 047988 from the National Cancer Institute; the Donald W. Reynolds Foundation; and the Leducq Foundation. Additional support for DNA extraction, reagents, and data analysis was provided by Roche Diagnostics and Amgen. Celera performed the genotyping of the 9p21.3 variant.

    • Potential Financial Conflicts of Interest: Employment: D. Shiffman (Celera Diagnostics). Stock ownership or options (other than mutual funds): D. Shiffman (Celera Diagnostics). Grants received: J.E. Buring (National Heart, Lung, and Blood Institute, National Cancer Institute, Donald W. Reynolds Foundation, Leducq Foundation, Roche Diagnostics, Amgen), P.M. Ridker (National Heart, Lung, and Blood Institute, National Cancer Institute, Donald W. Reynolds Foundation, Leducq Foundation, Roche Diagnostics, Amgen).

    • Reproducible Research Statement: Study protocol and statistical code: Available from Dr. Paynter (e-mail, npaynter{at}partners.org). Data set: Not available.

    • Requests for Single Reprints: Nina P. Paynter, PhD, Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue East, Boston, MA 02215; e-mail, npaynter{at}partners.org.

    • Current Author Addresses: Drs. Paynter, Chasman, Buring, Cook, and Ridker: Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue East, Boston, MA 02215.

    • Dr. Shiffman: Celera, 1401 Harbor Bay Parkway, Alameda, CA 94502.

    • Author Contributions: Conception and design: N.P. Paynter, D.I. Chasman, J.E. Buring, P.M. Ridker.

    • Analysis and interpretation of the data: N.P. Paynter, D.I. Chasman, J.E. Buring, N.R. Cook, P.M. Ridker.

    • Drafting of the article: N.P. Paynter, D.I. Chasman.

    • Critical revision of the article for important intellectual content: N.P. Paynter, J.E. Buring, N.R. Cook, P.M. Ridker.

    • Final approval of the article: N.P. Paynter, J.E. Buring, N.R. Cook, P.M. Ridker.

    • Provision of study materials or patients: P.M. Ridker.

    • Statistical expertise: N.P. Paynter, N.R. Cook.

    • Obtaining of funding: J.E. Buring, P.M. Ridker.

    • Collection and assembly of data: D. Shiffman, P.M. Ridker.

    Responses to this article

    • In Response:
      • Nina P. Paynter and
      • Nancy R. Cook, ScD, and Paul M Ridker, MD, MPH
      Ann Intern Med published online October 26, 2009
    • Paynter study does indeed support use of 9p21 for cardiovascular risk
      • Jeff Gulcher and
      • Kari Stefansson, MD PhD deCODE Genetics
      Ann Intern Med published online October 26, 2009
    • Comments on: Cardiovascular Disease Risk Prediction...
      • Lukasz Kiljanek
      Ann Intern Med published online October 26, 2009
    • Screening
      • John R. Schwarzenbach
      Ann Intern Med published online October 26, 2009

    Summary for Patients

    • Summaries for Patients:Does Measuring Genetic Variations at Chromosome 9p21.3 Help to Predict Cardiovascular Disease in Women? Ann Intern Med January 20, 2009 150:I-36; doi:10.1059/0003-4819-150-2-200901200-00001
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