Joint Effects of Common Genetic Variants on the Risk for Type 2 Diabetes in U.S. Men and Women of European Ancestry

doi:10.1059/0003-4819-150-8-200904210-00008

Joint Effects of Common Genetic Variants on the Risk for Type 2 Diabetes in U.S. Men and Women of European Ancestry

Marilyn C. Cornelis, PhD;
Lu Qi, MD, PhD;
Cuilin Zhang, MD, PhD;
Peter Kraft, PhD;
JoAnn Manson, MD, DPH;
Tianxi Cai, PhD;
David J. Hunter, MBBS, ScD; and
Frank B. Hu, MD, PhD

From Harvard School of Public Health, Channing Laboratory, and Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, Maryland.

Abstract

Background: Genome-wide association studies have identified novel type 2 diabetes loci, each of which has a modest impact on risk.

Objective: To examine the joint effects of several type 2 diabetes risk variants and their combination with conventional risk factors on type 2 diabetes risk in 2 prospective cohorts.

Design: Nested case–control study.

Setting: United States.

Participants: 2809 patients with type 2 diabetes and 3501 healthy control participants of European ancestry from the Health Professionals Follow-up Study and Nurses' Health Study.

Measurements: A genetic risk score (GRS) was calculated on the basis of 10 polymorphisms in 9 loci.

Results: After adjustment for age and body mass index (BMI), the odds ratio for type 2 diabetes with each point of GRS, corresponding to 1 risk allele, was 1.19 (95% CI, 1.14 to 1.24) and 1.16 (CI, 1.12 to 1.20) for men and women, respectively. Persons with a BMI of 30 kg/m² or greater and a GRS in the highest quintile had an odds ratio of 14.06 (CI, 8.90 to 22.18) compared with persons with a BMI less than 25 kg/m² and a GRS in the lowest quintile after adjustment for age and sex. Persons with a positive family history of diabetes and a GRS in the highest quintile had an odds ratio of 9.20 (CI, 5.50 to 15.40) compared with persons without a family history of diabetes and with a GRS in the lowest quintile. The addition of the GRS to a model of conventional risk factors improved discrimination by 1% (P < 0.001).

Limitation: The study focused only on persons of European ancestry; whether GRS is associated with type 2 diabetes in other ethnic groups remains unknown.

Conclusion: Although its discriminatory value is currently limited, a GRS that combines information from multiple genetic variants might be useful for identifying subgroups with a particularly high risk for type 2 diabetes.

Primary Funding Source: National Institutes of Health.

Article and Author Information

Acknowledgment: The authors thank Patrice Soule and Dr. Hardeep Ranu of the Dana Farber/Harvard Cancer Center Genotyping Core for sample preparation and genotyping and the participants in the NHS and HPFS for their dedication and commitment.
Grant Support: By the National Institutes of Health (grants DK58845 and CA87969). Dr. Cornelis is a recipient of a Canadian Institutes of Health Research Fellowship. Dr. Qi is a recipient of the American Heart Association Scientist Development Award. Dr. Zhang is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Potential Financial Conflicts of Interest: None disclosed.
Reproducible Research Statement: Study protocol and data set: Not available. Statistical code: Available from Dr. Cornelis (e-mail, mcorneli{at}hsph.harvard.edu).
Requests for Single Reprints: Frank B. Hu, MD, PhD, Department of Nutrition, Harvard School of Public Health, Building II, 665 Huntington Avenue, Boston, MA 02115; e-mail, frank.hu{at}channing.harvard.edu.
Current Author Addresses: Drs. Cornelis, Qi, Kraft, Cai, Hunter, and Hu: Harvard School of Public Health, Building II, 665 Huntington Avenue, Boston, MA 02115.
Dr. Zhang: Division of Epidemiology, Statistics, and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
Dr. Manson: 900 Commonwealth Avenue East, Boston, MA 02215.
Author Contributions: Conception and design: L. Qi, F.B. Hu.
Analysis and interpretation of the data: M.C. Cornelis, L. Qi, C. Zhang, P. Kraft, D.J. Hunter, F.B. Hu.
Drafting of the article: M.C. Cornelis, L. Qi.
Critical revision of the article for important intellectual content: M.C. Cornelis, L. Qi, C. Zhang, P. Kraft, J. Manson, D.J. Hunter, F.B. Hu.
Final approval of the article: L. Qi, C. Zhang, P. Kraft, J. Manson, D.J. Hunter, F.B. Hu.
Provision of study materials or patients: F.B. Hu.
Statistical expertise: M.C. Cornelis, L. Qi, P. Kraft, D.J. Hunter.
Obtaining of funding: L. Qi, F.B. Hu.
Administrative, technical, or logistic support: J. Manson, F.B. Hu.
Collection and assembly of data: L. Qi, J. Manson, F.B. Hu.