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, Lu Qi, Cuilin Zhang, Peter Kraft, Jo Ann Manson, Tianxi Cai, David J. Hunter, Frank B. Hu

Research output: Contribution to journalArticle

184 Scopus citations

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% Cl, 1.14 to 1.24) and 1.16 (Cl, 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 (Cl, 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 (Cl, 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.

Original languageEnglish (US)
Pages (from-to)541-550
Number of pages10
JournalAnnals of internal medicine
Volume150
Issue number8
DOIs
StatePublished - Apr 21 2009

ASJC Scopus subject areas

  • Internal Medicine

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