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. 2009 Apr 21;150(8):541-50.
doi: 10.7326/0003-4819-150-8-200904210-00008.

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  1 , Lu Qi, Cuilin Zhang, Peter Kraft, JoAnn Manson, Tianxi Cai, David J Hunter, Frank B Hu
Affiliations

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 et al. Ann Intern Med. .

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/m(2) 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/m(2) 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.

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Figures

Figure 1
Figure 1. Association of reported loci and risk for type 2 diabetes in pooled analysis of men and women
Odds ratios (95% CIs) are adjusted for age (quintiles), sex, and body mass index (quintiles). SNP = single nucleotide polymorphism.
Figure 2
Figure 2. Genetic risk score and risk for type 2 diabetes
Results are based on the count genetic risk score for pooled data from men and women. Adjusted for age (quintiles), sex, and body mass index (quintiles).
Figure 3
Figure 3. Joint effects of conventional risk factors and genetic risk score on risk for type 2 diabetes
Values on bars indicate sample size. Top. Joint effects of body mass index and count genetic risk score (adjusted for age and sex) for pooled data from men and women. Bottom. Joint effects of family history of diabetes and count genetic risk score (adjusted for age, sex, and body mass index) for pooled data from men and women.
Figure 4
Figure 4. Receiver-operating characteristic curves for type 2 diabetes
The curves are based on logistic regression models incorporating conventional risk factors (age, sex, body mass index, family history of diabetes, smoking, alcohol intake, and physical activity) with and without the count GRS. AUC = area under the curve; GRS = genetic risk score.
See this image and copyright information in PMC

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