Joint effects of common genetic variants on the risk for type 2 diabetes in U.S. men and women of European ancestry.
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.


METHODS
Nested case-control study.


METHODS
United States.


METHODS
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.


METHODS
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).


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


CONCLUSIONS
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.


BACKGROUND
National Institutes of Health.
Cornelis
Marilyn C
MC
Harvard School of Public Health, Channing Laboratory, Boston, MA 02115, USA.
Qi
Lu
L
Zhang
Cuilin
C
Kraft
Peter
P
Manson
JoAnn
J
Cai
Tianxi
T
Hunter
David J
DJ
Hu
Frank B
FB
D000368:Aged; D015992:Body Mass Index; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012372:ROC Curve; D012307:Risk Factors; D014481:United States; D044465:White People / Q000235:genetics*