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

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.

SUBMITTER: Cornelis MC

PROVIDER: S-EPMC3825275 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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

Cornelis Marilyn C MC Qi Lu L Zhang Cuilin C Kraft Peter P Manson JoAnn J Cai Tianxi T Hunter David J DJ Hu Frank B FB

Annals of internal medicine 20090401 8

<h4>Background</h4>Genome-wide association studies have identified novel type 2 diabetes loci, each of which has a modest impact on risk.<h4>Objective</h4>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.<h4>Design</h4>Nested case-control study.<h4>Setting</h4>United States.<h4>Participants</h4>2809 patients with type 2 diabetes and 3501 healthy control participants of Europ ...[more]

PMID: 19380854

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Project description:ContextA genome-wide association study has identified three loci (five independent signals) that confer risk for polycystic ovary syndrome (PCOS) in Han Chinese women. Replication is necessary to determine whether the same variants confer risk for PCOS in women of European ancestry.ObjectiveThe objective of the study was to test whether these PCOS risk variants in Han Chinese women confer risk for PCOS in women of European ancestry.DesignThis was a case-control study.SettingThe study was conducted at deCODE Genetics in Iceland and two academic medical centers in the United States.PatientsCases were 376 Icelandic women and 565 and 203 women from Boston, MA, and Chicago, IL, respectively, all diagnosed with PCOS by the National Institutes of Health criteria. Controls were 16,947, 483, and 189 women not known to have PCOS from Iceland, Boston, and Chicago, respectively.InterventionThere were no interventions.Main outcomesMain outcomes were allele frequencies for seven variants in PCOS cases and controls.ResultsTwo strongly correlated Han Chinese PCOS risk variants on chromosome 9q33.3, rs10986105[C], and rs10818854[A], were replicated in samples of European ancestry with odds ratio of 1.68 (P = 0.00033) and odds ratio of 1.53 (P = 0.0019), respectively. Other risk variants at 2p16.3 (rs13405728), 2p21 (rs12468394, rs12478601, and rs13429458), and 9q33.3 (rs2479106), or variants correlated with them, did not associate with PCOS. The same allele of rs10986105 that increased the risk of PCOS also increased the risk of hyperandrogenism in women without PCOS from Iceland and demonstrated a stronger risk for PCOS defined by the National Institutes of Health criteria than the Rotterdam criteria.ConclusionsWe replicated one of the five Chinese PCOS association signals, represented by rs10986105 and rs10818854 on 9q33, in individuals of European ancestry. Examination of the subjects meeting at least one of the Rotterdam criteria for PCOS suggests that the variant may be involved in the hyperandrogenism and possibly the irregular menses of PCOS.

Dataset Information

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

Publications

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

Similar Datasets

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