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dc.contributor.authorJablonski, Kathleen A.
dc.contributor.authorMcAteer, Jarred B.
dc.contributor.authorFranks, Paul W.
dc.contributor.authorMason, Clinton C.
dc.contributor.authorMather, Kieren
dc.contributor.authorGoldberg, Ronald
dc.contributor.authorDabelea, Dana
dc.contributor.authorKahn, Steven E.
dc.contributor.authorArakaki, Richard F.
dc.contributor.authorShuldiner, Alan R.
dc.contributor.authorKnowler, William C.
dc.contributor.authorFlorez, Jose Carlos
dc.contributor.authorHorton, Edward S.
dc.date.accessioned2013-03-25T19:22:08Z
dc.date.issued2012
dc.identifier.citationFlorez, Jose C., Kathleen A. Jablonski, Jarred B. McAteer, Paul W. Franks, Clinton C. Mason, Kieren Mather, Edward Horton et al. 2012. Effects of genetic variants previously associated with fasting glucose and insulin in the Diabetes Prevention Program. PLoS ONE 7(9): e44424.en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10463938
dc.description.abstractCommon genetic variants have been recently associated with fasting glucose and insulin levels in white populations. Whether these associations replicate in pre-diabetes is not known. We extended these findings to the Diabetes Prevention Program, a clinical trial in which participants at high risk for diabetes were randomized to placebo, lifestyle modification or metformin for diabetes prevention. We genotyped previously reported polymorphisms (or their proxies) in/near G6PC2, MTNR1B, GCK, DGKB, GCKR, ADCY5, MADD, CRY2, ADRA2A, FADS1, PROX1, SLC2A2, GLIS3, C2CD4B, IGF1, and IRS1 in 3,548 Diabetes Prevention Program participants. We analyzed variants for association with baseline glycemic traits, incident diabetes and their interaction with response to metformin or lifestyle intervention. We replicated associations with fasting glucose at MTNR1B (P<0.001), G6PC2 (P = 0.002) and GCKR (P = 0.001). We noted impaired β-cell function in carriers of glucose-raising alleles at MTNR1B (P<0.001), and an increase in the insulinogenic index for the glucose-raising allele at G6PC2 (P<0.001). The association of MTNR1B with fasting glucose and impaired β-cell function persisted at 1 year despite adjustment for the baseline trait, indicating a sustained deleterious effect at this locus. We also replicated the association of MADD with fasting proinsulin levels (P<0.001). We detected no significant impact of these variants on diabetes incidence or interaction with preventive interventions. The association of several polymorphisms with quantitative glycemic traits is replicated in a cohort of high-risk persons. These variants do not have a detectable impact on diabetes incidence or response to metformin or lifestyle modification in the Diabetes Prevention Program.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pone.0044424en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439414/pdf/en_US
dash.licenseLAA
dc.subjectBiologyen_US
dc.subjectAnatomy and Physiologyen_US
dc.subjectEndocrine Systemen_US
dc.subjectEndocrine Physiologyen_US
dc.subjectInsulinen_US
dc.subjectGeneticsen_US
dc.subjectHuman Geneticsen_US
dc.subjectGenetic Association Studiesen_US
dc.subjectPopulation Geneticsen_US
dc.subjectGenetic Polymorphismen_US
dc.subjectMedicineen_US
dc.subjectClinical Research Designen_US
dc.subjectClinical Trialsen_US
dc.subjectEndocrinologyen_US
dc.subjectDiabetic Endocrinologyen_US
dc.subjectDiabetes Mellitus Type 2en_US
dc.titleEffects of Genetic Variants Previously Associated with Fasting Glucose and Insulin in the Diabetes Prevention Programen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS ONEen_US
dash.depositing.authorFlorez, Jose Carlos
dc.date.available2013-03-25T19:22:08Z
dc.identifier.doi10.1371/journal.pone.0044424*
dash.authorsorderedfalse
dash.contributor.affiliatedHorton, Edward
dash.contributor.affiliatedFlorez, Jose


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