Effects of genetic variants previously associated with fasting glucose and insulin in the Diabetes Prevention Program.
Common 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 fo...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3439414?pdf=render |
| _version_ | 1818586372690149376 |
|---|---|
| author | Jose C Florez Kathleen A Jablonski Jarred B McAteer Paul W Franks Clinton C Mason Kieren Mather Edward Horton Ronald Goldberg Dana Dabelea Steven E Kahn Richard F Arakaki Alan R Shuldiner William C Knowler Diabetes Prevention Program Research Group |
| author_facet | Jose C Florez Kathleen A Jablonski Jarred B McAteer Paul W Franks Clinton C Mason Kieren Mather Edward Horton Ronald Goldberg Dana Dabelea Steven E Kahn Richard F Arakaki Alan R Shuldiner William C Knowler Diabetes Prevention Program Research Group |
| author_sort | Jose C Florez |
| collection | DOAJ |
| description | Common 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. |
| first_indexed | 2024-12-16T08:51:55Z |
| format | Article |
| id | doaj.art-184f6b243eb44be98ad6f7224b7b3386 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-16T08:51:55Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-184f6b243eb44be98ad6f7224b7b33862022-12-21T22:37:23ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0179e4442410.1371/journal.pone.0044424Effects of genetic variants previously associated with fasting glucose and insulin in the Diabetes Prevention Program.Jose C FlorezKathleen A JablonskiJarred B McAteerPaul W FranksClinton C MasonKieren MatherEdward HortonRonald GoldbergDana DabeleaSteven E KahnRichard F ArakakiAlan R ShuldinerWilliam C KnowlerDiabetes Prevention Program Research GroupCommon 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.http://europepmc.org/articles/PMC3439414?pdf=render |
| spellingShingle | Jose C Florez Kathleen A Jablonski Jarred B McAteer Paul W Franks Clinton C Mason Kieren Mather Edward Horton Ronald Goldberg Dana Dabelea Steven E Kahn Richard F Arakaki Alan R Shuldiner William C Knowler Diabetes Prevention Program Research Group Effects of genetic variants previously associated with fasting glucose and insulin in the Diabetes Prevention Program. PLoS ONE |
| title | Effects of genetic variants previously associated with fasting glucose and insulin in the Diabetes Prevention Program. |
| title_full | Effects of genetic variants previously associated with fasting glucose and insulin in the Diabetes Prevention Program. |
| title_fullStr | Effects of genetic variants previously associated with fasting glucose and insulin in the Diabetes Prevention Program. |
| title_full_unstemmed | Effects of genetic variants previously associated with fasting glucose and insulin in the Diabetes Prevention Program. |
| title_short | Effects of genetic variants previously associated with fasting glucose and insulin in the Diabetes Prevention Program. |
| title_sort | effects of genetic variants previously associated with fasting glucose and insulin in the diabetes prevention program |
| url | http://europepmc.org/articles/PMC3439414?pdf=render |
| work_keys_str_mv | AT josecflorez effectsofgeneticvariantspreviouslyassociatedwithfastingglucoseandinsulininthediabetespreventionprogram AT kathleenajablonski effectsofgeneticvariantspreviouslyassociatedwithfastingglucoseandinsulininthediabetespreventionprogram AT jarredbmcateer effectsofgeneticvariantspreviouslyassociatedwithfastingglucoseandinsulininthediabetespreventionprogram AT paulwfranks effectsofgeneticvariantspreviouslyassociatedwithfastingglucoseandinsulininthediabetespreventionprogram AT clintoncmason effectsofgeneticvariantspreviouslyassociatedwithfastingglucoseandinsulininthediabetespreventionprogram AT kierenmather effectsofgeneticvariantspreviouslyassociatedwithfastingglucoseandinsulininthediabetespreventionprogram AT edwardhorton effectsofgeneticvariantspreviouslyassociatedwithfastingglucoseandinsulininthediabetespreventionprogram AT ronaldgoldberg effectsofgeneticvariantspreviouslyassociatedwithfastingglucoseandinsulininthediabetespreventionprogram AT danadabelea effectsofgeneticvariantspreviouslyassociatedwithfastingglucoseandinsulininthediabetespreventionprogram AT stevenekahn effectsofgeneticvariantspreviouslyassociatedwithfastingglucoseandinsulininthediabetespreventionprogram AT richardfarakaki effectsofgeneticvariantspreviouslyassociatedwithfastingglucoseandinsulininthediabetespreventionprogram AT alanrshuldiner effectsofgeneticvariantspreviouslyassociatedwithfastingglucoseandinsulininthediabetespreventionprogram AT williamcknowler effectsofgeneticvariantspreviouslyassociatedwithfastingglucoseandinsulininthediabetespreventionprogram AT diabetespreventionprogramresearchgroup effectsofgeneticvariantspreviouslyassociatedwithfastingglucoseandinsulininthediabetespreventionprogram |