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Effects of Genetic Variants Previously Associated with Fasting Glucose and Insulin in the Diabetes Prevention Program

Florez, Jose C.; Jablonski, Kathleen A.; McAteer, Jarred B.; Franks, Paul LU ; Mason, Clinton C.; Mather, Kieren; Horton, Edward; Goldberg, Ronald; Dabelea, Dana and Kahn, Steven E., et al. (2012) In PLoS ONE 7(9).
Abstract
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... (More)
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 beta-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 beta-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. (Less)
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PLoS ONE
volume
7
issue
9
publisher
Public Library of Science
external identifiers
  • wos:000308638700060
  • scopus:84866289864
ISSN
1932-6203
DOI
10.1371/journal.pone.0044424
language
English
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yes
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10130a5f-7340-44ef-9bc2-df73fa34ebe9 (old id 3191181)
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2012-12-03 07:11:06
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2017-07-30 04:02:30
@article{10130a5f-7340-44ef-9bc2-df73fa34ebe9,
  abstract     = {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&lt;0.001), G6PC2 (P=0.002) and GCKR (P=0.001). We noted impaired beta-cell function in carriers of glucose-raising alleles at MTNR1B (P&lt;0.001), and an increase in the insulinogenic index for the glucose-raising allele at G6PC2 (P&lt;0.001). The association of MTNR1B with fasting glucose and impaired beta-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&lt;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.},
  author       = {Florez, Jose C. and Jablonski, Kathleen A. and McAteer, Jarred B. and Franks, Paul and Mason, Clinton C. and Mather, Kieren and Horton, Edward and Goldberg, Ronald and Dabelea, Dana and Kahn, Steven E. and Arakaki, Richard F. and Shuldiner, Alan R. and Knowler, William C.},
  issn         = {1932-6203},
  language     = {eng},
  number       = {9},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Effects of Genetic Variants Previously Associated with Fasting Glucose and Insulin in the Diabetes Prevention Program},
  url          = {http://dx.doi.org/10.1371/journal.pone.0044424},
  volume       = {7},
  year         = {2012},
}