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Variation in maturity-onset diabetes of the young genes influence response to interventions for diabetes prevention

Billings, Liana K.; Jablonski, Kathleen A; Warner, A. Sofia; Cheng, Yu Chien; McAteer, Jarred B.; Tipton, Laura; Shuldiner, Alan R.; Ehrmann, David A; Manning, Alisa K. and Dabelea, Dana, et al. (2017) In Journal of Clinical Endocrinology and Metabolism 102(8). p.2678-2689
Abstract

Context: Variation in genes that cause maturity-onset diabetes of the young (MODY) has been associated with diabetes incidence and glycemic traits. Objectives: This study aimed to determine whether genetic variation in MODY genes leads to differential responses to insulin-sensitizing interventions. Design and Setting: This was a secondary analysis of a multicenter, randomized clinical trial, the Diabetes Prevention Program (DPP), involving 27 US academic institutions. We genotyped 22 missense and 221 common variants in the MODY-causing genes in the participants in the DPP. Participants and Interventions: The study included 2806 genotyped DPP participants randomized to receive intensive lifestyle intervention (n = 935), metformin (n =... (More)

Context: Variation in genes that cause maturity-onset diabetes of the young (MODY) has been associated with diabetes incidence and glycemic traits. Objectives: This study aimed to determine whether genetic variation in MODY genes leads to differential responses to insulin-sensitizing interventions. Design and Setting: This was a secondary analysis of a multicenter, randomized clinical trial, the Diabetes Prevention Program (DPP), involving 27 US academic institutions. We genotyped 22 missense and 221 common variants in the MODY-causing genes in the participants in the DPP. Participants and Interventions: The study included 2806 genotyped DPP participants randomized to receive intensive lifestyle intervention (n = 935), metformin (n = 927), or placebo (n = 944). Main Outcome Measures: Association of MODY genetic variants with diabetes incidence at a median of 3 years and measures of 1-year β-Cell function, insulinogenic index, and oral disposition index. Analyses were stratified by treatment group for significant single-nucleotide polymorphism 3 treatment interaction (Pint, 0.05). Sequence kernel association tests examined the association between an aggregate of rare missense variants and insulinogenic traits. Results: After 1 year, the minor allele of rs3212185 (HNF4A) was associated with improved β-Cell function in the metformin and lifestyle groups but not the placebo group; the minor allele of rs6719578 (NEUROD1) was associated with an increase in insulin secretion in the metformin group but not in the placebo and lifestyle groups. Conclusions: These results provide evidence that genetic variation among MODY genes may influence response to insulin-sensitizing interventions.

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Journal of Clinical Endocrinology and Metabolism
volume
102
issue
8
pages
12 pages
publisher
The Endocrine Society
external identifiers
  • scopus:85026913235
  • wos:000407009500004
ISSN
0021-972X
DOI
10.1210/jc.2016-3429
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English
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yes
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7fd08be3-041e-4222-96c7-8638e41333f9
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2017-08-23 15:03:02
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2018-01-07 12:15:46
@article{7fd08be3-041e-4222-96c7-8638e41333f9,
  abstract     = {<p>Context: Variation in genes that cause maturity-onset diabetes of the young (MODY) has been associated with diabetes incidence and glycemic traits. Objectives: This study aimed to determine whether genetic variation in MODY genes leads to differential responses to insulin-sensitizing interventions. Design and Setting: This was a secondary analysis of a multicenter, randomized clinical trial, the Diabetes Prevention Program (DPP), involving 27 US academic institutions. We genotyped 22 missense and 221 common variants in the MODY-causing genes in the participants in the DPP. Participants and Interventions: The study included 2806 genotyped DPP participants randomized to receive intensive lifestyle intervention (n = 935), metformin (n = 927), or placebo (n = 944). Main Outcome Measures: Association of MODY genetic variants with diabetes incidence at a median of 3 years and measures of 1-year β-Cell function, insulinogenic index, and oral disposition index. Analyses were stratified by treatment group for significant single-nucleotide polymorphism 3 treatment interaction (Pint, 0.05). Sequence kernel association tests examined the association between an aggregate of rare missense variants and insulinogenic traits. Results: After 1 year, the minor allele of rs3212185 (HNF4A) was associated with improved β-Cell function in the metformin and lifestyle groups but not the placebo group; the minor allele of rs6719578 (NEUROD1) was associated with an increase in insulin secretion in the metformin group but not in the placebo and lifestyle groups. Conclusions: These results provide evidence that genetic variation among MODY genes may influence response to insulin-sensitizing interventions.</p>},
  author       = {Billings, Liana K. and Jablonski, Kathleen A and Warner, A. Sofia and Cheng, Yu Chien and McAteer, Jarred B. and Tipton, Laura and Shuldiner, Alan R. and Ehrmann, David A and Manning, Alisa K. and Dabelea, Dana and Franks, Paul W. and Kahn, Steven E and Pollin, Toni I and Knowler, William C and Altshuler, David and Florez, Jose C. and , },
  issn         = {0021-972X},
  language     = {eng},
  month        = {08},
  number       = {8},
  pages        = {2678--2689},
  publisher    = {The Endocrine Society},
  series       = {Journal of Clinical Endocrinology and Metabolism},
  title        = {Variation in maturity-onset diabetes of the young genes influence response to interventions for diabetes prevention},
  url          = {http://dx.doi.org/10.1210/jc.2016-3429},
  volume       = {102},
  year         = {2017},
}