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Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes

, ; Majithia, Amit R; Flannick, Jason; Shahinian, Peter; Guo, Michael; Bray, Mark-Anthony; Fontanillas, Pierre; Gabriel, Stacey B; Rosen, Evan D and Altshuler, David (2014) In Proceedings of the National Academy of Sciences of the United States of America 111(36). p.32-13127
Abstract

Peroxisome proliferator-activated receptor gamma (PPARG) is a master transcriptional regulator of adipocyte differentiation and a canonical target of antidiabetic thiazolidinedione medications. In rare families, loss-of-function (LOF) mutations in PPARG are known to cosegregate with lipodystrophy and insulin resistance; in the general population, the common P12A variant is associated with a decreased risk of type 2 diabetes (T2D). Whether and how rare variants in PPARG and defects in adipocyte differentiation influence risk of T2D in the general population remains undetermined. By sequencing PPARG in 19,752 T2D cases and controls drawn from multiple studies and ethnic groups, we identified 49 previously unidentified, nonsynonymous PPARG... (More)

Peroxisome proliferator-activated receptor gamma (PPARG) is a master transcriptional regulator of adipocyte differentiation and a canonical target of antidiabetic thiazolidinedione medications. In rare families, loss-of-function (LOF) mutations in PPARG are known to cosegregate with lipodystrophy and insulin resistance; in the general population, the common P12A variant is associated with a decreased risk of type 2 diabetes (T2D). Whether and how rare variants in PPARG and defects in adipocyte differentiation influence risk of T2D in the general population remains undetermined. By sequencing PPARG in 19,752 T2D cases and controls drawn from multiple studies and ethnic groups, we identified 49 previously unidentified, nonsynonymous PPARG variants (MAF < 0.5%). Considered in aggregate (with or without computational prediction of functional consequence), these rare variants showed no association with T2D (OR = 1.35; P = 0.17). The function of the 49 variants was experimentally tested in a novel high-throughput human adipocyte differentiation assay, and nine were found to have reduced activity in the assay. Carrying any of these nine LOF variants was associated with a substantial increase in risk of T2D (OR = 7.22; P = 0.005). The combination of large-scale DNA sequencing and functional testing in the laboratory reveals that approximately 1 in 1,000 individuals carries a variant in PPARG that reduces function in a human adipocyte differentiation assay and is associated with a substantial risk of T2D.

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organization
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published
subject
keywords
Adipocytes/pathology, Adult, Aged, Aged, 80 and over, Case-Control Studies, Cell Differentiation/genetics, Diabetes Mellitus, Type 2/genetics, Ethnic Groups/genetics, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, PPAR gamma/genetics, Polymorphism, Single Nucleotide/genetics, Risk Factors, Sequence Analysis, DNA
in
Proceedings of the National Academy of Sciences of the United States of America
volume
111
issue
36
pages
32 - 13127
publisher
National Acad Sciences
external identifiers
  • scopus:84907013152
ISSN
1091-6490
DOI
10.1073/pnas.1410428111
language
English
LU publication?
yes
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af35c767-5da5-480c-9ee6-29a073b5b40e
date added to LUP
2019-01-21 10:16:18
date last changed
2019-04-21 05:20:52
@article{af35c767-5da5-480c-9ee6-29a073b5b40e,
  abstract     = {<p>Peroxisome proliferator-activated receptor gamma (PPARG) is a master transcriptional regulator of adipocyte differentiation and a canonical target of antidiabetic thiazolidinedione medications. In rare families, loss-of-function (LOF) mutations in PPARG are known to cosegregate with lipodystrophy and insulin resistance; in the general population, the common P12A variant is associated with a decreased risk of type 2 diabetes (T2D). Whether and how rare variants in PPARG and defects in adipocyte differentiation influence risk of T2D in the general population remains undetermined. By sequencing PPARG in 19,752 T2D cases and controls drawn from multiple studies and ethnic groups, we identified 49 previously unidentified, nonsynonymous PPARG variants (MAF &lt; 0.5%). Considered in aggregate (with or without computational prediction of functional consequence), these rare variants showed no association with T2D (OR = 1.35; P = 0.17). The function of the 49 variants was experimentally tested in a novel high-throughput human adipocyte differentiation assay, and nine were found to have reduced activity in the assay. Carrying any of these nine LOF variants was associated with a substantial increase in risk of T2D (OR = 7.22; P = 0.005). The combination of large-scale DNA sequencing and functional testing in the laboratory reveals that approximately 1 in 1,000 individuals carries a variant in PPARG that reduces function in a human adipocyte differentiation assay and is associated with a substantial risk of T2D. </p>},
  author       = {,  and Majithia, Amit R and Flannick, Jason and Shahinian, Peter and Guo, Michael and Bray, Mark-Anthony and Fontanillas, Pierre and Gabriel, Stacey B and Rosen, Evan D and Altshuler, David},
  issn         = {1091-6490},
  keyword      = {Adipocytes/pathology,Adult,Aged,Aged, 80 and over,Case-Control Studies,Cell Differentiation/genetics,Diabetes Mellitus, Type 2/genetics,Ethnic Groups/genetics,Female,Genetic Predisposition to Disease,Humans,Male,Middle Aged,PPAR gamma/genetics,Polymorphism, Single Nucleotide/genetics,Risk Factors,Sequence Analysis, DNA},
  language     = {eng},
  month        = {09},
  number       = {36},
  pages        = {32--13127},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes},
  url          = {http://dx.doi.org/10.1073/pnas.1410428111},
  volume       = {111},
  year         = {2014},
}