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

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Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes. / GoT2D Consortium; Majithia, Amit R; Flannick, Jason; Shahinian, Peter; Guo, Michael; Bray, Mark-Anthony; Fontanillas, Pierre; Gabriel, Stacey B; Rosen, Evan D; Altshuler, David; Kravic, Jasmina (Medarbetare).

I: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, Nr. 36, 09.09.2014, s. 13127-32.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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GoT2D Consortium, Majithia, AR, Flannick, J, Shahinian, P, Guo, M, Bray, M-A, Fontanillas, P, Gabriel, SB, Rosen, ED, Altshuler, D & Kravic, J 2014, 'Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, nr. 36, s. 13127-32. https://doi.org/10.1073/pnas.1410428111

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GoT2D Consortium ; Majithia, Amit R ; Flannick, Jason ; Shahinian, Peter ; Guo, Michael ; Bray, Mark-Anthony ; Fontanillas, Pierre ; Gabriel, Stacey B ; Rosen, Evan D ; Altshuler, David ; Kravic, Jasmina. / Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes. I: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, Nr. 36. s. 13127-32.

RIS

TY - JOUR

T1 - Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes

AU - GoT2D Consortium

AU - Majithia, Amit R

AU - Flannick, Jason

AU - Shahinian, Peter

AU - Guo, Michael

AU - Bray, Mark-Anthony

AU - Fontanillas, Pierre

AU - Gabriel, Stacey B

AU - Rosen, Evan D

AU - Altshuler, David

A2 - Kravic, Jasmina

PY - 2014/9/9

Y1 - 2014/9/9

N2 - 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.

AB - 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.

KW - Adipocytes/pathology

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Case-Control Studies

KW - Cell Differentiation/genetics

KW - Diabetes Mellitus, Type 2/genetics

KW - Ethnic Groups/genetics

KW - Female

KW - Genetic Predisposition to Disease

KW - Humans

KW - Male

KW - Middle Aged

KW - PPAR gamma/genetics

KW - Polymorphism, Single Nucleotide/genetics

KW - Risk Factors

KW - Sequence Analysis, DNA

U2 - 10.1073/pnas.1410428111

DO - 10.1073/pnas.1410428111

M3 - Article

VL - 111

SP - 13127

EP - 13132

JO - Proceedings of the National Academy of Sciences

T2 - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 1091-6490

IS - 36

ER -