Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo

Raymond E Soccio; Eric R Chen; Satyajit R Rajapurkar; Pegah Safabakhsh; Jill M Marinis; Joanna R Dispirito; Matthew J Emmett; Erika R Briggs; Bin Fang; Logan J Everett; Hee-Woong Lim; Kyoung-Jae Won; David J Steger; Ying Wu; Mete Civelek; Benjamin F Voight; Mitchell A Lazar

doi:10.1016/j.cell.2015.06.025

Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo

Raymond E Soccio, Eric R Chen, Satyajit R Rajapurkar, Pegah Safabakhsh, Jill M Marinis, Joanna R Dispirito, Matthew J Emmett, Erika R Briggs, Bin Fang, Logan J Everett, Hee-Woong Lim, Kyoung-Jae Won, David J Steger, Ying Wu, Mete Civelek, Benjamin F Voight, Mitchell A Lazar

77 Citationer (Scopus)

Abstract

SNPs affecting disease risk often reside in non-coding genomic regions. Here, we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, a nuclear receptor for anti-diabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors and functionally regulate nearby genes whose expression is strain selective and imbalanced in heterozygous F1 mice. Moreover, genetically determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs, providing proof of concept for personalized medicine related to nuclear receptor genomic occupancy. In human fat, motif-altering SNPs cause differential PPARγ binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome-wide association studies. One PPARγ motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPARγ genomic occupancy determines individual disease risk and drug response.

Originalsprog	Engelsk
Tidsskrift	Cell
Vol/bind	162
Udgave nummer	1
Sider (fra-til)	33-44
Antal sider	12
ISSN	0092-8674
DOI	https://doi.org/10.1016/j.cell.2015.06.025
Status	Udgivet - 3 jul. 2015
Udgivet eksternt	Ja

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10.1016/j.cell.2015.06.025

http://www.cell.com/article/S0092867415007096/pdf

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Soccio, R. E., Chen, E. R., Rajapurkar, S. R., Safabakhsh, P., Marinis, J. M., Dispirito, J. R., Emmett, M. J., Briggs, E. R., Fang, B., Everett, L. J., Lim, H.-W., Won, K.-J., Steger, D. J., Wu, Y., Civelek, M., Voight, B. F., & Lazar, M. A. (2015). Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo. Cell, 162(1), 33-44. https://doi.org/10.1016/j.cell.2015.06.025

Soccio, RE, Chen, ER, Rajapurkar, SR, Safabakhsh, P, Marinis, JM, Dispirito, JR, Emmett, MJ, Briggs, ER, Fang, B, Everett, LJ, Lim, H-W, Won, K-J, Steger, DJ, Wu, Y, Civelek, M, Voight, BF & Lazar, MA 2015, 'Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo', Cell, bind 162, nr. 1, s. 33-44. https://doi.org/10.1016/j.cell.2015.06.025

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title = "Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo",

abstract = "SNPs affecting disease risk often reside in non-coding genomic regions. Here, we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, a nuclear receptor for anti-diabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors and functionally regulate nearby genes whose expression is strain selective and imbalanced in heterozygous F1 mice. Moreover, genetically determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs, providing proof of concept for personalized medicine related to nuclear receptor genomic occupancy. In human fat, motif-altering SNPs cause differential PPARγ binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome-wide association studies. One PPARγ motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPARγ genomic occupancy determines individual disease risk and drug response. ",

keywords = "Adipose Tissue, Animals, Gene Expression, Humans, Hypoglycemic Agents/metabolism, Mice, Mice, 129 Strain, Mice, Inbred C57BL, PPAR gamma/genetics, Polymorphism, Single Nucleotide, Transcription Factors/metabolism",

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year = "2015",

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doi = "10.1016/j.cell.2015.06.025",

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journal = "Cell",

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T1 - Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo

AU - Soccio, Raymond E

AU - Chen, Eric R

AU - Rajapurkar, Satyajit R

AU - Safabakhsh, Pegah

AU - Marinis, Jill M

AU - Dispirito, Joanna R

AU - Emmett, Matthew J

AU - Briggs, Erika R

AU - Fang, Bin

AU - Everett, Logan J

AU - Lim, Hee-Woong

AU - Won, Kyoung-Jae

AU - Steger, David J

AU - Wu, Ying

AU - Civelek, Mete

AU - Voight, Benjamin F

AU - Lazar, Mitchell A

PY - 2015/7/3

Y1 - 2015/7/3

N2 - SNPs affecting disease risk often reside in non-coding genomic regions. Here, we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, a nuclear receptor for anti-diabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors and functionally regulate nearby genes whose expression is strain selective and imbalanced in heterozygous F1 mice. Moreover, genetically determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs, providing proof of concept for personalized medicine related to nuclear receptor genomic occupancy. In human fat, motif-altering SNPs cause differential PPARγ binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome-wide association studies. One PPARγ motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPARγ genomic occupancy determines individual disease risk and drug response.

AB - SNPs affecting disease risk often reside in non-coding genomic regions. Here, we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, a nuclear receptor for anti-diabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors and functionally regulate nearby genes whose expression is strain selective and imbalanced in heterozygous F1 mice. Moreover, genetically determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs, providing proof of concept for personalized medicine related to nuclear receptor genomic occupancy. In human fat, motif-altering SNPs cause differential PPARγ binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome-wide association studies. One PPARγ motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPARγ genomic occupancy determines individual disease risk and drug response.

KW - Adipose Tissue

KW - Animals

KW - Gene Expression

KW - Humans

KW - Hypoglycemic Agents/metabolism

KW - Mice

KW - Mice, 129 Strain

KW - Mice, Inbred C57BL

KW - PPAR gamma/genetics

KW - Polymorphism, Single Nucleotide

KW - Transcription Factors/metabolism

U2 - 10.1016/j.cell.2015.06.025

DO - 10.1016/j.cell.2015.06.025

M3 - Journal article

C2 - 26140591

SN - 0092-8674

VL - 162

SP - 33

EP - 44

JO - Cell

JF - Cell

IS - 1

ER -

Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo

Abstract

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