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 Citations (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.

Original language	English
Journal	Cell
Volume	162
Issue number	1
Pages (from-to)	33-44
Number of pages	12
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2015.06.025
Publication status	Published - 3 Jul 2015
Externally published	Yes

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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, vol. 162, no. 1, pp. 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. ",

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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

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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

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KW - Mice, 129 Strain

KW - Mice, Inbred C57BL

KW - PPAR gamma/genetics

KW - Polymorphism, Single Nucleotide

KW - Transcription Factors/metabolism

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DO - 10.1016/j.cell.2015.06.025

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SP - 33

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JO - Cell

JF - Cell

IS - 1

ER -

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

Abstract

Keywords

UN SDGs

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