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

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 f...

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Published in:Cell 2015-07, Vol.162 (1), p.33-44
Main Authors: Soccio, Raymond E., Chen, Eric R., Rajapurkar, Satyajit R., Safabakhsh, Pegah, Marinis, Jill M., Dispirito, Joanna R., Emmett, Matthew J., Briggs, Erika R., Fang, Bin, Everett, Logan J., Lim, Hee-Woong, Won, Kyoung-Jae, Steger, David J., Wu, Ying, Civelek, Mete, Voight, Benjamin F., Lazar, Mitchell A.
Format: Article
Language:English
Subjects:
Adipose Tissue
Animals
Gene Expression
Humans
Hypoglycemic Agents - metabolism
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Polymorphism, Single Nucleotide
PPAR gamma - genetics
PPAR gamma - metabolism
Transcription Factors - metabolism
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Summary: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. [Display omitted] •SNPs determine genomic binding of adipose master regulator PPARγ in mice and humans•SNPs that impact PPARγ binding alter its motifs or those for cooperating factors•Variable PPARγ binding controls gene expression and anti-diabetic drug response•SNPs that alter PPARγ binding modulate human metabolic disease risk Single-nucleotide polymorphism alters the genome-wide binding of the transcription factor PPARγ, impacting the response of mice to anti-diabetic drugs and affecting individual risk for metabolic disease in humans.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2015.06.025