Genetic Variation Determines PPARγ Function and Antidiabetic 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 antidiabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors, and fu...

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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
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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 antidiabetic 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.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2015.06.025