| Autor: |
Chen, Eric R., Voight, Benjamin F., Emmett, Matthew J., Civelek, Mete, Dispirito, Joanna R., Safabakhsh, Pegah, Steger, David J., Soccio, Raymond E., Won, Kyoung Jae, Fang, Bin, Lim, Hee Woong, Rajapurkar, Satyajit R., Briggs, Erika R., Wu, Ying, Everett, Logan J., Lazar, Mitchell A., Marinis, Jill M. |
| Jazyk: |
angličtina |
| Rok vydání: |
2015 |
| DOI: |
10.17615/dyyn-7s17 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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