PLX230399

GSE64459: Genetic Variation Determines PPAR Function and Antidiabetic Drug Response In Vivo [RNA-seq]

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

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 PPAR, a nuclear receptor for antidiabetic drugs. Many such SNPs alter binding motifs for PPAR or cooperating factors, and functionally regulate nearby genes whose expression is strain-selective and imbalanced in heterozygous F1 mice. Moreover, genetically-determined binding of PPAR 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 PPAR binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome- wide association studies. One PPAR motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPAR genomic occupancy determines individual disease risk and drug response. SOURCE: Mitchell Lazar (lazar@mail.med.upenn.edu) - Lazar Lab University of Pennsylvania