Patient Adipose Stem Cell-Derived Adipocytes Reveal Genetic Variation that Predicts Antidiabetic Drug Response

Thiazolidinedione drugs (TZDs) target the transcriptional activity of peroxisome proliferator activated receptor gamma (PPAR gamma) to reverse insulin resistance in type 2 diabetes, but side effects limit their clinical use. Here, using human adipose stem cell-derived adipocytes, we demonstrate that SNPs were enriched at sites of patient-specific PPAR gamma binding, which correlated with the individual-specific effects of the TZD rosiglitazone (rosi) on gene expression. Rosi induction of ABCA1, which regulates cholesterol metabolism, was dependent upon SNP rs4743771, which modulated PPAR gamma binding by influencing the genomic occupancy of its cooperating factor, NFIA. Conversion of rs4743771 from the inactive SNP allele to the active one by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated editing rescued PPAR gamma binding and rosi induction of ABCA1 expression. Moreover, rs4743771 is a major determinant of undesired serum cholesterol increases in rosi-treated diabetics. These data highlight human genetic variation that impacts PPAR gamma genomic occupancy and patient responses to antidiabetic drugs, with implications for developing personalized therapies for metabolic disorders.