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

Cell Stem Cell. 2019 Feb 7;24(2):299-308.e6. doi: 10.1016/j.stem.2018.11.018. Epub 2019 Jan 10.


Thiazolidinedione drugs (TZDs) target the transcriptional activity of peroxisome proliferator activated receptor γ (PPARγ) 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 PPARγ 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 PPARγ 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 PPARγ 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 PPARγ genomic occupancy and patient responses to antidiabetic drugs, with implications for developing personalized therapies for metabolic disorders.

Keywords: ABCA1; PPARγ; adipocytes; adipose stem cell; antidiabetic drug; drug response; genetic variation; rosiglitazone.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / genetics
  • ATP Binding Cassette Transporter 1 / metabolism
  • Adipocytes / cytology*
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipose Tissue / cytology*
  • Adult
  • Aged
  • Base Sequence
  • Cell Line
  • Cholesterol / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / genetics
  • Gene Editing
  • Genetic Loci
  • Genetic Variation*
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Middle Aged
  • NFI Transcription Factors / metabolism
  • PPAR gamma / metabolism
  • Polymorphism, Single Nucleotide / genetics
  • Protein Binding / drug effects
  • Rosiglitazone / pharmacology
  • Stem Cells / cytology*
  • Stem Cells / drug effects
  • Stem Cells / metabolism


  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • Hypoglycemic Agents
  • NFI Transcription Factors
  • NFIA protein, human
  • PPAR gamma
  • Rosiglitazone
  • Cholesterol