GSE115421: Patient adipose stem cell-derived adipocytes reveal genetic variation that predicts anti-diabetic drug response

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GROUP CONDITION SAMPLES
Adipocytes
GSM3416393 GSM3416394 GSM3416395
GSM3416384 GSM3416385 GSM3416386
GSM3416387 GSM3416388 GSM3416389
GSM3416390 GSM3416391 GSM3416392
GSM3177923 GSM3177924 GSM3177925 GSM3177929 GSM3177930 GSM3177931 GSM3177935 GSM3177936 GSM3177937 GSM3177941 GSM3177942 GSM3177943 GSM3177947 GSM3177948 GSM3177949
GSM3177920 GSM3177921 GSM3177922 GSM3177926 GSM3177927 GSM3177928 GSM3177932 GSM3177933 GSM3177934 GSM3177938 GSM3177939 GSM3177940 GSM3177944 GSM3177945 GSM3177946
Description

Submission Date: Jun 06, 2018

Summary: Thiazolidinedione drugs (TZDs) target the transcriptional activity of PPARg 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 single-nucleotide polymorphisms (SNPs) were enriched at sites of patient-specific PPARg binding, which correlated with the individual-specific effects of TZD rosiglitazone (rosi) on gene expression. Rosi induction of ABCA1, which regulates cholesterol metabolism, was dependent upon SNP rs4743771, which modulated PPARg binding by influencing the genomic occupancy of its cooperating factor NFIA. Conversion of rs4743771 from the inactive SNP allele to the active one by CRISPR/Cas9-mediated editing rescued PPARg binding as well as 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 PPARg genomic occupancy and patient responses to antidiabetic drugs, with implications for developing personalized therapies for metabolic disorders

GEO Accession ID: GSE115421

PMID: 30639037

Description

Submission Date: Jun 06, 2018

Summary: Thiazolidinedione drugs (TZDs) target the transcriptional activity of PPARg 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 single-nucleotide polymorphisms (SNPs) were enriched at sites of patient-specific PPARg binding, which correlated with the individual-specific effects of TZD rosiglitazone (rosi) on gene expression. Rosi induction of ABCA1, which regulates cholesterol metabolism, was dependent upon SNP rs4743771, which modulated PPARg binding by influencing the genomic occupancy of its cooperating factor NFIA. Conversion of rs4743771 from the inactive SNP allele to the active one by CRISPR/Cas9-mediated editing rescued PPARg binding as well as 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 PPARg genomic occupancy and patient responses to antidiabetic drugs, with implications for developing personalized therapies for metabolic disorders

GEO Accession ID: GSE115421

PMID: 30639037

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