Fig. 5.

An upstream PPARγ motif-altering polymorphism drives genetic variation in TZD activation of PM20D1. (A) The consensus PPRE motif logo is shown above the first PPRE sequences in the intronic and upstream regions near PM20D1. A C variant in the upstream site is predicted to reduce PPARγ binding activity. (B) Luciferase reporter assay of upstream reporters, showing that the C variant has reduced activation by PPARγ and rosiglitazone (rosi). Mean and SEM, ^#P < 0.001 versus A allele; NS, not significant; 2-tailed type 2 Student’s t-test. (C) Human adipose stem cell-derived adipocytes were cultured from 26 individuals and treated with rosiglitazone, and induction of PM20D1 as measured by qPCR was variable. Mean and SEM. (D) Individuals with low response of PM20D1 to rosi enriched for C alleles at this PPRE SNP. Contingency P value by 2-sided Fisher’s exact test. (E) Schematic model showing requirement for both PPREs for maximal PPARγ activity.