Genetic analysis of the estrogen-related receptor α and studies of association with obesity and type 2 diabetes

Abstract

Background: The estrogen-related receptor α (ERRα or NR3B1) is a transcription factor from the nuclear receptor super-family, group III. The gene encoding ERRα (ESRRA) is located on chromosome 11q13, a region showing genetic linkage to body mass index and fat percentage. Through interaction with the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), ERRα regulates key enzymes involved in the β-oxidation of fatty acids. Results: By screening 48 overweight or obese subjects for variants in the exons, exon-intron boundaries and 1000 base pairs (bp) of the promoter region of ESRRA using bi-directional nucleotide sequencing, we identified seven variants. Four rare variants had minor allele frequencies (MAF) below 1%: Pro369Pro, Gly406Asp, 3′UTR+418G>A, 3′UTR+505C>A. Two single-nucleotide polymorphisms, Pro116Pro and IVS6+65C>T (MAF 15%), were in complete linkage disequilibrium (LD) (r 2=1). We also confirmed the presence of a reported 23 bp microsatellite repeat (ESRRA23). The Pro116Pro and ESRRA23 variants were not associated with obesity, type 2 diabetes or related phenotypes in a large population-based study of 6365 Danish whites. The two variants were examined for interactions with variants in the peroxisome proliferator-activated receptor-γ coactivator-1α and -β; however, no evidence of epistatic effects between the variants was demonstrated. Conclusion: The ESRRA23 and Pro116Pro variants of the gene encoding ERRα are not associated with obesity, type 2 diabetes or related quantitative traits in the examined Danish whites. © 2007 Nature Publishing Group All rights reserved.