Genetic analysis of the estrogen-related receptor alpha and studies of association with obesity and type 2 diabetes.
BACKGROUND
The estrogen-related receptor alpha (ERRalpha or NR3B1) is a transcription factor from the nuclear receptor super-family, group III. The gene encoding ERRalpha (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-gamma coactivator-1alpha (PGC-1alpha), ERRalpha regulates key enzymes involved in the beta-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-gamma coactivator-1alpha and -beta; however, no evidence of epistatic effects between the variants was demonstrated.


CONCLUSIONS
The ESRRA23 and Pro116Pro variants of the gene encoding ERRalpha are not associated with obesity, type 2 diabetes or related quantitative traits in the examined Danish whites.
Larsen
L H
LH
Steno Diabetes Center, Gentofte, Denmark.
Rose
C S
CS
Sparsø
T
T
Overgaard
J
J
Torekov
S S
SS
Grarup
N
N
Jensen
D P
DP
Albrechtsen
A
A
Andersen
G
G
Ek
J
J
Glümer
C
C
Borch-Johnsen
K
K
Jørgensen
T
T
Hansen
T
T
Pedersen
O
O
D000368:Aged; D000886:Anthropometry / Q000379:methods; D001786:Blood Glucose / Q000378:metabolism; D001824:Body Constitution; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000097:blood; D015810:Linkage Disequilibrium; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000235:genetics*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D014157:Transcription Factors / Q000235:genetics
D001786:Blood Glucose; D047628:Estrogen Receptor alpha; D006360:Heat-Shock Proteins; D007328:Insulin; D008055:Lipids; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors