Estrogen receptor alpha gene variants associate with type 2 diabetes and fasting plasma glucose.
OBJECTIVE
Estrogen receptor 1 (ESR1) mediates effects of estrogens on glucose homeostasis. Polymorphisms in intron 1, 2, and 4 of the ESR1 gene have been found to be associated with type 2 diabetes (T2D) in Hungarian, Chinese, and African-American and European-American cohorts. The aim of this study was to investigate the association between ESR1 polymorphisms and T2D as well as quantitative phenotypes related to glucose homeostasis in French and Swedish Caucasians.


METHODS
The French cohort included 941 normoglycemic controls and 988 T2D patients. The Swedish cohort consisted of 1045 controls with normal glucose tolerance, 324 participants with impaired glucose tolerance, and 276 T2D patients. A total of 20 single nucleotide polymorphisms (SNPs) distributed across the ESR1 gene were genotyped.


RESULTS
SNPs in introns 3 and 4 of the ESR1 gene associated significantly with T2D in the French cohort (rs3020314, rs985694, P = 0.0009-0.001) and with fasting plasma glucose in Swedish men (rs9397456, rs3020314 rs3020317, P = 0.0002-0.0022) after Bonferroni correction for the analysis of 20 SNPs. In addition, nominal association of ESR1 rs1884051 (P=0.011) with T2D in the French cohort replicates a previously observed association in Finns (empirical P=0.024) (http://www.broad.mit.edu/diabetes/).


CONCLUSIONS
This study provides further evidence that ESR1 genetic polymorphisms are associated with T2D and with fasting plasma glucose. No current evidence that the investigated SNPs are functional is present, thus, we suggest that the association between T2D and ESR1 variants may be because of other unidentified ESR1 polymorphisms that regulate glucose homeostasis.
Department of Medicine, Karolinska Institutet, Huddinge, Stockholm.
Ingrid
I
Dahlman
Martine
M
Vaxillaire
Maria
M
Nilsson
Cecile
C
Lecoeur
Harvest F
HF
Gu
Christine
C
Cavalcanti-Proença
Suad
S
Efendic
Claes G
CG
Ostenson
Kerstin
K
Brismar
Guillaume
G
Charpentier
Jan-Ake
JA
Gustafsson
Philippe
P
Froguel
Karin
K
Dahlman-Wright
Knut R
KR
Steffensen
D000483:Alleles; D001786:Blood Glucose / Q000235:genetics*; D015331:Cohort Studies; D003710:Demography; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005215:Fasting / Q000097:blood*; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D013548:Sweden
D001786:Blood Glucose; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha