Haplotype analysis of the estrogen receptor 1 gene in male genital and reproductive abnormalities.
BACKGROUND
We have recently suggested that homozygosity for a specific 'AGATA' haplotype within a approximately 50 kb linkage disequilibrium (LD) block of the gene for estrogen receptor alpha (ESR1) may raise the susceptibility to cryptorchidism by enhancing estrogenic effects of environmental endocrine disruptors (EEDs).


METHODS
Haplotype analysis of ESR1 was performed in 328 Japanese subjects, i.e. 70 patients with micropenis (MP), 43 patients with hypospadias (HS), 80 patients with spermatogenic failure (SF) and 135 control males. Genotyping was performed by the 5' nuclease assay.


RESULTS
The LD block was identified in each of the patient groups and in the control males. The frequency of homozygotes for the specific 'AGATA' haplotype was markedly higher in the HS patients [P = 0.0000033, odds ratio [OR] = 11.26] and slightly higher in the MP patients (P = 0.034, OR = 3.64) than in the control males, and the 'AGATA' haplotype was strongly associated with HS (P = 0.0000022, OR = 11.26) and weakly associated with MP (P = 0.040, OR = 3.64) in a recessive mode. There was no significant difference between the SF patients and the control males.


CONCLUSIONS
Our results support the hypothesis that homozygosity for the specific ESR1 'AGATA' haplotype may increase the susceptibility to the development of male genital abnormalities in response to estrogenic EEDs.
Watanabe
Masanori
M
Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo, Japan.
Yoshida
Rie
R
Ueoka
Katsuhiko
K
Aoki
Katsuya
K
Sasagawa
Isoji
I
Hasegawa
Tomonobu
T
Sueoka
Kou
K
Kamatani
Naoyuki
N
Yoshimura
Yasunori
Y
Ogata
Tsutomu
T
D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics; D053713:Azoospermia / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D052244:Endocrine Disruptors / Q000009:adverse effects; D047628:Estrogen Receptor alpha / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007021:Hypospadias / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D007248:Infertility, Male / Q000235:genetics*; D007564:Japan; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009845:Oligospermia / Q000235:genetics; D010413:Penis / Q000002:abnormalities*; D020641:Polymorphism, Single Nucleotide; D013091:Spermatogenesis / Q000235:genetics*
C506487:ESR1 protein, human; D052244:Endocrine Disruptors; D047628:Estrogen Receptor alpha