title: Genetic polymorphisms of 17 β-hydroxysteroid dehydrogenase 3 and the risk of hypospadias.
abstract: BACKGROUND
  Hypospadias is a common congenital anomaly caused by incomplete fusion of urethral folds. Development of the urethra and external genital system in the male fetus is an androgen-dependent process. In this regard, enzymes 17 β-hydroxysteroid dehydrogenase type 3 (17 β HSD3, encoded by HSD17B3) and steroid 5 α-reductase type 2 (encoded by SRD5A2) play crucial roles.
  
  
  OBJECTIVE
  To investigate the possible associations between common polymorphisms in HSD17B3 as well as well-known V89L polymorphism in SRD5A2 and risk of hypospadias.
  
  
  METHODS
  A case-control study was performed between 1999 and 2005. There were 89 Japanese boys with hypospadias and 291 newborn controls. We genotyped HSD17B3-1999T>C, +10A>G, +20A>G, +139G>A (V31I), +913G>A (G289S), and SRD5A2+336G>C (V89L) polymorphisms by allelic discrimination assay. We measured mRNA expression of the wildtype G289 allele and the mutant S289 allele of the HSD17B3 gene in the transfected human fetal kidney HEK293 cells.
  
  
  METHODS
  Assessment of hypospadias including its severity and HSD17B3 and SRD5A2 genes using DNA blood samples: allele and genotype distribution of single nucleotide polymorphisms in these two genes in cases and controls.
  
  
  RESULTS
  In our study, the risk of hypospadias was significantly higher in subjects carrying homozygous HSD17B3+913A (289S) alleles (odds ratio [OR]: 3.06; 95% confidence interval [CI]: 1.38-6.76). The risk of severe hypospadias was much higher in these subjects (OR: 3.93; 95% CI: 1.34-11.49). The mRNA expression levels of HSD17B3 G289 were higher than those of HSD17B3 S289 mutant (P < 0.001). In addition, the risk of severe hypospadias increased in boys carrying the SRD5A2+336C (89L) allele (OR: 3.19; 95% CI: 1.09-9.36).
  
  
  CONCLUSIONS
  These results suggest that the HSD17B3 G289S polymorphism may be a potential risk modifier for hypospadias. Our findings provide evidence that a certain genotype related to androgen production may potentiate risk of hypospadias.
authors.affiliation: Department of Public Health, Hokkaido University Graduate School of Medicine, Sapporo, Japan. sata@niph.go.jp
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sata
authors.forename: Norie
authors.initials: N
authors.lastname: Kurahashi
authors.forename: Susumu
authors.initials: S
authors.lastname: Ban
authors.forename: Kimihiko
authors.initials: K
authors.lastname: Moriya
authors.forename: Kazuyuki D
authors.initials: KD
authors.lastname: Tanaka
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ishizuka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakao
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Yahata
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Imai
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Kakizaki
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nonomura
authors.forename: Reiko
authors.initials: R
authors.lastname: Kishi
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics*; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005787:Gene Frequency / Q000235:genetics; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007021:Hypospadias / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D007564:Japan; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012307:Risk Factors
chemical_list: D008565:Membrane Proteins; D012333:RNA, Messenger; D015067:17-Hydroxysteroid Dehydrogenases; C476565:17beta-hydroxysteroid dehydrogenase type 3; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548468:SRD5A2 protein, human