• PMID: 30063927
• Gene Name: IRX6
• Condition: Hypospadias
• Association: Associated
• Mutation: rs6499755
• Population size: 169
• Population details: 169 cases
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

Single Nucleotide Polymorphisms of HAAO and IRX6 Genes as Risk Factors for Hypospadias

Kojima Y, Koguchi T, Mizuno K, Sato Y, Hoshi S, Hata J, Nishio H, Hashimoto D, Matsushita S, Suzuki K, Miyagawa S, Hui CC, Tanikawa C, Murakami Y, Yamada G, Hayashi Y, Matsuda K.

PURPOSE: We evaluated the association of hypospadias and 17 susceptibility loci previously identified by a European genome-wide association study in a cohort of Japanese patients. We also examined the expression of candidate genes in male mouse embryos to determine the possible underlying mechanisms of this disease. MATERIALS AND METHODS: We enrolled 169 Japanese patients (mean age at surgery 3.7 years) who underwent repair of hypospadias. Genotyping of 17 single nucleotide polymorphisms was performed using a multiplex polymerase chain reaction invader assay. We also performed in situ hybridization to determine whether candidate genes were expressed in the male genital tubercle during embryonic development of the external genitalia in mice. RESULTS: Single nucleotide polymorphism rs3816183 of HAAO was significantly associated with susceptibility to hypospadias in general (p = 0.0019) and to anterior/middle hypospadias (p = 0.0283) and posterior hypospadias (p = 0.0226), while single nucleotide polymorphism rs6499755 of IRX6 showed an association with susceptibility to anterior/middle hypospadias (p = 0.0472). In mouse embryos there was no significant upregulation of Haao expression in the developing male external genitalia. Irx3 and Irx5, which are linked to Irx6 within the IrxB cluster, were expressed in the mesenchyme remote from the urethral plate epithelium during the critical embryonic period for masculinization. Irx6 was expressed in the ectodermal epithelium, demonstrating prominent dorsal ectodermal expression without expression in the ventral ectoderm adjacent to the urethral plate during the same period. CONCLUSIONS: Genetic variations of HAAO and IRX6 influence susceptibility to hypospadias in the Japanese population. Further research is needed to clarify the mechanism by which variations in these genes contribute to the pathogenesis of hypospadias. FAU - Kojima, Yoshiyuki AU - Kojima Y AD - Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan. FAU - Koguchi, Tomoyuki AU - Koguchi T AD - Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan. FAU - Mizuno, Kentaro AU - Mizuno K AD - Department of Pediatric Urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. FAU - Sato, Yuichi AU - Sato Y AD - Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan. FAU - Hoshi, Seiji AU - Hoshi S AD - Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan. FAU - Hata, Junya AU - Hata J AD - Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan. FAU - Nishio, Hidenori AU - Nishio H AD - Department of Pediatric Urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. FAU - Hashimoto, Daiki AU - Hashimoto D AD - Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan. FAU - Matsushita, Shoko AU - Matsushita S AD - Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan. FAU - Suzuki, Kentaro AU - Suzuki K AD - Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan. FAU - Miyagawa, Shinichi AU - Miyagawa S AD - Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan. FAU - Hui, Chi Chung AU - Hui CC AD - Program in Developmental and Stem Cell Biology, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada. FAU - Tanikawa, Chizu AU - Tanikawa C AD - Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan. FAU - Murakami, Yoshimori AU - Murakami Y AD - Division of Molecular Pathology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. FAU - Yamada, Gen AU - Yamada G AD - Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan. FAU - Hayashi, Yutaro AU - Hayashi Y AD - Department of Pediatric Urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.