br Acknowledgments br Introduction Hypospadias is a common

Acknowledgments
Introduction Hypospadias is a common congenital malformation in males, in which the urethral orifice is found on the ventral side of the penis as a result of incomplete fusion of urethral folds. The mean prevalence in per 10,000 live births from 1910 to 2013 were: Europe 19.9, North America 34.2, South America 5.2, Asia 0.6–69, Africa 5.9, and Australia 17.1–34.8 [1]. In southeast China, prevalence of coronal hypospadias increased from 1.7 per 10,000 male births in 1993 to 3.6 per 10,000 male births in 2005 [2]. Numerous epidemiologic studies have shown that the incidence of hypospadias is still an increasing trend [2,3]. Based on the anatomical location of the urethral meatus, hypospadias is classified as mild (glanular, coronar, and distal penile form), moderate (penile with chordee), or severe phenotype (penoscrotal, scrotal, or perineal portion). However, the etiology of hypospadias is poorly understood and may be multifactorial, including genetic, endocrine, and environmental factors [4,5]. The steroid 5-alpha-reductase type 2 (SRD5A2) gene is located on chromosome 2p23 from 31388766 to 31834506 whose length is 445741bp. SRD5A2 contains five exons and four introns. SRD5A2 gene codes for 5α-reductase enzyme type 2, which is mainly expressed in the ventral side of the urethra in the process of male genital development, and plays an important role in urethral shaping [6]. 5α-reductase enzyme type 2 is involved in male sex differentiation by converting testosterone to 5α-dihydrotestosterone (DHT), which can subsequently induce the development of external genitalia [7]. Functional polymorphisms of genes controlling biosynthesis of testosterone and DHT are likely to be important in the etiology of hypospadias [8]. A major functional polymorphism of the SRD5A2 gene – V89L – is caused by a G to C transversion (valine to leucine, rs523349) at 900 80 synthesis 89. The leucine version of the enzyme is 30% less efficient than the valine variant (decreased DHT levels), which may contribute to the etiology of hypospadias [5,9]. A growing body of case–control studies on the roles of SRD5A2 V89L [5,7,10–13] in hypospadias has been conducted in the past decades; however, these studies have presented seemingly conflicting results. Therefore, the present institution performed a comprehensive meta-analysis of the available literature for the potential associations between SRD5A2 V89L and hypospadias risk.
Materials and methods
Results
Discussion Hypospadias is a common congenital malformation in males; the incidence is about 1 in 250–300 individuals at birth and is still on the rise [3,16]. The disease affects not only physical development of boys, but also normal mental growth, and will seriously affect fertility. Clinical surgery is the only treatment means for hypospadias. However, the clinical operation is very complex and has a certain rate of failure [17]. The general operation success rate of the first phase is about 80%, which is higher than that of mild hypospadias patients, while the success rate of severe hypospadias patients is the lowest [18]. Meanwhile, the etiology of the disease is viewed as multifactorial, as it involves both genes and environmental factors, and is still unclear, which is why further study is required [19]. During the first trimester of gestation, the male urethra/male external genitalia are formed by androgen regulation [8], such as testosterone (produced by the fetal testes and metabolized in several target tissues), and dihydrotestosterone (generated from testosterone via the 5α-reductase enzyme type II) [20]. Previous publications have revealed that the SRD5A2 gene has roles in androgen synthesis and metabolism, and then has an effect on genitalia differentiation in males [21]. Therefore, the abnormality of androgen metabolism may have roles in the occurrence and development of hypospadias. Mutation of residue 89 of the SRD5A2 gene with valine replaced by leucine (V89L) resulted in almost 30% enzyme activity reduction as well as lower concentration of testosterone metabolites [22,23]. However, most of the previous reports were confined to gene polymorphism and epidemiological research methods, so the regulation mechanism of differentiation, development, and formation of fetal genital, and the mechanism of occurrence and development of hypospadias are still unknown. Thus, the susceptibility of V89L polymorphism to hypospadias has been studied. For instance, some molecular epidemiologic studies have been conducted to evaluate the potential association between V89L polymorphism in the SRD5A2 gene and hypospadias risk; however, the results remain conflicting [5,7,10–13]. Therefore, a meta-analysis was conducted to evaluate the association between SRD5A2 V89L polymorphism and hypospadias risk. As a powerful statistical method, meta-analysis can pool the results of different studies on the same topic, which can provide a more objective evaluation of evidence, have a more accurate assessment on effect indicators, and can explain the heterogeneity between different research results.