The CAG repeat polymorphism in the Androgen receptor gene modifies the risk for hypospadias in Caucasians

Tatjana Adamovic,Agneta Nordenskjöld

doi:10.1186/1471-2350-13-109

Tatjana Adamovic, Agneta Nordenskjöld

Open Access

https://doi.org/10.1186/1471-2350-13-109

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Abstract

BackgroundHypospadias is a birth defect of the urethra in males, and a milder form of 46,XY disorder of sexual development (DSD). The disease is characterized by a ventrally placed urinary opening due to a premature fetal arrest of the urethra development. Moreover, the Androgen receptor (AR) gene has an essential role in the hormone-dependent stage of sexual development. In addition, longer AR polyglutamine repeat lengths encoded by CAG repeats are associated with lower transcriptional activity in vitro. In the present study, we aimed at investigating the role of the CAG repeat length in the AR gene in hypospadias cases as compared to the controls. Our study included 211 hypospadias and 208 controls of Caucasian origin.MethodsWe amplified the CAG repeat region with PCR, and calculated the difference in the mean CAG repeat length between the hypospadias and control group using the T-test for independent groups.ResultsWe detected a significant increase of the CAG repeat length in the hypospadias cases when compared to the controls (contrast estimate: 2.29, 95% Confidence Interval (1.73-2.84); p-value: 0.001). In addition, the odds ratios between the hypospadias and controls revealed that the hypospadias cases are two to 3 times as likely to have longer CAG repeats than a shorter length for each repeat length investigated.ConclusionsWe have investigated the largest number of hypospadias cases with regards to the CAG repeat length, and we provide evidence that a higher number of the CAG repeat sequence in the AR gene have a clear effect on the risk of hypospadias in Caucasians.

Highlights

Hypospadias is a birth defect of the urethra in males, and a milder form of 46,XY disorder of sexual development (DSD)
We first calculated the skewness for each group, and detected the CAG repeats to be normally distributed within each group
We further detected a significant difference in the median CAG repeat length between the two groups using the Chi-square test (p

Summary

Introduction

Hypospadias is a birth defect of the urethra in males, and a milder form of 46,XY disorder of sexual development (DSD). The Androgen receptor (AR) gene is located on chromosome Xq12 and is involved in the generation of the male internal and external genitalia through the actions of testosterone and 5α-dihydrotestosterone (DHT) [1] The product of this gene belongs to the nuclear receptor class, and is expressed in the developing human penis and urethra [2]. The malformation of hypospadias is described as a birth defect of the urethra in males, and is considered to be a milder form of 46,XY disorder of sex development (DSD) It is characterized by a ventrally placed urinary opening in boys and affects 3 per 1000 males in Sweden since the beginning of the 1970s (data from the annual Swedish Malformation Registry). Most cases with hypospadias are reported to be sporadic [11]

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