Role of Androgen Receptor CAG Repeat Polymorphism and X-Inactivation in the Manifestation of Recurrent Spontaneous Abortions in Indian Women

Meka Aruna,Shilpi Dasgupta,Pisapati V S Sirisha,Lalji Singh,Sadaranga Andal Bhaskar,B Mohan Reddy,Surapaneni Tarakeswari,Ralf Krahe

doi:10.1371/journal.pone.0017718

Abstract

The aim of the present study was to investigate the role of CAG repeat polymorphism and X-chromosome Inactivation (XCI) pattern in Recurrent Spontaneous Abortions among Indian women which has not been hitherto explored. 117 RSA cases and 224 Controls were included in the study. Cases were recruited from two different hospitals - Lakshmi Fertility Clinic, Nellore and Fernandez Maternity Hospital, Hyderabad. Controls were roughly matched for age, ethnicity and socioeconomic status. The CAG repeats of the Androgen Receptor gene were genotyped using a PCR-based assay and were analysed using the GeneMapper software to determine the CAG repeat length. XCI analysis was also carried out to assess the inactivation percentages. RSA cases had a significantly greater frequency of allele sizes in the polymorphic range above 19 repeats (p = 0.006), which is the median value of the controls, and in the biallelic mean range above 21 repeats (p = 0.002). We found no evidence of abnormal incidence of skewed X-inactivation. We conclude that longer CAG repeat lengths are associated with increased odds for RSA with statistical power estimated to be ∼90%.

Highlights

Recurrent Spontaneous Abortions (RSA) of unknown aetiology provide fundamental insights into the processes of embryogenesis and implantation and is a frustrating and emotionally charged clinical problem
We obtained a significant difference in the biallelic mean distribution pattern (Fig. 3) between the RSA cases and controls (p = 0.03) with the cases being more frequent in the upper polymorphic range
Our findings indicate that RSA women have a significantly greater frequency of longer androgen receptor (AR) CAG alleles (.19 repeats) and biallelic means ($21 repeats) than fertile control women

Summary

Introduction

Recurrent Spontaneous Abortions (RSA) of unknown aetiology provide fundamental insights into the processes of embryogenesis and implantation and is a frustrating and emotionally charged clinical problem. The results are essentially confounding, while some studies reported association of skewed Xinactivation with RSA [16,17,18], others did not Such studies have only been restricted to assess the skewed XCI pattern independent of the CAG repeat polymorphism among RSA women. Given the variation in the CAG repeat length of the androgen receptor (AR) gene and its inverse effect on the receptor activity, the alleles with longer CAG repeat length are expected to result in diminished androgen receptor activity, which might lead to a state of biochemical hyperandrogenism, i.e. increased serum levels of androgens as demonstrated in a couple of previous studies [5,7]. The present study was undertaken to investigate the possible role of the CAG repeat polymorphism and the XCI pattern in the manifestation of RSA in the southern Indian women with the underlying hypothesis that longer CAG repeat length (resulting in hyperandrogenemia) would be associated with RSA

Objectives

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Results

Conclusion