Haplotype Analyses of DNA Repair Gene Polymorphisms and Their Role in Ulcerative Colitis

Avinash Bardia,Shaik A Sultana,Yugandhar P Reddy,Md Aejaz Habeeb,Aleem A Khan,Sandeep K Vishwakarma,Santosh K Tiwari,Pratibha Nallari,Shaik A Pasha,Javier S Castresana

doi:10.1371/journal.pone.0108562

Avinash Bardia, Shaik A Sultana + Show 8 more

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https://doi.org/10.1371/journal.pone.0108562

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Abstract

Ulcerative colitis (UC) is a major clinical form of inflammatory bowel disease. UC is characterized by mucosal inflammation limited to the colon, always involving the rectum and a variable extent of the more proximal colon in a continuous manner. Genetic variations in DNA repair genes may influence the extent of repair functions, DNA damage, and thus the manifestations of UC. This study thus evaluated the role of polymorphisms of the genes involved in DNA repair mechanisms. A total of 171 patients and 213 controls were included. Genotyping was carried out by ARMS PCR and PCR-RFLP analyses for RAD51, XRCC3 and hMSH2 gene polymorphisms. Allelic and genotypic frequencies were computed in both control & patient groups and data was analyzed using appropriate statistical tests. The frequency of ‘A’ allele of hMSH2 in the UC group caused statistically significant increased risk for UC compared to controls (OR 1.64, 95% CI 1.16–2.31, p = 0.004). Similarly, the CT genotype of XRCC3 gene was predominant in the UC group and increased the risk for UC by 1.75 fold compared to controls (OR 1.75, 95% CI 1.15–2.67, p = 0.03), further confirming the risk of ‘T’ allele in UC. The GC genotype frequency of RAD51 gene was significantly increased (p = 0.02) in the UC group (50.3%) compared to controls (38%). The GC genotype significantly increased the risk for UC compared to GG genotype by 1.73 fold (OR 1.73, 95% CI 1.14–2.62, p = 0.02) confirming the strong association of ‘C’ allele with UC. Among the controls, the SNP loci combination of hMSH2:XRCC3 were in perfect linkage. The GTC and ACC haplotypes were found to be predominant in UC than controls with a 2.28 and 2.93 fold significant increase risk of UC.

Highlights

The repair of damaged DNA forms an integral part of cell rejuvenation and is known to protect against different diseases [1]
The human mutS homolog 2 (hMSH2) gene is located on chromosome 2p21, an area initially identified as an important candidate region for genes involved in hereditary nonpolyposis colorectal cancer (HNPCC) [9]. hMSH2 can form a heterodimer with one of the two other mismatch repair proteins, hMSH6 or hMSH3 [10]
The frequency of ‘A’ allele was found to be predominant in Ulcerative colitis (UC) group compared to controls (27% vs 18% respectively), with a 1.64 folds increased risk for UC (Table 1)

Summary

Introduction

The repair of damaged DNA forms an integral part of cell rejuvenation and is known to protect against different diseases [1]. An amino acid substitution at codon 322 (Gly322Asp) of hMSH2 may affect the heterodimer formation with other proteins. The XRCC3 and RAD51 gene encodes protein involved in homologous recombinational repair (HRR) of double strand DNA [11]. The XRCC3 gene has a sequence variation in exon 7 (C18067T), which result in an amino acid substitution at codon 241 (Thr241Met). This substitution may affect its interaction with other proteins involved in DNA damage and repair [12]. Two important meta-analyses [15,16], covering tens of other studies and thousands of subjects, were unanimous to state that the variant allele of RAD51 G135C may contribute to increased breast cancer susceptibility, which is in accordance with biological function study, which showed a more aggressive and poor prognosis phenotype [17]

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