Polymeric immunoglobulin receptor polymorphisms and risk of nasopharyngeal cancer

Abstract

Background: Epstein-Barr virus (EBV) associated nasopharyngeal cancer (NPC) is an important squamous cell cancer endemic in Southeast Asia and the Far East and can be considered a multifactorial genetic disease. This research explores potential associations between nasopharyngeal epithelial EBV receptor and NPC susceptibility. To prove the hypothesis, we evaluated two candidate genes, complement receptor 2 (CR2) and polymeric immunoglobulin receptor (PIGR) by using 4 SNPs, CR2IVS2-848C-->T, PIGRIVS3-156G-->T, PIGR1093G-->A and PIGR1739C-->T, to genotype 175 cases and 317 controls, divided into Thai, Chinese and Thai-Chinese based on their respective ethnic origins.

Results: The results obtained indicated that PIGR is an NPC susceptibility gene. The risk association pertaining to each ethnic group was detected for homozygous PIGR1739C with a significant ethnic group adjusted OR (95%CI) of 2.71(1.72-4.23) and p < 0.00001. Haplotype of the two missense PIGR SNPs, 1093G-->A and 1739C-->T, and sequence analyses have confirmed the role of the nucleotide PIGR1739 and excluded possibility of an additional significant nonsynonymous NPC susceptibility SNP.

Conclusions: We present genetic evidence leading to hypothesize a possibility of PIGR to function as the EBV nasopharyngeal epithelium receptor via IgA-EBV complex transcytosis failure. The PIGR1739C-->T is a missense mutation changing alanine to valine near endoproteolytic cleavage site. This variant could alter the efficiency of PIGR to release IgA-EBV complex and consequently increase the susceptibility of populations in endemic areas to develop NPC.

Figure 1

SNPs analysis of CR2 and PIGR. (A) The CR2IVS2-848C→T was distinguishable by TaqI restriction. Digestion of the 1241 bp amplicon yielded two DNA fragments, 750 and 491 bp. Lane 1, 3 and 4 were homozygous -/- and lane 2 was heterozygous +/-. (B-D) PIGR polymorphisms was investigated by PCR-RFLP and ARMS. (B) RFLP analysis of 1392 bp PIGRIVS3-156G→T PCR products with PvuII digestion yielded 1163 and 229 bp DNA fragments. Lane 1,2,4,7 and 8 were heterozygous +/-, samples 3,9 and 12 were homozygous +/+, and samples 5,6,10 and 11 were homozygous -/-. (C) RFLP of PIGR1739C of the 220 bp PCR product was analyzed by HgaI digestion and yielded two fragments of 180 and 40 bp, respectively, whereas 1739T remained as 220 bp DNA product. Heterozygous CT yielded 220,180 and 40 bp fragments. Negative control in lane1; homozygous CC in lanes 2,5,7 and 8; heterozygous CT in lanes 3 and 6, and homozygous TT in lane 4. (D) PIGR1093G→A was detected by ARMS. Negative control in lanes 1 and 2 for primer sets A and B. Samples S1, 2, 3, were homozygous 1093G. Samples S4, 5, 6 were homozygous 1093A, and S7 was heterozygous.