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Functional polymorphism in the 5'-UTR of CR2 is associated with susceptibility to nasopharyngeal carcinoma.

ABSTRACT: Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is a squamous cell cancer endemic in Southern China and Southeast Asia. It has been shown that inflammatory and immune responses during EBV infection contribute to the development of NPC. The complement receptor 2 (CR2) gene plays central roles during inflammatory and immune responses and, therefore, is a good candidate susceptibility gene for NPC. We performed PCR-based sequencing to identify multiple single-nucleotide polymorphisms (SNPs) within the exon regions of the CR2 gene in a Cantonese population. Two SNPs were screened in 528 NPC patients and 408 normal individuals to perform a case-control study matched according to age, gender and residence. Furthermore, we cloned the entire 5'-UTR and entire CR2 promoter into a luciferase report system and compared the luciferase activities between the different allelic constructs. A SNP in the 5'-UTR of CR2 (24 T/C, rs3813946) showed a significant association (P<0.01) with NPC in the Cantonese population studied. The subjects were categorized into 2 age groups: group 1, age ?45 years and group 2, age >45 years. In group 1, the allelic frequencies of 24 T/C in the patients were significantly different from those of the controls (P=0.0034). The odds ratio (OR=1.81) also indicated a higher risk of NPC in individuals who carried the minor allele C. All constructs exerted allelic differences on luciferase activities, but only the susceptible allele +24C construct showed increased activity. Our findings implicate CR2 as a susceptibility gene for NPC and suggest that enhanced CR2 expression may be involved in the oncogenesis and development of NPC.

SUBMITTER: Fan Q

PROVIDER: S-EPMC3729234 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Functional polymorphism in the 5'-UTR of CR2 is associated with susceptibility to nasopharyngeal carcinoma.

Fan Qin Q He Jun-Fang JF Wang Qi-Rui QR Cai Hong-Bing HB Sun Xue-Gang XG Zhou Xin-Xi XX Qin Hai-De HD Shugart Yin Yao YY Jia Wei-Hua WH

Oncology reports 20130423 1

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is a squamous cell cancer endemic in Southern China and Southeast Asia. It has been shown that inflammatory and immune responses during EBV infection contribute to the development of NPC. The complement receptor 2 (CR2) gene plays central roles during inflammatory and immune responses and, therefore, is a good candidate susceptibility gene for NPC. We performed PCR-based sequencing to identify multiple single-nucleotide polymorph ...[more]

PMID: 23612877

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Project description:ObjectiveSingle-nucleotide polymorphism (SNP) rs143383 (T to C) in the 5'-untranslated region (5'-UTR) of GDF5 has recently been reported to be associated with osteoarthritis (OA) susceptibility, with lower expression of the risk-associated T allele observed in vitro and in vivo. The in vivo studies were performed on cartilage tissue from OA patients. The present study was undertaken to expand the analysis of the effect of this SNP on GDF5 allelic expression to more joint tissue types, to investigate for cis and trans factors that interact with the SNP, and to examine novel cis-acting GDF5 regulatory polymorphisms.MethodsTissue samples were collected from OA patients undergoing joint replacement of the hip or knee. Nucleic acid was extracted, and, using rs143383 and an assay that discriminates and quantifies allelic expression, the relative amount of GDF5 expression from the T and C alleles was measured. Additional common variants in the GDF5 transcript sequence were interrogated as potential regulatory elements using allelic expression and luciferase reporter assays, and electrophoretic mobility shift assays were used to search for trans factors binding to rs143383.ResultsWe observed a consistent allelic expression imbalance of GDF5 in all tissues tested, implying that the functional effect mediated by rs143383 on GDF5 expression is joint-wide. We identified a second polymorphism, located in the 3'-UTR of GDF5, that influenced allelic expression of the gene independent of rs143383. Finally, we observed differential binding of deformed epidermal autoregulatory factor 1 (DEAF-1) to the 2 alleles of rs143383.ConclusionThese findings show that the OA susceptibility mediated by polymorphism in GDF5 is not restricted to cartilage, emphasizing the need to consider the disease as involving the whole joint. The existence of an additional cis-acting regulatory polymorphism highlights the complexity of the regulation of expression of this important OA susceptibility locus. DEAF-1 is a trans-acting factor that merits further investigation as a potential tool for modulating GDF5 expression.

Dataset Information

Functional polymorphism in the 5'-UTR of CR2 is associated with susceptibility to nasopharyngeal carcinoma.

Publications

Functional polymorphism in the 5'-UTR of CR2 is associated with susceptibility to nasopharyngeal carcinoma.

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