Association Of U2 - Dependent MRNA Splicing Complex - Associated Gene Polymorphism With The Risk Of Primary

BackgroundPrimary liver cancer (PLC) is the sixth most common cancer worldwide and the third most common cause of cancer mortality. Neoplasm of PLC might involve multiple environmental and genetic factors.Since 2011, gene mutations of spliceosome proteins, in particular mutation of U2-dependent spliceosome, have been reported associated with risk of several kinds of neoplasms such as Chronic Myelogenous Leukemia, breast cancer and pancreatic cancer.ObjectiveThis research is to determine the association between U2-dependent spliceosome related key genes and PLC, and their interaction with major environmental factors of PLC, including HBsAg positive, smoking and use of alcohol.MethodsA hospital-based, two-stage case-control study was conducted. In the screening stage,378 PLC incident cases and 461 controls who were adults attended regular med-check and without Neoplasms were chosen in a period of may of 2009 to June of 2012 in Tongji tertiary hospital of Wuhan,Hubei province.17 candidate tag single nucleotide polymorphisms (tagSNPs) were genotyped by Taqman Openarray assay, then we analysis the association between candidate SNPs and PLC under different genetic model and evaluate the interaction between smoking, drinking and infection of HBV in this sample. In validation stage,428 cases and 647 controls were chosen in a period of September of 2007 to Sept of 2009 in a tertiary hospital of Beijing. SNPs observed link to PLC in the sample of the screening stage were validated in second case-control sample by TaqMan real-time polymerase chain reaction.Results1. Four tagSNPs, including rs2074733, rs5994293, rs7288947 and rs9608886 in SF3A1 gene was significantly associated with PLC in the screening stage.2. We verified 4 SNPS in the validation stage, only rs5994293 was still associated with PLC in validation sample. Individuals with G allele had a lower risk of PLC compared to those with the TT genotype (OR=0.66,95%CI:0.44-0.99,P=0.042)for the combined sample.3. Considering the strong linkage disequilibrium of rs7288947-rs5994293 in SF3A1 gene.Haplotype CG of rs7288947-rs5994293 was significantly associated with PLC in both stage one sample and combined sample. Subjects with haplotype CG of rs7288947-rs5994293 had a lower risk of PLC compared to those with the haplotype CT with OR of 0.67(95%CI:0.55-0.82, P=0.001)for the combined sample.4. In combined analysis of two stages, HBsAg positive was shown to be risk factor for PLC risk, with OR of 50.70(95%CI:37.08-69.31) compared with HBsAg-negative individuals. Besides, smoking was associated with PLC risk, with an OR of 1.36(95% CI: 0.99-1.87) for smokers compared with non-smokers.5. Significantly gene-environment between the rs5994293 polymorphism and smoking or drinking interactions and environment-environment between HBsAg and smoking or drinking were found. The additive interaction of smoking, drinking and rs5994293 TT was observed in HBsAg negative subjects of the combined sample and the SI is 2.27(95%CI:1.43-3.12). The additive interaction of smoking, drinking and HBsAg was observed in combined sample and the SI is 2.12(95%CI:1.59-2.65),1.83 (95%CI:1.26-2.40).ConclusionIndividuals with SF3A1-rs5994293 TT genotype may increase risk of PLC; Those subjects with smoking and drinking may increase risk of PLC in HBsAg negative population. The findings should be confirmed by further independently large-scale population-based studies and functional analysis.