Genetic Association Between Candidate Genes Polymorphisms And Susceptibility To Chronic Hepatitis B, Hepatocellular Carcinoma And Nasopharyngeal Carcinoma In Chinese Population

Our country with the largest population has most abundant disease population in the world. Spectrums of disease in China have both characteristics of developed countries and developing countries. Some proper or high incidence disease in China, such as nasopharyngeal carcinoma(NPC), hepatocellular carcinoma(HCC) and chronic hepatitis B(CHB), which is the most serious and common infectious in China, remain higher incidence in developed region of China than in western country. Above-mentioned diseases, which endanger public health, all have its heredity. The main form of this heredity is single nucleotide polymorphism (SNP). The identification of susceptibility genes contributing to these disorders may help to clarify the pathogenesis and improve the prevention and treatment of these malignancies.Hepatitis B virus (HBV) infection is one of the major infectious diseases. The clinical course of HBV infection varies from spontaneous recovery after acute hepatitis to chronic persistent infection, including asymptomatic carrier, chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The immune response initiated by the T-cell response to HBV antigens is thought to be fundamental for viral clearance and disease pathogenesis in HBV infection. Activation of lymphocytes requires a second signal through constitutively expressed co-stimulatory receptors and ligands. We evaluated 41 htSNP of 15 co-stimulators genes (include TNFRSF4, TNFSF4, CD40, CD40L, TNFRSF9, TNFSF9, CD80, CD86, CD28, CTLA4, PDCD1, CD274, PDCD1LG2, ICOS, and ICOSL) and their effects on the diseases progression of HBV infection association in a population-based case-control study of 192 asymptomatic carriers (ASC), 73 chronic hepatitis B (CHB) patients. The polymorphisms were genotyped with Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The association between these polymorphisms and disease status was evaluated with unconditional logistic regression and adjusted for age, sex, status of smoking and drinking, and pack-years of smoking. Considering multiple testing, we adjusted P value by Bonferroni and False discovery rate (FDR) method. Our study shows that T-1722C polymorphism in CTLA4 promoter region is associated with CHB susceptibility. Individuals with the T/T homozygous were over twice as likely (OR = 2.66, 95% CI = 1.46-4.88, P = 0.0015) to develop the disease compared with those C/T or T/T genotypes. Our results implicate that CTLA4 in susceptibility to CHB, while T-1722C is susceptible SNP for CHB. CTLA4 may play an important role in pathogenesis of CHB.In China, hepatitis B virus infection is main risk factor, together with aflatoxin intake from contaminated food. However, not all individuals explored to risk factor develop HCC. NPC is the serious health problems in southern Chinese, with an incidence rate ranging from 15 to 50/100000. These incidence rates are almost 100-fold higher than in the Caucasian populations. So host genetic factors may play important roles in these disease progressions. There is growing evidence that chromosomal and genetic alterations arising from flawed DNA synthesis or altered methylation of oncogenes and tumor suppressor genes may influence susceptibility to cancers. The 5,10-methylenetetrahydrofolate reductase (MTHFR) acts at a critical juncture in DNA synthesis and methylation. We examined whether these two functional polymorphisms, i.e. C677T and A1298C, were related to the risk of hepatocellular carcinoma (HCC) and nasopharyngeal carcinoma (NPC) in Chinese population. The C677T and A1298C polymorphism were genotyped in 328 patients with HBV related HCC, 593 patients with NPC and 480 control by PCR-RFLP method. The association between these polymorphisms and disease status was evaluated while controlling for confounding factors. However, we found no evidence for significant association between the C677T and A1298C polymorphism and risk of HCC and NPC. When the analyses were stratified by age, sex, status of smoking and drinking, and pack-years of smoking, the association remained negative. Our findings therefore suggest that the MTHFR C677T and A1298C polymorphisms may not play a major role in mediating susceptibility to HCC and NPC.