Association Study Between ERAP1Polymorphisms And The Infection Of Hepatitis C Virus And Non-small Cell Lung Cancer

Background:MHC class I antigen-presenting gene system plays a key role in effective response to virus. The endoplasmic reticulum aminopeptidase1(ERAP1) is a critical molecule in the antigen presentation and several studies have reported that its genetic polymorphism influences antigen presenting and causes different immune response, finally leading to different association with diseases. Till now, most of the studies were conducted to explore the association between the genetic polymorphism of ERAP1and the pathogenesis of autoimmune disorder. However, whether the ERAP1genetic polymorphism is associated with hepatitis C virus (HCV) infection and the risk of non-small cell lung cancer (NSCLC) through affecting antigen presenting remains to be elucidated. Furthermore, located in the southwest of China, Yunnan province serves as a very important gateway for the propagation of HCV-associated hematologic diseases, which makes the distribution of HCV showing different from other regions in China. So present investigation was undertaken for the first time to explore the association between ERAP1and the infection of hepatitis C and non-small cell lung cancer. In addition, combining with the characteristics of HCV infection in Yunnan, preliminary study was also conducted to explore the relationship between different HCV genotypes and ERAP1genetic polymorphisms.Methods:Present study included three sections. In the first section, a total of376patients with HCV infection and324healthy controls in Yunnan province were obtained to investigate the association of ERAP1genetic polymorphisms and HCV infection. Taq Man probe genotyping was employed to detect the genetic polymorphism of ERAP1and the correlation of HCV infection was analyzed. In the second section, HCV genotypes and subtypes was investigated in general population (GP) of HCV infection in Yunnan province. HCV NS5B fragments were amplified using RT-PCR method and subsequently sequenced, to exploring the epigenetic tendency of HCV in GP. Thereafter, combined with the ERAP1gene information of HCV infection, the association of different HCV genotypes and ERAP1genetic polymorphisms were analyzed. In the third section, a total of224NSCLC patients and207matched healthy controls in Yunnan province was collected to study the association of ERAP1genetic polymorphism and the risk of NSCLC via Taq Man probe genotyping technique. Results:(1) The distribution of four SNPs in HCV infection and healthy control groups was according to HWE balance. The genotype and allelic frequencies of ERAP1rs26618in case groups was evidently different from those in control group (P<0.05). In addition, the haplotype of rs27044/rs30187/rs26618/rs26653-CCCG was significant in case group than those in controls (P<0.05).(2) Four HCV genotypes (1,2,3and6) and seven HCV subtypes(lb,2a,3a,3b,6a,6n and6k) were found among GP in Yunnan province. The HCV genotype3, was predominant(0.484), followed by genotype1(0.283),6(0.133) and2(0.100), HCV subtype3b(0.292) and1b(0.283) were the most common subtypes. Comparing HCV genotypes among GP in Yunnan with other regions in China, the frequency of HCV genotype1and3in Yunnan was different from that in Chongqing and Guangdong, but was similar to that in Guangxi. As to HCV genotype6be considered, it showed a similar frequency in Yunnan and Chongqing. Whereas, there was a significant difference between Yunnan and Guangxi, Guangdong, Vietnam, Myanmar (P＜0.05). Comparing with HCV genotypes among GP with IDUs in Yunnan, the frequencies of HCV genotypes (1,2and6) and subtypes (1b,2a,6a and6n) were differentially distributed (P<0.05). Similarly, the HCV genotype had a "crossing" distribution between GP and IDUs in Yunnan. The genotype frequencies of ERAP1rs30187in different HCV genotypes(1,2,3and6) as well as in different HCV subtypes(1b,2a,3a,3b,6n) showed difference (P＜0.05).(3) The genotype distribution of two SNPs in NSCLC and healthy control groups were according to HWE balance. The difference of the genotypes and allelic frequencies of ERAP1rs26618and rs26653were investigated (P<0.05). The haplotype frequency of rs26618/rs26653-CG/TC was remarkably different in case and control groups (P<0.05). Nevertheless, the genotypes and allelic frequencies of ERAP1rs26618and rs26653had no statistical significance in patients with adenocarcinoma, squamous cell carcinoma, Phase Ⅰ+Ⅱ NSCLC and Phase III+IV NSCLC (P>0.05).Conclusions:(1) The genetic polymorphism of ERAP1was closely associated with the HCV infection, among which the haplotype of rs27044/rs30187/rs26618/rs26653-CCCG might increase the risk of HCV infection (OR=1.311,95%CI:1.028-1.671).(2) It was concluded that the distribution of HCV genotypes and subtypes among GPs in Yunnan province were markedly different from those in IDUs. Furthermore, the HCV genotypes and subtypes were spreading from IDUs to GP. And different HCV genotypes and subtypes were associated with ERAP1genetic polymorphisms.(3) ERAP1polymorphisms were associated with the susceptibility of NSCLC. In details, the haplotype of rs26618/rs26653-CG was likely to increase the risk of NSCLC(OR=1.725,95%CI:1.270-2.343), the haplotype of rs26618/rs26653-TC was likely to exert a protective role on NSCLC (OR=0.668,95%CI:0.510-0.874).