Avaliação de polimorfismos de único nucleotídeo (SNPs) envolvidos com a gravidade da doença hepática crônica causada pelo vírus da hepatite C (HCV)

Abstract

The hepatitis C virus (HCV) represents a worldwide health problem, with over 170 million people infected all over the world, corresponding to almost 3% of the world’s population. Approximately 70% of the individuals will develop the chronic form of the disease; 25% will develop cirrhosis and about 5% among the cirrhotic will develop hepatocellular carcinoma (HCC). The reason why some individuals evolve more rapidly to the severe forms is still unknown, however, several studies have pointed the influence of genetic factors of the host which are involved with the disease progression in the liver. Single nucleotide polymorphisms (SNPs) are the most common type of genetic variation in humans, and they might alter serum levels or even the function of important proteins. Pentraxin 3 (PTX3) is an acute phase protein that is able to bind the surface of microorganisms and to regulate the complement system. Studies have demonstrated that PTX3 may influence positively the progression of various types of cancer. Additionally, some studies have demonstrated an important influence of a chromosomic region (6q23), associated with the progression of liver fibrosis in schistosomiasis. The IL22RA2 gene is located in this region e may be associated with the severity of fibrosis in HCV, once this gene codifies an inhibitor of an important cytokine correlated with the repair of liver damage, the interleukin-22 (IL-22). Thus, the aim of the present study was to associate the severity of the liver disease caused by HCV with SNPs in the PTX3 and IL22RA2 genes, as well as to identify new SNPs through exome sequencing approach. Patients with chronic hepatitis C were recruited and attended at the service of Gastrohepatology of the Oswaldo Cruz University Hospital/Liver Institute of Pernambuco (Recife, Pernambuco, Brazil) between August 2010 and December 2014. The detection of SNPs was performed by real time PCR using TaqMan probes (Thermo Fisher Scientific). Regarding the exome sequencing, it was used the IonTorrent platform (Thermo Fisher Scientific). A total of three studies were performed, the first study identified two polymorphisms (rs6570136 and rs2064501) on the IL22RA2 gene, associated with the severity of hepatic fibrosis, in a total of 532 patients. It was observed a higher frequency of genotypes GG/GA of rs6570136 and TT/TC of rs2064501 in the group of individuals with severe fibrosis (p=0,007 OR 1,7 and p=0,004 OR 2,4). On the second study, with a total of 524 patients, it was possible to notice a significant association of the genotype AA in the PTX3 gene (rs2305619) with risk of HCC (p=0.024 OR 1,94). Finally, the exome sequencing was carried in 9 HCC cases and 10 cirrhotic controls, where it was possible to identify two genes (PRSS58 and SOCS5), which are possibly associated with the development of HCC. Therefore, through this study we have demonstrated, for the first time, the association of SNPs in IL22RA2, PTX3, PRSS58 and SOCS5 with the progression of the hepatic disease caused by HCV. Other studies are needed in order to evaluate the use of these SNPs as progression markers of hepatitis C; as well as to evaluate the possible use of these molecules as therapeutic targets.