Human Leukocyte Antigen Class Ii and Iii Alleles and Severity of Hepatitis C Virus-Related Chronic Liver Disease

Abstract

Hepatitis C outcome is likely related both to viral factors and host's immune responses. We correlated the severity of liver disease with human leukocyte antigen (HLA) genes (C4A, C4B, TNFA, TNFB, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, TAP1, and TAP2) in three groups of subjects: 99 patients with chronic hepatitis, 41 asymptomatic carriers, and 179 uninfected controls. Patients with grade/stage 3 to 4 hepatitis significantly differentiated for their low frequency of alleles TNFB*1, DRB1*1104, and DRB3*03, which had a protective role, and high frequency of allele DRB1*1001, which was associated with disease severity. HLA-DRB*11 subtypes were differentially distributed: DRB1*1104 was most frequent in carriers, whereas DRB1*1101 was more frequent in patients. The TAP1C,2A haplotype was also underrepresented in patients with respect to controls. Finally, a decrease of heterozygous subjects was observed in patients with respect to carriers at the DQB1 locus. Multivariate analysis by correspondence analysis and multiple logistic regression indicated that age, sex, and hepatitis C virus (HCV) type were the strongest risk factors; however, some immunogenetic variables (TNFB*1, DRB1*1104, and DRB3*03) showed an independent contribution, especially in comparing patients with extreme manifestations of disease. The involvement of different genes in various HLA subregions suggests that anti-HCV responses are modulated by a complex gene interplay rather than by single alleles. (HEPATOLOGY 1999;29: 1272-1279.)Hepatitis C virus (HCV) is the major cause of chronic liver disease in Italy and accounts for over 70% of cirrhosis and hepatocellular carcinomas. 1 HCV infection results in high rates of chronicization and in a broad spectrum of liver lesions, ranging from mild inflammation to liver failure.Mechanisms underlying viral persistence and liver damage in chronic HCV infection are marginally known, a complex interplay of viral and immunologic factors being likely involved. Immunomediated mechanisms are believed to play a major role, 2-4 as is suggested by the lack of evidence for a cytopathic effect of the virus, 2 the severe course of infection in immunosuppressed patients, 5 the frequent occurrence of immunologic disorders, 6 and the cytokine-mediated expression of immunoregulatory molecules in the infected liver. 7

Viral clearance in hepatitis C (1b) infection: Relationship with human leukocyte antigen class II in a homogeneous population

“…27 This apparent lack of agreement among studies may reflect both viral and study group heterogeneity and/or the influence of specific polymorphisms in immunoregulatory genes in linkage disequilibrium with the HLA class II alleles. 26,37 Evidence from the study presented here and others may lead to the identification of crucial T-cell epitopes presented by HCV 1b-infected cells, which stimulate virus clearance.…”

“…Additionally, the DRB1*1104 and DQB1*0301 alleles have been found by many groups to occur with significantly greater frequency in those individuals who had a self-limiting HCV infection. 23,26,35,36 However, DRB1*1104 is reported to have an association with viral persistence in a recently reported investigation. 27 This apparent lack of agreement among studies may reflect both viral and study group heterogeneity and/or the influence of specific polymorphisms in immunoregulatory genes in linkage disequilibrium with the HLA class II alleles.…”

“…[24][25][26][27] We have circumvented this by comparing HLA frequencies between patients who have persistent viremia and those who have evidence of past infection but effected viral clearance, and where all of the individuals were exposed to HCV 1b from the same source. An additional advantage to investigating which immunogenetic elements are important in the immune response to HCV in a single source outbreak of iatrogenic HCV infection, is that these elements are more easily detected in patient cohorts with similar ethnogeograhphic backgrounds.…”

“…[18][19][20][21][22] Although HLA class II genes have shown associations with viral clearance or persistence of the HCV these findings are not uniform. [23][24][25][26][27][28] In addition, direct comparisons between studies is often difficult because of heterogeneity of ethnic background, viral genotype, phenotype frequencies of individual alleles between populations, gender, and duration of disease. To avoid heterogeneity of risk factors and confounding variables in viral type/subtype we studied a unique cohort of individuals all infected by anti-D contaminated from a single source of HCV 1b.…”

Host genetic determinants in hepatitis C virus infection

“…71,72 Studies of HCV progression or severity of disease A total of 44 studies were found to address the topic of host genetics and HCV progression, severity or activity of disease, and have largely been inconsistent. 16,18,27,29,32,34,37,39,47,[68][69][70]80, There is a trend with DRB1*11 alleles and less severe liver disease. Asti 68 reported an association between DRB1*1201 with less severe liver disease (OR not reported) as well.…”