Epistatic Effects of Immunoglobulin GM and KM Allotypes on Outcome of Infection with Hepatitis C Virus

Abstract

Immunoglobulin GM and KM allotypes-genetic markers of ␥ and chains, respectively-are associated with immune responsiveness to several infectious pathogens and with survival in certain viral epidemics. We hypothesized that GM and KM allotypes affect the outcome of hepatitis C virus (HCV) infection. To test this hypothesis, we serologically allotyped 100 persons with well-documented clearance of HCV infection and 198 matched persistently infected persons. None of the GM or KM phenotypes by itself was associated with the clearance or persistence of HCV infection. Particular combinations of these phenotypes, however, were significantly associated with the outcome of HCV infection. Subjects with GM 1,17 5,13 and KM 1,3 phenotypes were over three times (odds ratio Hepatitis C virus (HCV) is a major health problem, affecting over 170 million people worldwide (47). Of persons acutely infected with HCV, about 15% spontaneously clear the virus. Among the factors influencing the outcome of HCV infection, the host genetic factors are thought to play a predominant role. Reports from several studies documenting consistent associations of particular HLA alleles with viral persistence and clearance support this contention (40,41,43). Allelic variation at the HLA loci, however, accounts for only a small percentage of the total interindividual variation in the outcome of HCV infection (41), suggesting involvement of additional genetic factors that might modify the host immune responsiveness to this pathogen.[Immunoglobulin (Ig) GM and KM allotypes-hereditary antigenic determinants of IgG heavy chains and -type light chains, respectively-are associated with viral immunological properties and thus are ideal candidate genetic systems for investigations to identify risk-conferring factors in HCV pathogenesis. GM and KM allotypes are associated with the susceptibility to and outcome of infection by several infectious agents (1-3, 6-13, 21, 23-26, 28-30, 33, 35). GM allotypes are strongly associated with IgG subclass concentrations (19,22,27,34), making them relevant to viral immunity, as the antibody responses to most viral epitopes appear to be IgG subclass (IgG1 and IgG3) restricted (15,37,39).These observations led us to hypothesize that GM and KM allotypes might contribute to the outcome of HCV infection through their possible influence on allotype-restricted antibody responses to the viral antigens. In addition, since particular GM and KM phenotypes have been shown to interact in influencing humoral immunity to certain viral epitopes (1), we wished to determine whether such epistatic interactions were associated with the outcome of HCV infection. MATERIALS AND METHODSStudy population. Between 1988 and 1989, a cohort was recruited in Baltimore, Md., of persons who had injected illicit drugs in the preceding 10 years, were more than 17 years of age, and were free of manifestations of AIDS (44). Within this cohort, a subset of 1,667 individuals was identified as the HCV subcohort because they had antibodies to HCV and had made at le...

Hepatitis C Virus Core Protein Discriminates Between the Two IgG2 Allotypes

“…This would suggest a higher prevalence of GM23 in subjects with persistent HCV infection compared to those who have cleared the virus. This appears to be the case in a study population we reported on earlier (8). Among subjects with persistent HCV infection (n ϭ 196), there were 51 subjects (26%) CORE PROTEIN AND IgG 2 ALLOTYPES carrying the GM23 allele, while among patients that cleared the virus (n ϭ 99), there were 22 subjects (22%) carrying the GM23 allele.…”

“…Among the factors influencing the outcome of HCV infection, the host genetic factors are thought to play a predominant role (4,6). We have previously reported involvement of immunoglobulin (Ig) GM and KM allotypes-genetic markers of ␥ and chains, respectively-in the outcome of HCV infection (8). The mechanisms underlying this association are not completely understood.…”

Innate IgG Molecules and Innate B Cells Expressed by Immunoglobulin Constant Heavy G Chain (Fcγ) Genetic Marker Genes Are Involved in the ‘Allergic March' of IgE Sensitization in Children

“…Individuals with the IGHG * bfn haplotype are high producers of antibodies against encapsulated bacteria and in vaccination with bacterial polysaccharides [22,23]. The influence of viral particles acting as FcγRs with preference of binding to different IGHG (Fcγ) allotypes [25,26,27] is important and can be applied also to allergic disease, possibly related to exacerbations. Severe infections in infants with respiratory syncytial virus are associated with the IGHG * bf-n/ * bf-n diplotype and the IGHG2 * -n alleles [35].…”

“…Allergens, bacteria [22,23] and virus [25,26,27] affect IGHG genes of individuals differently and relate to the diseases as allergy [7,8,9,10,11,12], primary immunodeficiency [28], autoimmunity [29,30] and malignancy [31,32]. …”

Immunoglobulin GM and KM Allotypes and Prevalence of Anti-LKM1 Autoantibodies in Patients with Hepatitis C Virus Infection

“…They also influence immune responsiveness to infectious epitopes as well as to certain autoantigens (10,25,26,28,29). Of particular relevance here, certain GM and KM determinants interact to influence the outcome of HCV infection (22). These observations led us to hypothesize that GM and KM allotypes may contribute to the generation of anti-LKM1 autoantibodies in HCV-infected subjects.…”