title: The haplotype block, NFKBIL1-ATP6V1G2-BAT1-MICB-MICA, within the class III-class I boundary region of the human major histocompatibility complex may control susceptibility to hepatitis C virus-associated dilated cardiomyopathy.
abstract: Cardiomyopathy is a heart muscle disease with impaired stretch response that can result in severe heart failure and sudden death. A small proportion of hepatitis C virus (HCV)-infected patients may be predisposed to develop dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). The molecular mechanisms involved in the predisposition remain unknown due in part to the lack of information on their genetic background. Because the human leukocyte antigen (HLA) region has a pivotal role in controlling the susceptibility to HCV-induced liver disease, we hypothesized that particular HLA alleles and/or non-HLA gene alleles within the human major histocompatibility complex (MHC) genomic region might control the predisposition to HCV-associated DCM (HCV-DCM) and/or HCV-associated HCM (HCV-HCM). Here, we present mapping results of the MHC-related susceptibility gene locus for HCV-associated cardiomyopathy by analyzing microsatellite and single nucleotide polymorphism markers. To delineate the susceptibility locus, we genotyped 44 polymorphic markers scattered across the entire MHC region in a total of 59 patients (21 HCV-DCM and 38 HCV-HCM) and 120 controls. We mapped HCV-DCM susceptibility to a non-HLA gene locus spanning from NFKBIL1 to MICA gene loci within the MHC class III-class I boundary region. Our results showed that HCV-DCM was more strongly associated with alleles of the non-HLA genes rather than the HLA genes themselves. In addition, no significant association was found between the MHC markers and HCV-HCM. This marked difference in the MHC-related disease susceptibility for HCV- associated cardiomyopathy strongly suggests that the development of HCV- DCM and HCV-HCM is under the control of different pathogenic mechanisms.
authors.affiliation: Department of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Shichi
authors.forename: E F
authors.initials: EF
authors.lastname: Kikkawa
authors.forename: M
authors.initials: M
authors.lastname: Ota
authors.forename: Y
authors.initials: Y
authors.lastname: Katsuyama
authors.forename: A
authors.initials: A
authors.lastname: Kimura
authors.forename: A
authors.initials: A
authors.lastname: Matsumori
authors.forename: J K
authors.initials: JK
authors.lastname: Kulski
authors.forename: T K
authors.initials: TK
authors.lastname: Naruse
authors.forename: H
authors.initials: H
authors.lastname: Inoko
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D002311:Cardiomyopathy, Dilated / Q000276:immunology* / Q000821:virology; D002312:Cardiomyopathy, Hypertrophic / Q000276:immunology* / Q000821:virology; D002874:Chromosome Mapping; D053487:DEAD-box RNA Helicases; D017931:DNA Primers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D016678:Genome; D005838:Genotype; D006680:HLA Antigens / Q000276:immunology; D006239:Haplotypes; D016174:Hepacivirus / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D000949:Histocompatibility Antigens Class II; D006801:Humans; D015810:Linkage Disequilibrium; D018895:Microsatellite Repeats / Q000235:genetics; D008957:Models, Genetic; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D020365:RNA Helicases / Q000235:genetics*; D012306:Risk; D016896:Treatment Outcome; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C099187:MHC class I-related chain A; C098080:MICB antigen; C120111:NFKBIL1 protein, human; C506469:ATP6V1G2 protein, human; C487886:DDX39B protein, human; D025262:Vacuolar Proton-Translocating ATPases; D053487:DEAD-box RNA Helicases; D020365:RNA Helicases