Human leukocyte antigen class II and III alleles and severity of hepatitis C virus-related chronic liver disease.
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.
Asti
M
M
Department of Pathology, Università and IRCCS Policlinico San Matteo, Pavia, Italy.
Martinetti
M
M
Zavaglia
C
C
Cuccia
M C
MC
Gusberti
L
L
Tinelli
C
C
Cividini
A
A
Bruno
S
S
Salvaneschi
L
L
Ideo
G
G
Mondelli
M U
MU
Silini
E M
EM
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D000368:Aged; D000483:Alleles; D015331:Cohort Studies; D015934:Complement C4a / Q000235:genetics; D015935:Complement C4b / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005802:Genes, MHC Class II / Q000235:genetics*; D006680:HLA Antigens / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000097:blood / Q000276:immunology*; D006579:Heterozygote; D006801:Humans; D008233:Lymphotoxin-alpha / Q000235:genetics; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D006680:HLA Antigens; D008233:Lymphotoxin-alpha; C073119:TAP1 protein, human; D014409:Tumor Necrosis Factor-alpha; C071692:TAP2 protein, human; D015934:Complement C4a; D015935:Complement C4b