Pediatric and adult forms of type I autoimmune hepatitis in Argentina: Evidence for differential genetic predisposition

Marcelo Pando, Julian Larriba, Gabriela C. Fernandez, Hugo Fainboim, Mirta Ciocca, Margarita Ramonet, Isabel Badia, Jorge Daruich, Jorge Findor, Hugo Tanno, Cristina Canero-Velasco, Leonardo Fainboim

Research output: Contribution to journalArticle

150 Citations (Scopus)

Abstract

The aim of this study was to compare major histocompatibility complex (MHC) class II susceptibility to type 1 autoimmune hepatitis (AH) between children and adults of the same ethnic group. HLA-DRB1, HLA-DRB3, HLA-DQA1, and HLA-DQB1 gene subtypes were examined by high resolution oligonucleotide typing in 122 pediatric (PAH) and 84 adult (AAH) patients and in 208 controls. In children, HLA-DRB1*1301 was the primary susceptibility allele (66.4% patients vs. 10.6% controls, relative risk [RR] = 16.3, Pc < 10-24) whereas HLA-DRB1*1302, which differs from HLA-DRB1*1301 by only 1 amino acid, appeared to be protective. The exclusion of individuals with HLA- DRB1*1301 from control and pediatric patients allowed us to find a secondary association of PAH with HLA-DRB1*0301. Possession of HLA-DRB1*1301, however, was associated with a lower therapeutic response rate. Analysis of peptide binding pocket residues indicated that Tyr 10, Ser 11, Ser 13, and Val 86 in the class II β chain were present in 85% of patients compared with 37% of controls, suggesting that a high proportion of AH susceptibility is attributable to these residues (etiologic fraction [EF] = 76%). In contrast to the class II associations in children, AAH was associated with HLA- DRB1*0405 (RR = 10.4, Pc < .005) but not with HLA-DRB1*1301 or HLA- DRB1*0301. In addition, HLA-DR4 with the class I gene, HLA-A11, appeared synergistic in predisposing AAH patients to develop extra-hepatic autoimmune (AI) manifestations (odds ratio [OR] = 104.9, Pc < 10-4). Concomitant differences in autoantibody profiles were also observed in PAH versus AAH: smooth muscle antibodies (SMA) were most prevalent in PAH but antinuclear antibodies were most prevalent in AAH (P = .003). This study therefore reveals that different HLA-DRB1 allotypes confer susceptibility to AH in children and adults and raises the possibility that PAH and AAH may be triggered by different factors.

Original languageEnglish (US)
Pages (from-to)1374-1380
Number of pages7
JournalHepatology
Volume30
Issue number6
StatePublished - 1999
Externally publishedYes

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HLA-DRB1 Chains
Autoimmune Hepatitis
Argentina
Genetic Predisposition to Disease
Pediatrics
HLA-DRB3 Chains
HLA-A11 Antigen
HLA-DR4 Antigen
MHC Class I Genes
Antinuclear Antibodies
Major Histocompatibility Complex
Ethnic Groups
Oligonucleotides
Autoantibodies
Smooth Muscle
Alleles
Odds Ratio
Amino Acids
Peptides
Antibodies

ASJC Scopus subject areas

  • Hepatology

Cite this

Pando, M., Larriba, J., Fernandez, G. C., Fainboim, H., Ciocca, M., Ramonet, M., ... Fainboim, L. (1999). Pediatric and adult forms of type I autoimmune hepatitis in Argentina: Evidence for differential genetic predisposition. Hepatology, 30(6), 1374-1380.

Pediatric and adult forms of type I autoimmune hepatitis in Argentina : Evidence for differential genetic predisposition. / Pando, Marcelo; Larriba, Julian; Fernandez, Gabriela C.; Fainboim, Hugo; Ciocca, Mirta; Ramonet, Margarita; Badia, Isabel; Daruich, Jorge; Findor, Jorge; Tanno, Hugo; Canero-Velasco, Cristina; Fainboim, Leonardo.

In: Hepatology, Vol. 30, No. 6, 1999, p. 1374-1380.

Research output: Contribution to journalArticle

Pando, M, Larriba, J, Fernandez, GC, Fainboim, H, Ciocca, M, Ramonet, M, Badia, I, Daruich, J, Findor, J, Tanno, H, Canero-Velasco, C & Fainboim, L 1999, 'Pediatric and adult forms of type I autoimmune hepatitis in Argentina: Evidence for differential genetic predisposition', Hepatology, vol. 30, no. 6, pp. 1374-1380.
Pando M, Larriba J, Fernandez GC, Fainboim H, Ciocca M, Ramonet M et al. Pediatric and adult forms of type I autoimmune hepatitis in Argentina: Evidence for differential genetic predisposition. Hepatology. 1999;30(6):1374-1380.
Pando, Marcelo ; Larriba, Julian ; Fernandez, Gabriela C. ; Fainboim, Hugo ; Ciocca, Mirta ; Ramonet, Margarita ; Badia, Isabel ; Daruich, Jorge ; Findor, Jorge ; Tanno, Hugo ; Canero-Velasco, Cristina ; Fainboim, Leonardo. / Pediatric and adult forms of type I autoimmune hepatitis in Argentina : Evidence for differential genetic predisposition. In: Hepatology. 1999 ; Vol. 30, No. 6. pp. 1374-1380.
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abstract = "The aim of this study was to compare major histocompatibility complex (MHC) class II susceptibility to type 1 autoimmune hepatitis (AH) between children and adults of the same ethnic group. HLA-DRB1, HLA-DRB3, HLA-DQA1, and HLA-DQB1 gene subtypes were examined by high resolution oligonucleotide typing in 122 pediatric (PAH) and 84 adult (AAH) patients and in 208 controls. In children, HLA-DRB1*1301 was the primary susceptibility allele (66.4{\%} patients vs. 10.6{\%} controls, relative risk [RR] = 16.3, Pc < 10-24) whereas HLA-DRB1*1302, which differs from HLA-DRB1*1301 by only 1 amino acid, appeared to be protective. The exclusion of individuals with HLA- DRB1*1301 from control and pediatric patients allowed us to find a secondary association of PAH with HLA-DRB1*0301. Possession of HLA-DRB1*1301, however, was associated with a lower therapeutic response rate. Analysis of peptide binding pocket residues indicated that Tyr 10, Ser 11, Ser 13, and Val 86 in the class II β chain were present in 85{\%} of patients compared with 37{\%} of controls, suggesting that a high proportion of AH susceptibility is attributable to these residues (etiologic fraction [EF] = 76{\%}). In contrast to the class II associations in children, AAH was associated with HLA- DRB1*0405 (RR = 10.4, Pc < .005) but not with HLA-DRB1*1301 or HLA- DRB1*0301. In addition, HLA-DR4 with the class I gene, HLA-A11, appeared synergistic in predisposing AAH patients to develop extra-hepatic autoimmune (AI) manifestations (odds ratio [OR] = 104.9, Pc < 10-4). Concomitant differences in autoantibody profiles were also observed in PAH versus AAH: smooth muscle antibodies (SMA) were most prevalent in PAH but antinuclear antibodies were most prevalent in AAH (P = .003). This study therefore reveals that different HLA-DRB1 allotypes confer susceptibility to AH in children and adults and raises the possibility that PAH and AAH may be triggered by different factors.",
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AU - Fainboim, Hugo

AU - Ciocca, Mirta

AU - Ramonet, Margarita

AU - Badia, Isabel

AU - Daruich, Jorge

AU - Findor, Jorge

AU - Tanno, Hugo

AU - Canero-Velasco, Cristina

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N2 - The aim of this study was to compare major histocompatibility complex (MHC) class II susceptibility to type 1 autoimmune hepatitis (AH) between children and adults of the same ethnic group. HLA-DRB1, HLA-DRB3, HLA-DQA1, and HLA-DQB1 gene subtypes were examined by high resolution oligonucleotide typing in 122 pediatric (PAH) and 84 adult (AAH) patients and in 208 controls. In children, HLA-DRB1*1301 was the primary susceptibility allele (66.4% patients vs. 10.6% controls, relative risk [RR] = 16.3, Pc < 10-24) whereas HLA-DRB1*1302, which differs from HLA-DRB1*1301 by only 1 amino acid, appeared to be protective. The exclusion of individuals with HLA- DRB1*1301 from control and pediatric patients allowed us to find a secondary association of PAH with HLA-DRB1*0301. Possession of HLA-DRB1*1301, however, was associated with a lower therapeutic response rate. Analysis of peptide binding pocket residues indicated that Tyr 10, Ser 11, Ser 13, and Val 86 in the class II β chain were present in 85% of patients compared with 37% of controls, suggesting that a high proportion of AH susceptibility is attributable to these residues (etiologic fraction [EF] = 76%). In contrast to the class II associations in children, AAH was associated with HLA- DRB1*0405 (RR = 10.4, Pc < .005) but not with HLA-DRB1*1301 or HLA- DRB1*0301. In addition, HLA-DR4 with the class I gene, HLA-A11, appeared synergistic in predisposing AAH patients to develop extra-hepatic autoimmune (AI) manifestations (odds ratio [OR] = 104.9, Pc < 10-4). Concomitant differences in autoantibody profiles were also observed in PAH versus AAH: smooth muscle antibodies (SMA) were most prevalent in PAH but antinuclear antibodies were most prevalent in AAH (P = .003). This study therefore reveals that different HLA-DRB1 allotypes confer susceptibility to AH in children and adults and raises the possibility that PAH and AAH may be triggered by different factors.

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