CTLA-4/CD 28 region polymorphisms in children from families with autoimmune hepatitis.
Susceptibility to autoimmune hepatitis is associated with particular human leucocyte antigen class II alleles. However, non-HLA genetic factors are likely to be required for development of the disease. Among the candidate genes, the cytotoxic T-lymphocyte antigen 4 (CTLA-4) and CD28 genes, located on chromosome 2q33 in humans, encode a cell surface molecule playing a dominant role in the regulation of T-cell activation. The CTLA-4 and CD28 polymorphisms were investigated in children from 32 families with autoimmune hepatitis (AIH). The transmission/disequilibrium test revealed increased transmission of the (AT)8 (dinucleotide repeat) and A (exon 1) alleles of CTLA-4 gene from heterozygous parents to affected offspring (87.5% and 83.5%) with type 1 AIH, compared with unaffected offspring (50.0% for both, p = 0.009 and 0.02, respectively). In contrast, no deviation in transmission for CTLA-4 polymorphisms was found between type 2 AIH patients and unaffected offspring. No evidence for association was found between CD28 gene polymorphism or D2S72 genetic marker and both types of AIH. This study identified the CTLA-4 gene polymorphism as a non-HLA determinant that predisposes to AIH type 1 in children. The genetic heterogeneity seen in the present study provides a new argument in favor of pathogenic differences between type 1 and type 2 AIH.
Djilali-Saiah
I
I
Gastroenterology Division, Hôpital Sainte-Justine, Montreal, Quebec, Canada. saiahi@magellan.umontreal.ca
Ouellette
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P
Caillat-Zucman
S
S
Debray
D
D
Kohn
J I
JI
Alvarez
F
F
D000069594:Abatacept; D000293:Adolescent; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D018106:CD28 Antigens / Q000235:genetics*; D060908:CTLA-4 Antigen; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D005260:Female; D020022:Genetic Predisposition to Disease; D019693:Hepatitis, Autoimmune / Q000235:genetics*; D006801:Humans; D018796:Immunoconjugates; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D000069594:Abatacept