Genetic analysis of the HLA region of Japanese patients with type 1 autoimmune hepatitis.
OBJECTIVE
Genetic predisposition to type 1 autoimmune hepatitis (AIH) is linked mainly to HLA-class II genes. The aim of this study is to scan the HLA region for additional genes which may contribute to type 1 AIH susceptibility.


METHODS
We performed association analysis using HLA class I and II alleles and 18 polymorphic microsatellite markers distributed throughout the HLA region. We specifically assessed tumor necrosis factor (TNF)-alpha gene polymorphisms.


RESULTS
The frequencies of HLA-DRB1*0405, DRB4 and DQB1*0401 alleles were significantly higher in AIH patients. The association study revealed the presence of three segments in the HLA region showing significantly low P (Pc) values. The first segment was located around the HLA-DR/-DQ subregion, the second was around the HLA-B54 allele, and the third was around two microsatellites near the TNF gene cluster. However, stratification analysis for the effect of DRB1*0405 eliminated association of the latter two segments. Haplotype D of the TNF-alpha promoter gene polymorphisms was weakly associated with susceptibility, but was found to be not significant after stratification analysis.


CONCLUSIONS
The most influential gene on type 1 AIH pathogenesis in Japanese is the HLA-DRB1. Other genes in the HLA region, including TNF-alpha, have little or no association with type 1 AIH susceptibility.
Yoshizawa
Kaname
K
Department of Medicine, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto 390-8621, Japan. kanamey@hsp.md.shinshu-u.ac.jp
Ota
Masao
M
Katsuyama
Yoshihiko
Y
Ichijo
Tetsuya
T
Matsumoto
Akihiro
A
Tanaka
Eiji
E
Kiyosawa
Kendo
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D059845:HLA-DRB4 Chains; D019693:Hepatitis, Autoimmune / Q000235:genetics*; D006801:Humans; D007564:Japan; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C493960:HLA-DRB1*04:05 antigen; D059845:HLA-DRB4 Chains; D014409:Tumor Necrosis Factor-alpha