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Association of HLA-DR with progressive systemic sclerosis in Japanese
F Takeuchi1, K Nakano, H Yamada
1Department of Medicine and Physical Therapy, Faculty of Medicine, University of Tokyo, Japan.
Objective:
To clarify the contribution of HLA-DR genes to the susceptibility to progressive systemic sclerosis (PSS).
Methods:
HLA-DR typing was carried out in 36 Japanese patients with PSS, 42 with systemic lupus erythematosus and 104 healthy subjects by polymerase chain reaction (PCR) method using specific primers and by PCR-SSCP (single-standard DNA conformation polymorphism) method.
Results:
A haplotype DRB1*1502-DRB5*0102 was significantly increased in PSS (50.0%, p < 0.00004, pc < 0.001), especially in antitopoisomerase I antibody (a-Scl-70) positive patients (62.5%, p < 0.00003, pc < 0.001) and PSS with diffuse scleroderma (75.0%, p < 0.00001, pc < 0.0001). In addition, DRB1*0802 was also increased in DRB1*1502 negative patients with a-Scl-70, (50.0%, p = 0.033, pc = not significant) and in DRB1*1502 negative patients with diffuse scleroderma (75.0%, p = 0.008, pc = not significant). Thus, 81.3% of a-Scl-70 positive patients, and 93.8% of patients with PSS with diffuse scleroderma showed either HLA-DRB1*1502 or 0802.
Conclusions:
Our observations show the extreme difference of genetic background of a-Scl-70 positive PSS, with regard to HLA-DR, between Japanese and other ethnic groups including Caucasian and American black persons. The increase in DRB1*1502-DRB5*0102 haplotype supported the hypothesis of Reveille, et al that uncharged polar amino acid residue at position 30 of HLA-DQB1 allele was important for a-Scl-70 positive PSS because close association of the haplotype with DQB1*0601 was well established in Japanese; listed as a hypothetical candidate of PSS susceptible DQB1 allele. DRB1*0802 were also associated with hypothetical candidates of DQ alleles. Furthermore, the sharing of the particular amino acid sequence: valine38 and phenylalanine67-lysine68-glutamic acid69-asparic acid70-arginine71, by DRB5*0102, DRB1*0802 and DR11 (associated with Caucasian PSS) also suggests a contribution of the sequence in HLA-DR molecules to the pathogenesis of PSS according to the shared epitope hypothesis.