ASSOCIATION OF HLA-DR WITH PROGRESSIVE SYSTEMIC-SCLEROSIS IN JAPANESE

Objective. To clarify the contribution of HLA-DR genes to the suscepti bility to progressive systemic sclerosis (PSS). Methods. HLA-DR typing was carried out in 36 Japanese patients with PSS, 42 with systemic lu pus erythematosus and 104 healthy subjects by polymerase chain reactio n (PCR) method using specific primers and by PCR-SSCP (single-standard DNA conformation polymorphism) method. Results. A haplotype DRB11502 -DRB50102 was significantly increased in PSS (50.0%, p < 0.00004, pc < 0.001), especially in antitopoisomerase I antibody (a-Scl-70) positi ve patients (62.5%, p < 0.00003, pc < 0.001) and PSS with diffuse scle roderma (75.0%, p < 0.00001, pc < 0.0001). In addition, DRB10802 was also increased in DRB11502 negative patients with a-Scl-70, (50.0%, p = 0.033, pc = not significant) and in DRB11502 negative patients wit h 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 wi th diffuse scleroderma showed either HLA-DRB11502 or 0802. Conclusion s. 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. Th e increase in DRB11502-DRB5*0102 haplotype supported the hypothesis o f 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 DQB10601 was well established in Japanese; listed as a hypothetical candidate of PSS susceptible DQ B1 allele. DRB10802 were also associated with hypothetical candidates of DQ alleles. Furthermore, the sharing of the particular amino acid sequence: valine(38) and phenylalanine(67)-lysine(68)-glutamic acid(69 )-asparic acid(70)-arginine(71), by DRB50102, DRB1*0802 and DR11 (ass ociated with Caucasian PSS) also suggests a contribution of the sequen ce in HLA-DR molecules to the pathogenesis of PSS according to the sha red epitope hypothesis.