INTERRELATIONSHIP OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II ALLELES AND AUTOANTIBODIES IN 4 ETHNIC-GROUPS WITH VARIOUS FORMS OF MYOSITIS

Objective. To examine interrelationships among myositis subsets, autoa ntibodies, and major histocompatibility complex (MHC) class II alleles across ethnic lines, and to localize genetic susceptibility (presence of HLA-DR versus DQ) to myositis within the MHC class II region. Meth ods. MHC class II alleles (HLA-DRB1, DQA1, and DQB1, detected by DNA o ligotyping) and myositis-specific autoantibodies (MSA) were determined in 224 patients with various myositis syndromes, including 89 whites, 89 African-Americans, 25 Mexican-Americans, and 21 Japanese. Results. Anti-Jo-1 (histidyl-transfer RNA [tRNA] synthetase) and other MSAs (a nti-PL-12, anti-PL-7, anti-OJ, anti-EJ, anti-KJ, anti-tRNA, and anti-s ignal recognition particle) were equally distributed among the races, but occurred more often in patients with polymyositis (PM) than in tho se with dermatomyositis (DM) or other myositis syndromes. MSA frequenc ies were significantly positively associated with anti-Re (SS-A) (P = 0.002), and significantly negatively associated with anti-U1 RNP (P = 0.003). Frequencies of the HLA-DRB10301 (DR3), DQA1*0501, and DQB1*02 01 (DQ2) alleles (and haplotype) were each increased in white patients with myositis, especially those with PM, but most strikingly in those with MSAs. However, in the other ethnic groups, except the Japanese g roup, only frequencies of HLA-DQA10501 and the structurally similar D QA10401 alleles were significantly increased. The presence of HLA-DQA 10501 or *0401 was most significantly associated with anti-Jo-1, anti -PL-12, and other MSAs, compared with myositis patients without MSAs ( P = 0.0008, P-corr = 0.01, odds ratio [OR] = 3.7), and with normal, et hnically matched controls (P = 3 x 10(-7), P-corr = 1 x 10(-6), OR = 6 .5). Among MSA-positive patients who were negative for HLA-DQA10501 a nd 0401, including Japanese patients, the HLA-DQA1*0102 and *0103 all eles predominated. In addition, there appeared to be a negative associ ation of the HLA-DR2 alleles (DRB11501 and *1503) with PM (P = 0.007, P-corr not significant, OR = 0.39), but not with DM or myositis overa ll. Conclusion. By transracial gene mapping, genetic susceptibility to anti-Jo-1 and other MSAs in patients with myositis can be localized w ithin the MHC region to the HLA-DQA1 locus.