Association of amino acid sequences in the HLA-DQB1 first domain with antitopoisomerase I autoantibody response in scleroderma (progressive systemic sclerosis).

Objective. To examine whether the affected firstdegree relatives within multicase systemic sclerosis (SSc; scleroderma) families are concordant for autoantibody profile, disease type, and HLA class II haplotypes and whether clinical expression and serologic characteristics of familial SSc differ from those of sporadic SSc.Methods. Seven hundred ten SSc families from the Scleroderma Family Registry and DNA Repository (Scleroderma Registry) were examined, and 18 multicase families were identified. SSc cases and their firstdegree family members underwent serologic testing for different autoantibodies. The disease type and various disease features were abstracted from the available medical records. Additionally, HLA class II typing was performed on the multicase SSc sibpairs.Results. The observed SSc-specific antibody concordance within each multicase SSc family was statistically more common than expected by chance alone (P ‫؍‬ 0.007). The autoantibody profile and disease features of familial and sporadic SSc cases did not differ significantly. The frequency of autoantibody positivity was not different between unaffected first-degree family members of patients from multicase versus singleton SSc families. HLA haplotype sharing between SSc sibpairs was significantly more common than expected (P ‫؍‬ 0.011).Conclusion. The affected members within multicase SSc families tend to be concordant for SSc-specific autoantibodies and HLA haplotypes; familial SSc does not appear to be a unique disease subset.

“…HLA class II alleles were determined by DNA oligotyping, with high-resolution DRB1 typing performed by direct sequencing, as previously described (13,14). Statistical analysis.…”

Section: Methodsmentioning

confidence: 99%

Clinical, immunologic, and genetic features of familial systemic sclerosis

Assassi¹,

Arnett²,

Reveille³

et al. 2007

“…Genomic DNA was extracted from peripheral blood leukocytes by standard methods. HLA class I1 (DRBI, DQAI, and DQUI) alleles were determined using PCR and hybridization to sequence-specific oligonucleotide probes, as previously described (26,27).…”

Section: Methodsmentioning

confidence: 99%

Interrelationship of major histocompatibility complex class II alleles and autoantibodies in four ethnic groups with various forms of myositis

Arnett

Targoff

Mimori

et al. 1996

156

136

Objective. To examine interrelationships among myositis subsets, autoantibodies, and major histocompatibility complex (MHC) class 1 1 alleles across ethnic lines, and to localize genetic susceptibility (presence of HLA-DR versus DQ) to myositis within the MHC class 1 1 region.Methods. MHC class I1 alleles (HLA-DRBZ, DQM, and DQBI, detected by DNA oligotyping) and myositis-specific autoantibodies (MSA) were determined in 224 patients with various myositis syndromes, including 89 whites, 89 African-Americans, 25 MexicanAmericans, and 21 Japanese.Results. Anti-Jo-1 (histidyl-transfer RNA [tRNA] synthetase) and other MSAs (anti-PL-12, anti-PL-7, anti-OJ, anti-EJ, anti-KJ, anti-tRNA, and antisignal recognition particle) were equally distributed among the races, but occurred more often in patients with polymyositis (PM) than in those with dermatomyositis (DM) or other myositis syndromes. MSA frequencies were significantly positively associated with anti-Ro (SS-A) (P = 0.002), and significantly negatively associated with anti-U1 RNP (P = 0.003). Frequencies of the HLA-DRBI *0301 (DR3), DQAZ*0501, and DQBl*O2OISupported by grants from the Muscular Dystrophy Association, the RGK Foundation, NIH grants R-29AR-39325, AR-32214, and AI-27181, and medical research funds from (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 group, only frequencies of HLA-DQAI *0501 and the structurally similar DQAI *0402 alleles were significantly increased. The presence of HLA-D@iI*0501 or *040I was most significantly associated with anti-Jo-1, anti-PLU, and other MSAs, compared with myositis patients without MSAs (P = 0.0008,Pc,, = 0.01, odds ratio [OR] = 3.7), and with normal, ethnically matched controls (P = 3 X lo-', P,,, = 1 x OR = 6.5). Among MSApositive patients who were negative for HLADQAl*O501 and *0401, including Japanese patients, the HLA-D&iI *OI02 and *OI03 alleles predominated. In addition, there appeared to be a negative association of the HLA-DR2 alleles (DRBI*I501 and *1503) with PM (P = 0.007, P,,, not significant, OR = 039), but not with DM or myositis overall.Conclusion. By transracial gene mapping, genetic susceptibility to anti-Jo-1 and other MSAs in patients with myositis can be localized within the MHC region to the HLA-DQ4I locus.Polymyositis (PM) and dermatomyositis (DM) are idiopathic inflammatory myopathies that are characterized clinically by proximal muscle weakness, elevations in the level of serum muscle enzymes, especially creatine kinase (CK), and typical abnormal findings on electromyography. Histopathologic analysis has revealed that affected skeletal muscles are infiltrated by inflammatory mononuclear cells, predominantly CDS+ T lymphocytes, and that those muscles show myofibril degeneration, regeneration, and/or necrosis. Similar clinical and histopathologic features of myositis have been observed in association with malignancies, other connective ti...

“…Samples were identified by the patient's study number. The buffy coat was separated, and typing and subtyping were performed on genomic DNA extracted using standard techniques (16).…”

Section: Methodsmentioning

confidence: 99%

HLA—DRB1 genes and disease severity in rheumatoid arthritis

Reveille

Alarcón

Fowler

et al. 1996

Objective. To examine the effect of alleles encoding the "shared"/"rheumatoid" epitope on rheumatoid arthritis (RA) disease severity in patients who participated In the minocycline in RA (MIRA) trial.Methods. Of 205 patients with a week-48 visit, blood was available for typing of HLA-DRB1 and HLA-DQB1 in 174 (85%) and successfully completed in 169 (82%). Baseline erosioes were used to assess disease severity and new erosions a t the last visit served as a proxy for progression.Results. At baseline, there was no association between the presence of erosive disease or rheumatoid factor status and the dose of rheumatoid epitope (homozygous, heterozygous, none) or the specific alleles identified. At the final visit, a gradient was observed for the 3 allelic subgroups (and their gene doses) in the occurrence of new erosions among the Caucasian placebo-