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Objective: Reported associations between HLA alleles and both susceptibility to and features of scleroderma have been conflicting. Our objective was (1) to determine the role of HLA alleles in the susceptibility to scleroderma; and (2) to determine the role of HLA alleles in various aspects of disease expression., Methods: Consecutive patients were followed in the scleroderma clinic between 1996 and 1998. Clinical data were obtained through chart review. Healthy volunteers as well as cadaveric donors served as controls. Molecular HLA typing was performed (polymerase chain reaction/sequence-specific oligonucleotides). Statistical analysis included Fisher's exact test and multivariate analyses, using logistic and linear regression models., Results: Ninety-five Caucasian patients (75 women, 20 men, age 43.9 yrs, disease duration 11.9 yrs) with scleroderma and 416 controls were studied. HLA-DRB1*01 and HLA-DRB1*11 were associated with susceptibility to scleroderma, whereas HLA-DRB1*07 was protective. HLA-A*30 and HLA-A*32 were also associated with susceptibility to scleroderma, while HLA-B*57 and HLA-Cw*14 were protective. HLA-B*62 and HLA-DRB1*07 had a significant correlation with the presence of diffuse skin involvement in both univariate and multivariate analyses. HLA-DRB1*11 was associated with high skin score values, while lower values were related to the presence of HLA-Cw*14 and HLA-DQB1*06. Both alleles retained significance in a linear regression model. High skin score values were related to the absence of anticentromere antibodies. Pulmonary fibrosis was associated with HLA-B*62 and HLA-Cw*0602, whereas pulmonary hypertension was associated with HLA-B*13 and HLA-B*65., Conclusion: HLA alleles play a role in susceptibility to scleroderma and its disease expression.

Psoriatic arthritis (PsA) is an inflammatory arthritis that may affect as many as 30% of patients with psoriasis (Ps). Genetic factors play an important role in the susceptibility to and the expression of PsA. The objective of this study was to identify whether haplotype sharing among affected sibling pairs of individuals with PsA is increased compared with unaffected sibling pairs. We collected 182 sibling pairs of probands affected with PsA. Extracted genomic DNA was amplified in polymerase chain reactions using locus specific primers homologous to nucleotide sequences for each of the HLA-A, -B, -C, -DR, and -DQ loci. Polymerase chain reaction amplicons were identified by reverse line blot assay using sequence-specific oligonucleotide probes. Evidence for excessive haplotype sharing was examined through Green and Woodrow's test. Results indicate that of the 182 sibling pairs, 46 were affected by PsA, 48 by Ps, and 88 were unaffected. The sharing of 2, 1, and 0 haplotypes for the PsA affected sibling pairs was 14, 27, and 5, respectively (p = 0.04); whereas the haplotype sharing for the Ps affected sibling pairs was 12, 26, and 10, respectively (p = 0.38). In conclusion, the human leukocyte antigen region on chromosome 6p is implicated as one of the candidate regions in PsA.

Objective: To investigate whether the addition of all serologically defined HLA antigens to a baseline model further influences the predisposition to disease progression in psoriatic arthritis (PsA)., Methods: Patients with PsA followed prospectively over 19 years were studied. Clinical and laboratory assessments of both active inflammation and clinical damage were performed at 6 month intervals according to a standard protocol. Progression of damage was defined as transition to higher damage states defined by the number of damaged joints. A model that provides estimates of the ratio of transition rates for an individual with the antigen versus one without, and examines the antigen effect on each of the 3 transition rates, was used. HLA antigens were examined in groups by loci under the assumption of common effects across transitions when added to the basic model. The significance levels were examined in comparison with Bonferroni type corrections. Likelihood ratio chi-squared statistics were used as a basis for the significance levels. In total, 292 patients with PsA were included in the study., Results: Only HLA-B22 was added to the original model, which includes HLA-B39, providing risk for progression in early stages, HLA-B27 in the presence of HLA-DR7 providing risk for progression through all states, and DQw3 providing increased risk in the absence of DR7, while in the presence of DR7 it provides "protection." HLA-B22 provides protection from disease progression through all states., Conclusion: This study extends our report that HLA antigens serve as markers for disease progression in PsA.

Objective: To identify HLA markers for the development of severe disease in psoriatic arthritis (PsA)., Methods: Patients with PsA who were followed up prospectively over a 14-year period were included. Clinical and laboratory assessments of both active inflammation and clinical damage were performed at 6-month intervals according to a standard protocol, which also included serologic HLA typing for class I and II antigens. Progression of damage was defined as transition into higher damage states, defined by the number of damaged joints. Both univariate and multivariate models were developed to identify predictors for progression of damage., Results: Univariate analysis revealed that the HLA antigens B27, B39, and DQw3 were associated with disease progression, while HLA-DR7 was "protective." The best multivariate model identified the HLA antigens B27, when DR7 was present, and DQw3, when DR7 was not present, as predicting disease progression across all transitions, while HLA-B39 was associated with progression in early disease. The addition of these HLA indicators to a model containing clinical variables resulted in a significant improvement in fit., Conclusion: The HLA antigens associated with PsA, B27 and B39, are risk factors for disease progression, as is the HLA class II antigen DQw3. In combination with clinical measures of disease, these HLA variables are the dominant predictors of progression.

HLA antigen distribution was studied in 126 patients with systemic sclerosis (SSc) followed prospectively and compared to that of 325 healthy controls. The frequencies of HLA antigens DR3, DR5 and DRw52 were increased in patients with diffuse skin involvement (P = 0.02, 0.05, 0.03). The presence of DRw52 (relative risk [RR] much much greater than 1) and DRw6 (RR = 54.5) was associated with significantly increased risks of a fatal disease outcome with pulmonary hypertension (PHT). In the absence of PHT, DRw252 was inversely associated with the risk of death. These findings indicate an adverse prognosis in SSc when PHT is present in association with DRw52.

Psoriatic spondyloarthropathy as defined by the presence of inflammatory back pain and stiffness, sacroiliitis on physical examination, radiographic evidence of grade greater than or equal to 2 sacroiliitis, and classical or paramarginal syndesmophytes on spinal radiographs was identified in 82 women and 112 men followed at the Psoriatic Arthritis Clinic according to a standard protocol. A logistic regression analysis was performed to look for variables which discriminate between men and women with this condition. No differences in type of peripheral arthritis, degree of damage, or medication were noted between the two groups. However, there was some evidence for more advanced spondyloarthropathy in men. There were no differences in the frequency of HLA B27 or any of the psoriatic arthritis-related HLA antigens. Thus, there may be gender-related differences in the expression of psoriatic spondyloarthropathy, which are unrelated to HLA antigens.

A link between the HLA system and disease susceptibility can be assessed through the observation of families containing two or more affected siblings. Departures from Mendelian inheritance of the parental haplotypes among the affected siblings are an indication of such a relationship. Other variables, such as environmental factors, may also be related to disease susceptibility. An approach to examining the degree of haplotype sharing and the effect of other variables of interest on observed sharing is presented and two examples analyzed.

The estimation of gene frequencies, linkage disequilibrium and disease associations for the human leukocyte antigen (HLA) system is considered. Comprehensive models for HLA data are introduced and contrasted with simpler approaches to the analysis of such data.