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The frequency of certain HLA class II alleles has been reported to be high in patients with systemic sclerosis (SSc), especially in the clinical subsets defined by SSc related antinuclear antibodies and ethnicity.1 2 In anticentromere antibody (ACA) positive SSc, a high frequency of HLA-DQB1*0501 has been reported by some investigators.1 In addition, we found a high frequency of DRB1*0101 in ACA positive Japanese patients with SSc (J Rheumatol, in press).
ACA is also found in patients with primary biliary cirrhosis (PBC),3 and patients with SSc and ACA commonly overlap PBC or Sjögren's syndrome (SS), or both.4 Some studies on HLA class II alleles in Japanese patients with PBC showed high frequencies of DRB1*0803 and DPB1*0501.5 However, we found no reports which analysed HLA class II alleles in patients with PBC with respect to the relation with ACA or SSc.
To clarify the relation of HLA class II alleles with ACA, SSc, and PBC we carried out molecular genetic analyses of HLA-DQB1 and DRB1 alleles6 in 86 Japanese patients with SSc or PBC, or both (55 SSc, 24 PBC, and 7 SSc-PBC overlap) who had a genetically and racially homogeneous background. These patients were divided into 26 with ACA and 60 without ACA. All patients with SSc were definite SSc fulfilling the American Rheumatism Association's preliminary criteria for SSc, and no patient overlapped with systemic lupus erythematosus, polymyositis/dermatomyositis, or rheumatoid arthritis. For accurate comparison of SSc and PBC, we excluded patients with PBC who had some SSc related features (for example, Raynaud's phenomenon) without satisfying criteria for SSc. The diagnosis of PBC or SS was established based on the criteria by the Japanese Research Committee.7 8 Healthy controls consisted of 215 unrelated Japanese subjects.5 9
Table 1 summarises the gene frequency in ACA positive patients with SSc or PBC. HLA-DRB1*0101 and DQB1*0501 were frequently found in SSc, and HLA-DRB1*0803 was frequently found in PBC compared with the healthy controls. These results were consistent with previous reports analysing HLA-DRB1 and DQB1 in patients with SSc or PBC from different institutions.1 5
In PBC, no difference in phenotype frequency (the number of patients positive for an allele) of DRB1*0803 was found between ACA positive patients and ACA negative ones (6/13 (46%)v 5/18 (28%)). Patients with PBC who were ACA positive frequently overlapped SSc compared with ACA negative patients (6/13 (46%) v 1/18 (6%), p<0.05). On the other hand, DRB1*0803 in PBC showed no association with overlapping SSc; phenotype frequency of DRB1*0803 was 43% (3/7) in SSc-PBC overlap and 33% (8/24) in PBC without SSc related features.
Table 2 shows clinical analyses in patients with SSc classified by the presence of ACA and DRB1*0803. Phenotype frequency of DRB1*0803 was not different between ACA positive SSc and ACA negative SSc. ACA positive SSc frequently overlapped SS and PBC compared with ACA negative SSc. In ACA negative SSc, DRB1*0803 positive patients frequently overlapped SS compared with DRB1*0803 negative ones, and one of the five patients with DRB1*0803 overlapped PBC. DRB1*0803 may be a candidate allele to determine the susceptibility to SS and PBC in patients with SSc with no relation to the presence of ACA, and the existence of common candidate alleles in PBC and SS may explain the high frequency of overlap of both the diseases.10 There was no significant difference in skin sclerosis or organ involvement in patients with SSc classified by the presence of DRB1*0803 (data not shown).
Our report describes the variation of HLA class II alleles among ACA positive patients according to their clinical features; high frequency of HLA-DRB1*0101/DQB1*0501 and DRB1*0803 are restrictively found in SSc and PBC, respectively. Although DRB1*0803 is not related to the production of ACA, this allele may be related to the susceptibility not only to PBC but also to SS in patients with SSc.
We thank Dr Takehiko Abe and Dr Akira Kojima, The First Department of Internal Medicine, for their help in collecting blood samples from patients with PBC.
This study was partly supported by grants from Kanzawa Medical Research Foundation (1999) and a Scleroderma Grant for Intractable Disease from the Japanese Ministry of Health and Welfare (1999).
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