HLA DR-DQ haplotypes and genotypes in patients with systemic lupus erythematosus with co-existing Sjogren's syndrome, systemic lupus erythematosus without Sjogren's syndrome and primary Sjogren's syndrome: clinical and laboratory associations
© BioMed Central Ltd 2005
Received: 11 January 2005
Published: 17 February 2005
Comparative immunogenetic studies of systemic lupus erythematosus with co-existing Sjogren's syndrome (SLE-SS), systemic lupus erythematosus without Sjogren's syndrome (SLE-noSS) and primary Sjogren's syndrome (pSS) are lacking.
In the present study, we conducted a thorough evaluation of the genotype and haplotype profiles in well-defined subgroups of patients with SLE-SS, SLE-noSS and pSS, including their association with disease parameters.
HLA-DRB1, HLA-DQA1 and HLA-DQB1 alleles were determined by PCR and hybridization with sequence-specific oligonucleotide probes in DNA specimens derived from 23 patients with SLE-SS, 41 patients with SLE-noSS and 55 patients with pSS (all Caucasians). Patients' records were retrospectively evaluated for various clinical and laboratory parameters.
Compared with healthy controls (odds ratios analyses), SLE-SS and pSS patients displayed a statistically increased frequency of the DRB1*0301-*1104 heterozygote genotype, whereas SLE-noSS patients had an increased frequency of the genotypes DQA1*0401-*0501, DRB1*0301-*1501 and DQB1*0201-*0602. Such statistical associations were stronger for genotypes than single alleles. The analysis of haplotype estimated frequencies (by EM algorithm) had revealed an increased frequency of the DRB1*0301-DQA1*0501-DQB1*0201 haplotype, as well as of the extended haplotype DRB1*0301-DQA1*0501-DQB1*0201/DRB1*1104-DQA1*0501-DQB1*0301 in SLE-SS and pSS patients. In contrast, SLE-noSS patients had an increased estimated frequency of the DRB1*1501-DQA1*0102-DQB1*0602 haplotype. In SLE-SS patients, positive associations of the DQB1*0201 allele with anti-dsDNA (strong) and of DQA1*0501 with anti-La/SSB (marginal) were observed. In SLE-noSS, DQB1*0301-*0602 was strongly positively associated with interstitial lung disease, DQB1*0201-*0602 with central nervous system involvement, DQA1*0501 with serositis and DRB1*1501 with anti-dsDNA, whereas DQB1*0301 homozygosity demonstrated a significant protective effect for glomerulonephritis. In pSS patients, the DRB1*0301-*1104 and DQB1*0201-*0301 genotypes were strongly positively associated with purpura, DRB1*1104-*1601 with arthritis, DQB1*0201-*0502 with renal tubular acidosis, DQB1*0301 homozygosity with lymphadenopathy, DQA1*0501 homozygosity with low C4 and DRB1*0301 allele with anti-La/SSB, low C4 and cryoglobulinemia. In these patients, the extended haplotype DRB1*0301-DQA1*0501-DQB1*0201/ DRB1*1104-DQA1*0501-DQB1*0301 associated strongly with the occurrence of low C4, anti-La/SSB and purpura.
The present study indicates that SLE-SS and the SLE-noSS patients are immunogenetically dissimilar, whereas there is an apparent close immunogenetic relationship between SLE-SS and pSS patients. Furthermore, our data corroborate that the synergistic interactions between distinct pairs of alleles in the DR or the DQ locus confer higher relative risk for these diseases and for distinct clinical manifestations than each of these alleles individually. In pSS, the presence of the extended haplotype DRB1*0301-DQA1*0501-DQB1*0201/ DRB1*1104-DQA1*0501-DQB1*0301 appears to associate with adverse predictors for lymphoma development.