Molecular analysis of major histocompatibility complex allelic associations with systemic lupus erythematosus in Taiwan
Veterans General Hospital, Kaohsiung, Taiwan. Arthritis & Rheumatology
(Impact Factor: 7.76).
07/1997; 40(6):1138-45. DOI: 10.1002/1529-0131(199706)40:6<1138::AID-ART18>3.0.CO;2-D
To investigate the association of HLA class II alleles/haplotypes, type I C2 deficiency gene, and tumor necrosis factor a gene promoter allele (TNF2) with systemic lupus erythematosus (SLE) in the Chinese population in Taiwan.
The HLA-DRB1 and DQB1 alleles were studied in 105 SLE patients and 115 controls by the polymerase chain reaction (PCR)/sequence-specific oligonucleotide probe method, the subtyping of DRB1*15/16 and DRB5 by PCR with sequence-specific primers, type I C2 deficiency gene by PCR, and TNF2 by PCR-Nco I restriction fragment length polymorphism.
The frequencies of the HLA class II alleles DRB1*02, DRB1*1502, DRB5*0102, DQB1*0501, and DQB1*0602 and DR2-associated haplotypes DRB1* 1501,DRB5*0101,DQB1*0602 and DRB1*1502,DRB5* 0102,DQB1*0501 were higher among SLE patients than among controls; however, only DQB1*0501 was statistically significantly associated with SLE. No specific allele/haplotype was significantly associated with lupus nephritis. No subject had type I C2 deficiency. SLE patients had a marginally higher percentage of TNF2, which was in linkage disequilibrium with DR3. Since DR3 was not associated with SLE in this Taiwanese Chinese population, TNF2 might play a role in the immunopathogenesis of SLE.
Although no HLA-DRB1 allele was found to be significantly associated with SLE, the associations with DQB1*0501 and TNF2 suggest that DQB1 and tumor necrosis factor a may be important genetic factors in SLE susceptibility in the Chinese population in Taiwan.
Available from: Isao Matsumoto
- "To the best of our knowledge, this is the first report of a negative association of the HLA-DR6 alleles DRB1*13:02 and *14:03 with Japanese SLE, although a lower frequency of DR5  or DR6  alleles in Asian patients with SLE has been reported before. Several studies have noted positive associations of DRB1*15:01
, , , *15:02
,  or *09:01
, , ,  alleles with SLE in Asians. However, here we only confirmed the association with *15:01, but not *15:02 or *09:01 in Japanese SLE patients in general (Table 1). "
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ABSTRACT: Many studies on associations between human leukocyte antigen (HLA) allele frequencies and susceptibility to systemic lupus erythematosus (SLE) have been performed. However, few protective associations with HLA-DRB1 alleles have been reported. Here, we sought protective, as well as predispositional, alleles of HLA-DRB1 in Japanese SLE patients. An association study was conducted for HLA-DRB1 in Japanese SLE patients. Relative predispositional effects were analyzed by sequential elimination of carriers of each allele with the strongest association. We also explored the association of DRB1 alleles with SLE phenotypes including the presence of autoantibody and clinical manifestations. Significantly different carrier frequencies of certain DRB1 alleles were found to be associated with SLE as follows: increased DRB1*15:01 (P = 5.48×10(-10), corrected P (Pc) = 1.59×10(-8), odds ratio [OR] 2.17, 95% confidence interval [CI] 1.69-2.79), decreased DRB1*13:02 (P = 7.17×10(-5), Pc = 0.0020, OR 0.46, 95% CI 0.34-0.63) and decreased DRB1*14:03 (P = 0.0010, Pc = 0.0272, OR 0.34, 95% CI 0.18-0.63). Additionally, the "*15:01/*13:02 or *14:03" genotype tended to be negatively associated with SLE (P = 0.4209, OR 0.66), despite there being significant positive associations with *15:01 when present together with alleles other than *13:02 or *14:03 (P = 1.79×10(-11), OR 2.39, 95% CI 1.84-3.10). This protective effect of *13:02 and *14:03 was also confirmed in SLE patients with different clinical phenotypes. To the best of our knowledge, this is the first report of a protective association between the carrier frequencies of HLA-DRB1*13:02 and *14:03 and SLE in the Japanese population.
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ABSTRACT: DRB1*1506, a new allele of DR2, differs from DRB1*1501 only at codon 50 in the second exon, where the nucleotide sequence has changed from GTG to GCG resulting in an amino acid substitution from valine to alanine in DRB1*1506. Since codon 50 was considered non-polymorphic until the discovery of this new allele by sequence-based typing, it became necessary to study what fraction of subjects thought to have DRB1*1501 actually had DRB1*1506. For this purpose, 116 DNA samples with DR2 coming from normal healthy individuals, leprosy patients and childhood tuberculosis patients were amplified using PCR and hybridized with 32P-labeled probes specific for DRB1*1501, DRB1*1502, DRB1*1503, DRB1*1506, DRB1*1601 and DRB1*1602. The oligonucleotide probe for DRB1*1506 was designed to span codons 47-52 based on the published nucleotide sequence. DRB5, DQA1 and DQB1-specific amplifications and hybridizations were also carried out to study the diversity of DR2 haplotypes. It was found that 21% of the samples identified previously as DRB1*1501 were actually DRB1*1506. DRB1*1506 was found to be associated with DQB1*0502 and DQB1*0601. Haplotypes of DRB1*1501, DRB1*1502, DRB1*1506 and DRB1*1602 showed a marked heterogeneity. Besides the rare haplotypes which have not yet been reported in any other populations, haplotypes characteristic of different ethnic groups, such as Croatians, South Chinese and Gypsies, were also found in the North Indians, suggesting the extent of racial admixture and migrations to and from India.
Available from: Eric Zanelli
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To evaluate the respective contributions of tumor necrosis factor (TNF) promoter polymorphisms and HLA–DR alleles to susceptibility to systemic lupus erythematosus (SLE).MethodsTNF-238G/A and 308G/A promoter polymorphisms and HLA–DRB1 alleles were determined in 99 consecutive Caucasian SLE patients and 177 Caucasian controls. Standard and Mantel-Haenszel odds ratios were calculated to assess the magnitude of the susceptibility factors. The presence or absence of the SLE classification criteria was determined and correlated with the TNF promoter and HLA–DRB1 genotypes.ResultsThe frequency of the TNF-308A/A and 308G/A genotypes was significantly higher in SLE patients (odds ratio 5.0). Conversely, TNF-238G/A and 238A/A genotypes were equally prevalent in SLE patients and controls. The HLA–DR3 specificity (DRB1*0301 allele) was significantly more prevalent in the SLE population (odds ratio 4.4). Stratification to correct for interdependence of the 2 loci confirmed the association of both TNF-308A and HLA–DR3 with SLE (Mantel-Haenszel odds ratio 3.2 and 2.4, respectively). No correlation was found between TNF promoter and HLA–DRB1 genotypes and any SLE classification criterion or disease manifestation.ConclusionTNF-308A and HLA–DR3 alleles are independent susceptibility factors for SLE.
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