MHC class I chain-related gene B (MICB) is associated with rheumatoid arthritis susceptibility

OBJECTIVES: Several recent studies have shown that the MHC class III region, located telomeric to HLA-DRB1, contains an additional genetic factor that predisposes to rheumatoid arthritis (RA). In this study, we investigate whether inhibitor of kappaB-like (IkappaBL), MICB or MICA located in the MHC class III region are the second susceptibility gene associated with RA. METHODS: A total of 154 healthy controls and 140 RA patients were genotyped for HLA-DRB1, MICA, MICB and the polymorphism -62 of the IkappaBL gene. RESULTS: A significant increase of HLA-DRB1 shared epitope (SE) alleles was detected in RA patients (61.4 vs 43.5%, P(c) = 0.01, OR = 2.1, 95% CI = 1.3-3.3). Among SE alleles, the HLA-DRB1*0401 (13.5 vs 5.1%, P(c) = 0.04, OR = 3.2, 95% CI = 1.3-8.1) and HLA-DRB1*0404 (6.4 vs 1.2%, P = 0.02, P(c) = NS) showed the most significantly association with RA. No increase of risk was associated with HLA-DRB1*01. Remarkably, the allele MICB*004 was also significantly associated with RA susceptibility (40.7 vs 23.3%, P(c) = 0.01, OR = 2.2, 95% CI = 1.3-3.7). MICB*004 was in linkage disequilibrium with HLA-DRB1*0404 (lambda(s) = 0.33) and HLA-DRB1*0405 (lambda(s) = 0.34). However, MICB*004 was also increased in HLA-DRB1 SE negative patients (37 vs 21.5%, P = 0.04). No significant association between IkappaBL and MICA with RA was found. CONCLUSIONS: MICB*004 allele was associated with RA susceptibility. This allele was in linkage disequilibrium with HLA-DRB1*0404 and DRB1*0405. The association of MICB with RA susceptibility and the functional role of MIC genes in the pathogenesis of RA converts MICB into a candidate to be an additional MHC gene associated with RA susceptibility.     

Tumour necrosis factor-alpha polymorphism and the HLA-Cw*0602 allele in psoriatic arthritis

OBJECTIVES: To investigate polymorphisms in the genes for tumour necrosis factor alpha (TNFA), interleukin 10 (IL10) and tumour necrosis factor receptor II (TNFRII) in patients with psoriatic arthritis (PsA) and their relationship to the HLA-Cw*0602 allele and to the ages at onset of psoriasis and arthritis and the pattern of joint involvement. METHODS: One hundred and twenty-four well-characterized patients with PsA were studied. Controls were 101 cadaveric organ donors. All were genotyped for single-nucleotide polymorphisms in TNFA (positions -308, -238, +488), IL10 (-1082, -819, -592) and in the 3'-untranslated region of TNFRII (+1663, +1668, +1690). The HLA-Cw*0602 allele was detected by polymerase chain reaction-based techniques. The frequencies of the respective variants were compared between patients and controls and in relation to the ages at onset of psoriasis and arthritis, to clinical subsets of the disease and to the presence of erosions. RESULTS: HLA-Cw*0602 was significantly increased in frequency in PsA (40 vs 26%; P<0.05) and was associated with younger age of onset of psoriasis (P<0.05). There was no significant increase in any of the polymorphisms studied within TNFA, IL10 or TNFRII in the total PsA group. Although the frequency of TNFA allele -238A was not increased in the total PsA group or in patients with a younger age of onset of psoriasis, TNFA allele -238A was absent in the spondyloarthritis group and increased in frequency in patients with peripheral polyarthritis. However, these latter findings could be explained by linkage disequilibrium as all TNFA -238A alleles (23/23) in patients with PsA were HLA-Cw*0602-positive (P<0.0001). CONCLUSIONS: An association between young age of onset of psoriasis and HLA-Cw*0602 is confirmed in patients with PsA. The uncommon TNFA -238A allele is strongly linked to HLA-Cw*0602 and as such is associated with the development of peripheral polyarthritis rather than spondylitis. Further investigation of possible HLA-Cw*0602 linked genes in PsA is warranted.     

Association of SEEK1 and psoriatic arthritis in two distinct Canadian populations

OBJECTIVE: To examine the relationship between SNP +39604 in SEEK1 and psoriatic arthritis (PsA) in two distinct Canadian populations. METHODS: 103 patients with PsA and 105 ethnically matched controls from Newfoundland and 202 patients with PsA and 100 controls from Ontario were studied. Patients and controls were genotyped for SNP +39604 of SEEK1 by time of flight mass spectrometry, using the Sequenom platform. Genomic DNA was amplified by the Dynal RELI SSO HLA-Cw* typing kit for HLA-C typing. RESULTS: The frequency of the minor SEEK1(T) allele in subjects with PsA and controls was 48.5% and 32.4%, respectively (odds ratio (OR) = 2.0; p = 0.017), in the Newfoundland population and 46.5% and 38.0%, respectively (OR = 1.4; p = 0.16), in the Ontario population. Although SEEK1 is associated with PsA, particularly in the Newfoundland population, multivariate analysis showed that SEEK1 does not seem to be a further susceptibility factor if the HLA-Cw*0602 status is already known. No association was noted between SEEK1(T) allele and onset of psoriasis, PsA, or arthritis pattern. CONCLUSION: SEEK1 is associated with PsA in the Newfoundland founder population. This association is probably due to linkage disequilibrium between SEEK1 and HLA-Cw*0602 in this population.     

HLA-Cw6 and HLA-DRB1*07 together are associated with less severe joint disease in psoriatic arthritis

BACKGROUND: Human leucocyte antigen (HLA) genes predict disease severity in psoriasis (HLA-Cw6) and rheumatoid arthritis (shared epitope (SE)), but the situation is unclear for psoriatic arthritis (PsA). AIM: To determine the association of the HLA-Cw6 and HLA-DRB1 gene with disease severity in a large UK cohort with PsA. METHODS: Genotyping of the HLA-Cw and HLA-DRB1 loci was undertaken in DNA samples from patients with PsA (n = 480). Stratification and regression analysis were used within the PsA cases to determine whether HLA-Cw6, HLA-DRB1 or the presence of the SE alleles predicted disease severity as measured by the Health Assessment Questionnaire score, the total number of damaged or involved joints adjusted for disease duration and disease-modifying antirheumatic treatments. RESULTS: HLA-Cw6 was found to be in linkage disequilibrium with HLA-DRB1*07 (r(2) = 0.46). Patients with PsA who carried both HLA-Cw6 and HLA-DRB1*07 had fewer damaged or involved joints (41% fewer damaged (95% CI 23% to 55%, p = 0.02) and 31% fewer involved joints (95% CI 16% to 44%, p<0.001)) compared with those who carried neither HLA-Cw6 nor HLA-DRB1*07 alleles. Those who carried either HLA-Cw6 or HLA-DRB1*07 alleles alone had no evidence of a reduction in joint involvement. The SE, HLA-DRB1*03 and HLA-DRB1*04 alleles did not predict severity using these outcome measures. CONCLUSION: Patients with PsA carrying both HLA-Cw6 and HLA-DRB1*07 alleles have a less severe course of arthritis. This suggests that a protective locus lies on a haplotype marked by these alleles. No association was detected with disease severity and SE status.     

Association of MHC class I related gene B (MICB) to celiac disease

BACKGROUND AND AIMS: Celiac disease (CD) is an enteropathic disorder characterized by strong association with HLA-DQ2. Our aim was to investigate whether MICB, a gene located in the MHC class I region, may contribute to CD susceptibility. PATIENTS AND METHODS: Total of 133 CD patients, previously reported to be associated with MICA-A5.1, and 116 controls were initially analyzed. Twenty-eight additional DQ2-negative CD patients were also studied. MICB was typed by PCR using sequence-specific primers. HLA-B, -DRB1, -DQA1, -DQB1, and MICA were also typed. RESULTS: The allele MICB0106 was strongly associated with CD (pc < 0.000001, odds ratio (OR) = 5.6, 95% confidence interval (CI) = 3.1-10.1) and it was overrepresented in atypical patients compared with typical ones (pc = 0.04, OR = 2.9, CI = 1.4-6.1). MICB0106 was part of DR3-DQ2 haplotype (B8-MICA-A5.1-MICB0106-DR3-DQ2), and consequently a strong linkage disequilibrium between MICB0106 with DQ2 (lambdas = 1) and MICA-A5.1 (lambdas = 0.55) was found. To analyze whether the association of MICB is independent of this haplotype, its association was also studied in DQ2-negative patients (n = 46). DQ8 (28%vs 9%, p = 0.0085, pc = NS) and MICB0104 (52%vs 30%, p = 0.01, pc = NS) were increased in DQ2-negative patients. MICA-A5.1 was significantly increased in atypical patients (p(c)= 0.001, OR = 6.4, CI = 2.2-18.4), and this association was independent of DQ2 and DQ8 (pc = 0.02, OR = 2.6, CI = 1.1-6.1). CONCLUSIONS: The expression of MIC genes on enterocytes under stressful conditions and their function as ligands of intraepithelial gammadelta and CD8 T cells, together with the data presented here suggest a potential role of MIC genes in the pathogenesis of CD.     

MHC class I chain related gene A (MICA) modulates the development of coeliac disease in patients with the high risk heterodimer DQA1*0501/DQB1*0201

BACKGROUND AND AIMS: Coeliac disease (CD) is an enteropathic disorder characterised by a strong association with major histocompatibility complex (MHC) heterodimer HLA-DQ2. It has been suggested that other HLA class I genes in combination with DQ may also contribute to CD susceptibility. The aim of this study was to investigate whether other candidate genes modify the risk of developing different clinical forms of CD. PATIENTS AND METHODS: We studied 133 Spanish coeliac patients, divided according to their clinical presentation into typical and atypical groups, and 116 healthy controls. All were typed by polymerase chain reaction-sequence specific primers (PCR-SSP) at HLA-B, DRB1, DQA1, and DQB1 loci and for exon 5 of the MHC class I chain related gene A (MICA). RESULTS: No differences were found in the frequency of the DQA1*0501/DQB1*0201 heterodimer in either group. The risk of typical CD was significantly associated with the DR7/DQ2 haplotype (p(c)=0.02, odds ratio (OR)=3.4, ethiological fraction (EF)=0.4). Extended haplotype (EH) 8.1 (B8/DR3/DQ2) was found to be overrepresented in the atypical form compared with the typical form (p(c)=0.001, OR=4.19, EF=0.56). The trinucleotide repeat polymorphism MICA-A5.1 was found to be increased in the atypical group of patients compared with the typical group (p(c)=0.00006, OR=8.63, EF=0.81). This association was independent of linkage disequilibrium with EH8.1 as this was also found to be increased in EH8.1 negative atypical patients compared with the typical group (p(c)=0.004, OR=6.66, EF=0.56). CONCLUSIONS: Our results showed that the risk of developing typical forms of CD was associated with DR7/DQ2 haplotype, and the presence of B8/DR3/DQ2 was significantly increased in atypical patients. In these, the MICA-A5.1 allele confers an additive effect to the DR3/DQ2 haplotype that may modulate the development of CD.     

HLA-Cw*06 class I region rather than MICA is associated with psoriatic arthritis in Czech population

Psoriatic arthritis (PsA) is a chronic inflammatory joint disease which affects patients suffering from psoriasis. The genetic background especially the susceptibility loci on the short arm of the chromosome six contribute to PsA development. In our study, we looked for the role of the MICA and HLA-Cw genes polymorphisms in PsA pathogenesis. We investigated 100 PsA patients and 94 healthy Czech individuals. We found an association between HLA-Cw*06 and PsA namely PsA with psoriasis type I (age of psoriasis onset before 40 years) compared to healthy individuals (P _corrected < 0.05, OR 2.56, CI 95% 1.33–4.76 and P _corrected = 0.01, OR 3.03, CI 95% 1.53–5.88, respectively). The MICA-A9 allele of the transmembrane microsatelite MICA polymorphism occurred more frequently in PsA with psoriasis type II group (age of psoriasis onset after 40 years) than in controls, 58.6 versus 38.0%, respectively however, this finding did not reach a statistical significance after correction (P _corrected = 0.085).     

The effect of HLA-DR antigens on the susceptibility to, and clinical expression of psoriatic arthritis

OBJECTIVE: To analyse the relative role of HLA-DR antigens in the susceptibility to, and clinical expression of psoriatic arthritis (PsA). PATIENTS AND METHODS: A retrospective cohort study of 120 patients with PsA who were assessed according to a standard protocol. Patients were classified in accordance with the predominant pattern observed in the last 5 years of disease evolution: polyarthritis (n = 33), oligoarthritis (n = 45), and spondylitis (n = 42). HLA-Cw gene typing was done by the polymerase chain reaction (PCR) sequence-specific oligonucleotide probes (PCR-SSOP) method, while HLA-DR and B27 typing were performed by serological methods. The distribution of HLA-DR and Cw antigens was also analysed in 50 patients with psoriasis alone. One hundred and seventy subjects from our general population served as controls. RESULTS: No definite association was found between HLA-DR alleles and the risk of psoriasis or PsA. HLA-DR4 was found to be under-represented in arthritic patients [probability (p) = 0.03]. HLA-DR7 showed association with oligoarthritis [odds ratio (OR) 6, 95% confidence interval (CI): 2-16, corrected probability (Pc) = 0.01], whereas HLA-DR8 appeared to be related to the risk of polyarthritis (OR 9.5, 95% CI: 2-42, Pc = 0.02). HLA-Cw*0602 conferred risk for psoriasis (Pc < 0.00001), but not for PsA. As expected, HLA-B27 appeared to be over-represented in patients with spondylitis (p = 0.03). CONCLUSIONS: This is the first report that associates HLA-DR8 with psoriatic polyarthritis. Although HLA-DR antigens have a marginal role in PsA or psoriasis susceptibility, they may be relevant to the modulation of the clinical expression of PsA. These HLA data add support to the classification of PsA into three disease subsets.     

Autoimmune hepatitis in Brazilian patients is not linked to tumor necrosis factor alpha polymorphisms at position -308

BACKGROUND/AIMS: Susceptibility to autoimmune hepatitis (AIH) has been linked to different HLA-DR antigens. Recently, AIH type 1 was associated with polymorphisms in the tumor necrosis factor alpha gene promoter (TNFA) at position -308. In this respect, the frequency of the TNFA*2 allele, in linkage disequilibrium with HLA-DRB1*0301, was shown to be significantly increased in whites with AIH type 1. The aim of this study was to assess the role of TNFA alleles in conferring susceptibility to AIH, studying a population where the disease is not primarily associated with HLA-DRB1*03. METHODS: The determination of HLA-DRB1 and TNFA alleles was performed in 92 patients with AIH type 1, 29 subjects with AIH type 2 and 83 healthy controls by polymerase chain reaction-based techniques. RESULTS: The distribution of TNFA alleles was similar in patients with AIH types 1 and 2, when compared with controls. In addition, the TNFA*2 allele was identified in patients carrying HLA-DR antigens other than HLA-DRB1*03. Interestingly, higher gammaglobulin levels were observed in TNFA*2 positive patients. CONCLUSIONS: Our data indicate that susceptibility to AIH remains primarily linked to the HLA-DRB1 locus, and suggest that the association of AIH with TNFA*2 previously observed in whites might be secondary to a linkage disequilibrium with HLA-DRB1*0301.     

Contribution of MHC class I region to genetic susceptibility for giant cell arteritis

OBJECTIVE: The aim of this study was to assess the potential contribution of HLA-class I MICA and HLA-B gene polymorphisms towards the pathogenesis of giant cell arteritis (GCA). METHODS: Ninety-eight biopsy-proven GCA patients and 225 ethnically matched controls from Lugo, Northwest Spain, were genotyped for the MICA-TM microsatellite polymorphism using a polymerase chain reaction (PCR)-based method. Genotyping of HLA-B was performed using PCR and detection with a reverse sequence-specific oligonucleotide (SSO) probes system. RESULTS: A significant difference in the distribution of the alleles of MICA between patient and control groups (P = 0.005) was found. This was due to an increased frequency of the MICA A5 allele in GCA patients compared with controls (26 vs 13.6%; P = 0.0001; P(C) = 0.0005; OR 2.2, 95% CI 1.4-3.4). In addition, the HLA-B*15 allele showed a higher frequency in GCA patients compared with controls (P = 0.004; P(C) = 0.04; OR 2.7, 95% CI 1.3-5.7). Interestingly, the association observed with the MICA A5 allele seems to be independent of linkage disequilibrium with HLA-B, as well as independent of that previously described with HLA-DRB1*04. Remarkably, simultaneous presence of MICA A5 and HLA-B*15 or HLA-DRB1*04 genetic markers leads to an increase in the OR obtained for each individual genetic marker (MICA A5 + B*15 OR 3.2; MICA A5 + DRB1*04 OR 5.8). CONCLUSIONS: Our results provide the first evidence that the MICA and HLA-B genes are independently associated with the genetic susceptibility to GCA, and suggest that several genes within the MHC might have independent effects in the susceptibility to this systemic vasculitis.     

Major histocompatility complex haplotypic associations in Felty's syndrome and large granular lymphocyte syndrome are secondary to allelic association with HLA-DRB1 *0401

OBJECTIVE: To investigate the role of HLA class I in susceptibility to Felty's syndrome (FS) and large granular lymphocyte (LGL) syndrome. METHODS: Fifty caucasoid FS patients, and 55 patients with LGL syndrome, of whom 26 had arthritis and 29 did not, were studied. Complete HLA class I and HLA-DR typing including, where relevant, DRB1*04 subtyping was carried out by molecular methods. Comparison was made with 78 unselected healthy caucasoid controls and a further 29 DRB1*0401+ individuals. RESULTS: A significant association was found between HLA-A*02 and FS [odds ratio (OR) 3.9, 95% confidence interval (95% CI) 1.8-8.4, P = 0.0004]. At the B locus, there was an association between B*44 and LGL with arthritis [OR 3.5 (1.3-9.2), P = 0.01]. For HLA-Cw*0501, there was an association with FS [OR 4 (1. 7-9.2) P = 0.0008]. For both FS and LGL with arthritis, the extended haplotype HLA-A*02;B*44;Cw*0501;DRB1*0401 was significantly associated [OR 9.5 (2.6-35), P = 0.0001; OR 4.6 (1-22.4), P = 0.05, respectively]. There was no association between HLA class I or II and LGL without arthritis. All the allelic and haplotypic associations were lost on comparison with HLA-DRB1*0401+ controls. The strongest HLA association was with HLA-DRB1*0401 for FS [OR 27.9 (10.3-75.5), P = 10(-13)], and LGL with arthritis [OR 35.4 (9.6-131. 3), P = 10(-10)]. CONCLUSIONS: The major histocompatibility locus (MHC) associations with FS reported here are due to linkage disequilibrium with HLA-DRB1*0401. LGL syndrome with arthritis shows identical class II associations with FS, although there may be subtle immunogenetic differences between the two in the class I region. One of the extended haplotypes reported in a number of studies for FS and rheumatoid arthritis (summarized as HLA-A*02;Cw*0501; B*44;TNFb5;TNFa6;TNFd4;C4A*3;C4BQ*0;DRB1*0 401;DQB1*0301) is likely to be attributable to strong primary association with HLA-DRB1*0401, rather than to epistatic interaction between these loci.     

No primary association of MICA polymorphism with systemic lupus erythematosus

OBJECTIVE: To replicate the described association between MHC class I chain-related A (MICA) gene polymorphism and susceptibility to systemic lupus erythematosus (SLE). METHODS: MICA transmembrane microsatellite polymorphism was genotyped using a polymerase chain reaction (PCR)-based method. Genotyping of HLA-B* and DRB1* was performed using PCR and detection with a reverse sequence-specific oligonucleotide (SSO) probe system. Combined data for these three loci (HLA-B*, DRB1* and MICA) were obtained from a total of 333 patients and 361 healthy controls. RESULTS: Significant association with B*08 [P < 10(-7), odds ratio (OR) 3.17, 95% confidence interval (CI) 2.02-5.00], DRB1*0301 (P < 10(-7), OR 2.07, 95% CI 1.59-2.68) and MICA5.1 (P = 0.01, OR 1.23, 95% CI 1.04-1.46) was observed. The combinations DRB1*0301-MICA5.1-B8 and HLA-DRB1*0301-B*08-positive and MICA5-1-negative were more frequent among SLE patients (11.4 vs 3.3% in healthy controls, P = 3.9 x 10(-5), OR 3.76, 95% CI 1.85-7.73, and 6.9 vs 1.7%, P = 0.0007, OR 4.32, 95% CI 1.68-13.10, respectively). Additionally, individuals who were HLA-DRB1*0301-B*08-negative and MICA5-1-positive were less frequent among patients (22.2 vs 31.3% in healthy controls, P = 0.007, OR 0.63, 95% CI 0.44-0.89) and the magnitude of the OR was similar to that obtained in individuals negative for all the three factors (OR 0.69, 95% CI 050-0.94). Further analysis performed to detect independent association strongly suggested that the association between MICA5.1 and SLE is secondary to the linkage disequilibrium of this allele with B*08. CONCLUSIONS: Our results do not support an independent association of MICA gene polymorphism with susceptibility to SLE.     

Epistasis among HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci determines multiple sclerosis susceptibility

Multiple sclerosis (MS), a common central nervous system inflammatory disease, has a major heritable component. Susceptibility is associated with the MHC class II region, especially HLA-DRB5*0101–HLA-DRB1*1501–HLA-DQA1*0102–HLA-DQB1*0602 haplotypes(hereafter DR2), which dominate genetic contribution to MS risk. Marked linkage disequilibrium (LD) among these loci makes identification of a specific locus difficult. The once-leading candidate, HLA-DRB1*15, localizes to risk, neutral, and protective haplotypes. HLA-DRB1*15 and HLA-DQB1*0602, nearly always located together on a small ancestral chromosome segment, are strongly MS-associated. One intervening allele on this haplotype, viz. HLA-DQA1*0102, shows no primary MS association. Two Canadian cohorts (n = 830 and n = 438 trios) genotyped for HLA-DRB1, HLA-DQA1 and HLA-DQB1 alleles were tested for association using TDT. To evaluate epistasis involving HLA-DRB1*15, transmissions from HLA-DRB1*15-negative parents were stratified by the presence/absence of HLA-DRB1*15 in affected offspring. All 3 alleles contribute to MS susceptibility through novel epistatic interactions. HLA-DQA1*0102 increased disease risk when combined with HLA-DRB1*1501 in trans, thereby unambiguously implicating HLA-DQ in MS susceptibility. Three-locus haplotypes demonstrated that HLA-DRB1*1501 and HLA-DQB1*0602 each influence risk. Transmissions of rare morcellated DR2 haplotypes showed no interaction with HLA-DQA1*0102. Incomplete haplotypes bearing only HLA-DRB1*1501 or HLA-DQB1*0602 did not predispose to MS. Balanced reciprocal transmission distortion can mask epistatic allelic association. These findings implicate epistasis among HLA class II alleles in human immune responses generally, provide partial explanation for intense linkage disequilibrium in the MHC, have relevance to animal models, and demonstrate key roles for DR2-specific interactions in MS susceptibility. MHC disease associations may be more generally haplotypic or diplotypic.     

Analysis of single-nucleotide polymorphisms in Japanese rheumatoid arthritis patients shows additional susceptibility markers besides the classic shared epitope susceptibility sequences

OBJECTIVE: To examine the entire HLA region for loci (other than the DRB1 locus) associated with rheumatoid arthritis (RA) susceptibility, by typing HLA-DRB1 alleles and multiple single-nucleotide polymorphisms (SNPs) in the Japanese population. METHODS: The HLA-DRB1 alleles and 88 SNPs distributed over the HLA gene complex were genotyped, for 828 patients with RA and 1,032 control subjects. The data were evaluated for linkage disequilibrium, and case-control associations were analyzed in 2 ways, in the presence or absence of the disease-susceptibility DRB1 allele, to detect loci independent of the DRB1 allele. RESULTS: HLA-DRB1 alleles *0405, *0401, *0901, *0101, *1401, *1602, *0403, and *1405 were significantly associated with RA in the Japanese population. The smallest P value (P = 1.4 x 10(-27)) was observed in association with an intronic SNP of the NOTCH4 gene, which was due to strong linkage disequilibrium with the HLA-DRB1 allele. A strong association that was independent of HLA-DRB1 shared epitope alleles was observed in 2 SNPs: one in the intron of the MICA gene, the other in the intron of the HLA-DQB2 gene. Their association with RA, independent of HLA-DRB1 shared epitope alleles, was suggestive (P = 0.0024 [corrected P (P(corr)) = 0.068, and P = 0.00037 [P(corr) = 0.012], respectively). CONCLUSION: These findings suggest that 1 or more other loci besides the HLA-DRB1 or other DRB1 (non-shared epitope, non-*0901) alleles are involved in RA susceptibility/protection.     

Association of MICA alleles with psoriatic arthritis and its clinical forms. A multicenter Italian study

OBJECTIVE:Analysis of the association between psoriatic arthritis (PsA) clinical forms and MICA gene transmembrane polymorphisms.METHODS:Patients were classified as having peripheral asymmetric oligoarthritis (AO), peripheral symmetric poly-arthritis (PA) and spondylitis (SP), or disease combinations (PA/SP, OA/SP). Two hundred and twenty-six patients with PsA were typed for MICA exon 5 microsatellite (TM) by heteroduplex analysis and compared with 225 normal controls. RESULTS:MICA-TM microsatellite typing revealed that, among the different clinical forms of PsA, only the combined PA/SP subset shows a significant positive association with MICA-A9 and a lower frequency of MICA-A4, A5 genotype in PsA patients with a decrease, only in the PA/SP cohort, of all MICA-A5 combinations except MICA-A5, -A9.CONCLUSION:These results suggest a role for genes within the HLA region in the pathogenesis of PsA, and reinforce the idea that the different forms of PsA may have heterogeneous genetic basis.     

BAT1 promoter polymorphism is associated with rheumatoid arthritis susceptibility

OBJECTIVE: To analyze whether the polymorphisms -22 (G/C) and -348 (C/T) of the BAT1 gene are associated with susceptibility to rheumatoid arthritis (RA). METHODS: One hundred fifty-six patients with RA and 154 controls were genotyped for HLA-DRB1 and the polymorphisms -22 and -348 of the BAT1 gene. RESULTS: HLA-DRB1*04 alleles were associated with RA susceptibility (33.9% vs 20.1%; pc = 0.04). Among these, HLA-DRB1*0401 (13.4% vs 5.1%; pc = 0.04) and HLA-DRB1*0404 (5.7% vs 1.2%; pc = 0.2) were increased in patients with RA. Additionally, carriage of BAT1 -348T polymorphism was strongly associated with RA (23.7% vs 12.1%; pc = 0.0002). Significantly, BAT1 -348T was in linkage disequilibrium with HLA-DRB1*0404 and HLA-DRB1*0405. However, BAT1 -348 T was associated independently with HLA-DRB1 shared-epitope alleles (42.6% vs 18.9%; p = 0.001). CONCLUSION: The BAT1 -348T polymorphism is associated with RA susceptibility independently of HLA-DRB1. The role of BAT1 in the regulation of tumor necrosis factor-a suggests that BAT1 may regulate the inflammatory response observed in patients with RA.     

HLA class II and T cell receptor gene polymorphisms in psoriatic arthritis and psoriasis

HLA-DRB, DQA and DQB genes as well as the T cell receptor (TcR) alpha, beta, and gamma genes were studied by Southern blot analysis of genomic DNA from patients with psoriatic arthritis (PsA) and psoriasis alone (Ps). A subtype of DR7, DR7a, was found in 38.8% of patients with PsA, 41.5% of patients with Ps, and in 8% of healthy individuals (N) (PsA vs N: pc = 0.0002, RR = 7.1; Ps vs N: pc = 0.0002, RR = 7.9). No association with TcR genes was found. Our findings suggest either that the DR7a allele may be in linkage disequilibrium with HLA-Cw6 or that it may be an important susceptibility factor for PsA and Ps.     

Association of tumor necrosis factor alpha polymorphism, but not the shared epitope, with increased radiographic progression in a seropositive rheumatoid arthritis inception cohort

OBJECTIVE: To determine whether the tumor necrosis factor alpha (TNFA) -308 guanine-to-adenosine polymorphism and/or the shared epitope (SE) is associated with radiographic damage in patients with early rheumatoid arthritis (RA). METHODS: The cohort consisted of 189 patients with early seropositive RA (median 5.6 months since symptom onset) who had active disease, no previous disease-modifying antirheumatic drug treatment, and >or=2 sets of scored radiographs of the hands/wrists and forefeet. TNFA -308 polymorphism was analyzed by polymerase chain reaction pyrosequencing. The SE was defined as presence of any 1 of the following HLA-DRB1 alleles: *0101, *0102, *0401, *0404, *0405, *0408, *0410, *1001, *1402, or *1406. Radiographic progression was assessed by the total Sharp score. RESULTS: Using a weighted least-squares regression analysis, patients with the -308 TNFA AA plus AG genotypes (n=49) had significantly higher rates of progression in erosion scores (median 0.84 versus 0.48 units/year), joint space narrowing (JSN) scores (0.42 versus 0.04), and total Sharp scores (1.70 versus 0.61) compared with patients with the TNFA GG genotype (n=140). Presence of the SE (n=137) was associated with significantly lower progression rates (per year) for total Sharp scores (median 0.9 versus 1.25 units/year) and JSN scores (0.04 versus 0.41), but not for erosion scores (0.50 versus 0.61) compared with patients without the SE (n=52). In a least-squares multiple linear regression model, the presence of the AA plus AG genotypes was associated with a significantly higher progression rate after adjusting for the presence of the SE, interaction between the SE and the AA plus AG genotypes, baseline log C-reactive protein level, Health Assessment Questionnaire Disability Index, total Sharp score, swollen joint count, and presence of osteophytes (osteoarthritis). There was a strong linkage disequilibrium between DRB1*0301 and TNFA polymorphism (D'=0.84, r2=0.45, P<0.001). CONCLUSION: This study showed an association between the TNFA -308 polymorphism and progression of radiographic damage in patients with early seropositive RA. This association appeared to be independent of the SE, but might be dependent on other genetic variants in linkage disequilibrium with the -308 TNFA A allele and DRB1*0301. Further studies should be conducted to validate these results in both longitudinal observational cohorts and randomized clinical trials.     

Association of the HLA-DRB1*0301 and HLA-DQA1*0501 alleles with Graves' disease in a population representing the gene contribution from several ethnic backgrounds.

Graves' disease (GD) is the most frequent cause of hyperthyroidism. Although the etiology is not completely elucidated, there are several lines of evidence suggesting multifactorial mechanisms. Genetic, constitutional, and environmental factors are involved in its pathogenesis. Major histocompatibility complex (MHC) class II alleles have been associated with GD in several populations of distinct ethnic backgrounds and there is increasing evidence supporting an association between GD and HLA-DR3 in Caucasian populations. The MHC class II alleles were evaluated in 75 Brazilian patients presenting with GD and in 166 control individuals from the same geographic area. HLA-DRB, DQB, and DQA alleles were identified using polymerase chain reaction (PCR)-amplified DNA hybridized with sequence-specific probes. The HLA-DRB1*0301 allele was significantly increased in patients (34/75, 45.3%) as compared with controls (37/166, 22.3%, p = 0.009), conferring a relative risk (RR) of 2.8 and an etiologic fraction (EF) of 0.287. The HLA-DQA1*0501 allele was also overrepresented in patients (48/71, 67.6%) in relation to controls (24/71, 33.8%; p = 0.004), conferring an RR of 3.74 and an EF of 0.351. The susceptibility conferred by HLA-DQA1*0501 was independent of the HLA-DRB1*0301 allele. On the other hand, the HLA-DQB1*0602 allele was significantly decreased in patients (6/75, 8.0%) in relation to controls (53/166, 31.9%, p = 0.0008), conferring an RR of 0.18 and a preventive fraction of 0.267. Although the Brazilian population comprises individuals of several ethnic backgrounds, these results corroborate the participation of the HLA-DRB1*0301 and HLA-DQA1*0501 alleles as susceptibility markers for GD, and emphasize the participation of the HLA-DQB1*0602 allele as conferring protection against the development of the disease.     

HLA antigens may influence the age of onset of psoriasis and psoriatic arthritis

OBJECTIVE: To analyze whether HLA antigens may influence the age of onset of both psoriasis and psoriatic arthritis (PsA). METHODS: One hundred thirty-five patients with PsA (77 men, 58 women, mean age 47 +/- 12 yrs) were analyzed. All were studied with a standard protocol and consecutively recruited to evaluate the relative contribution of HLA-Cw and HLA-B27 alleles to PsA susceptibility. Fifty patients with psoriasis alone were also recruited to analyze the role of HLA-Cw genes on disease susceptibility. HLA-Cw antigens were investigated by DNA based methods (PCR-SSOP), while HLA-B27 antigen was studied using serological methods, and their frequencies were compared to 177 healthy controls. RESULTS: In PsA Cw6+ patients, the mean age at psoriasis onset was 23 +/- 12 years compared to 32 +/- 12 years in Cw6- patients (p = 0.012). Age of arthritis onset was 35 +/- 13 years in Cw6+ patients versus 38 +/- 12 years in Cw6- patients (p = NS). In patients with psoriasis alone, the age at onset was 18 +/- 10 years in Cw6+ versus 30 +/- 11 years in Cw6- patients (p < 0.01). Cw6 correlated well with a positive family history of psoriasis among first-degree relatives (64% of patients with family history were Cw6+, whereas only 30% of those without family history had this allele (p < 0.05). The onset age of psoriasis in HLA-B27+ patients was 24 +/- 8 years vs 32 +/- 14 years in B27- patients (p = 0.026), whereas onset age of arthritis was 30 +/- 10 years in B27+ compared to an age of onset of 40 +/- 12 in B27- patients (p = 0.0056). CONCLUSION: Our results confirm the known association between Cw6, early onset psoriasis and positive family history (type I psoriasis). The association between HLA-B27 and earlier onset ages for both psoriasis and arthritis in PsA had not previously been emphasized. The HLA antigens may determine not only disease susceptibility, but also the age of disease onset in psoriasis and PsA.