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Ankylosing spondylitis (AS) is the prototypic form of axial spondyloarthritis (axSpA). It is highly heritable, with studies conducted in twins and in unrelated cases and controls showing that the heritability for AS is much higher than those for inflammatory bowel disease or rheumatoid arthritis. To date, 116 loci have been identified, contributing to 28% of the genetic variation in the disease. These loci provide important clues into pathogenic pathways in the disease that have led to therapeutic advances such as the repositioning of IL-17 inhibitors in the disease. Much more research is currently required to determine the functional mechanisms by which the genetic associations operate, from which it is likely that novel therapeutic approaches will be developed.

The IL23R region on chromosome 1 exhibits complex associations with ankylosing spondylitis (AS). We used publicly available epigenomic information and historical genetic association data to identify a putative regulatory element (PRE) in the intergenic region between IL23R and IL12RB2, which includes two single-nucleotide polymorphisms (SNPs) independently associated with AS—rs924080 (P=2 × 10−3) and rs11578380 (P=2 × 10−4). In luciferase reporter assays, this PRE showed silencer activity (P<0.001). Haplotype and conditional analysis of 4230 historical AS cases and 9700 controls revealed a possible AS-associated extended haplotype, including the PRE and risk variants at three SNPs (rs11209026, rs11209032 and rs924080), but excluding the rs11578380 risk variant. However, the rs924080 association was absent after conditioning on the primary association with rs11209032, which, in contrast, was robust to conditioning on all other AS-associated SNPs in this region (P<2 × 10−8). The role of this putative silencer on some IL23R extended haplotypes therefore remains unclear.

Ankylosing spondylitis (AS), an immune-mediated arthritis, is the prototypic member of a group of conditions known as spondyloarthropathies that also includes reactive arthritis, psoriatic arthritis and enteropathic arthritis. Patients with these conditions share a clinical predisposition for spinal and pelvic joint dysfunction, as well as genetic associations, notably with HLA-B*27. Spondyloarthropathies are characterized by histopathological inflammation in entheses (regions of high mechanical stress where tendons and ligaments insert into bone) and in the subchondral bone marrow, and by abnormal osteoproliferation at involved sites. The association of AS with HLA-B*27, first described >40 years ago, led to hope that the cause of the disease would be rapidly established. However, even though many theories have been advanced to explain how HLA-B*27 is involved in AS, no consensus about the answers to this question has been reached, and no successful treatments have yet been developed that target HLA-B27 or its functional pathways. Over the past decade, rapid progress has been made in discovering further genetic associations with AS that have shed new light on the aetiopathogenesis of the disease. Some of these discoveries have driven translational ideas, such as the repurposing of therapeutics targeting the cytokines IL-12 and IL-23 and other factors downstream of this pathway. AS provides an excellent example of how hypothesis-free research can lead to major advances in understanding pathogenesis and to the development of innovative therapeutic strategies.

OBJECTIVE: To investigate the association of CD14 and Toll-like receptor (TLR4) with ankylosing spondylitis (AS). METHODS: A promoter variant in CD14 and 2 coding polymorphisms in TLR4 were investigated in UK and Finnish families with AS and in a UK case-control study. A metaanalysis of published TLR4 and CD14 studies was performed. RESULTS: In the Finnish study the CD14-260bp T variant showed an association (p = 0.006), and the common 2-marker TLR4 haplotype showed a weak association (global p = 0.03), with AS. No associations were seen in the UK based studies or in the metaanalyses. CONCLUSION: CD14 and TLR4 showed an association with AS in the Finns only.

Objectives. Strong genetic association of rheumatoid arthritis (RA) with PADI4 (peptidyl arginine deiminase) has previously been described in Japanese, although this was not confirmed in a subsequent study in the UK. We therefore undertook a further study of genetic association between PADI4 and RA in UK Caucasians and also studied expression of PADI4 in the peripheral blood of patients with RA.Methods. Seven single-nucleotide polymorphisms (SNP) were genotyped using polymerase chain reaction (PCR)–restriction fragment length polymorphism in 111 RA cases and controls. A marker significantly associated with RA (PADI4_100, rs#2240339) in this first data set (P = 0.03) was then tested for association in a larger group of 439 RA patients and 428 controls. PADI4 transcription was also assessed by real-time quantitative PCR using RNA extracted from peripheral blood mononuclear cells from 13 RA patients and 11 healthy controls.Results. A single SNP was weakly associated with RA (P = 0.03) in the initial case–control study, a single SNP (PADI4_100) and a two marker haplotype of that SNP and the neighbouring SNP (PADI4_104) were significantly associated with RA (P = 0.02 and P = 0.03 respectively). PADI4_100 was not associated with RA in a second sample set. PADI4 expression was four times greater in cases than controls (P = 0.004), but expression levels did not correlate with the levels of markers of inflammation.Conclusion. PADI4 is significantly overexpressed in the blood of RA patients but genetic variation within PADI4 is not a major risk factor for RA in Caucasians.

Objectives. To examine the relationship between the severity of nail disease and characteristics of psoriatic arthritis (PsA). We also wished to assess the clinical management of nail disease in patients with PsA.Methods. We studied 69 patients with PsA at two visits. On the first visit, a rheumatology assessment of joint, skin and nail disease was made. On the second visit, a detailed dermatology assessment of skin and nails was made. Nail disease was analysed using a 20-nail psoriasis nail severity score (PNSS).Results..There were 57 (83%) patients with clinical evidence of psoriatic nail disease. Although 66 (96%) patients had been treated for skin disease, only one (1%) had received any treatment for nail disease. Severe nail disease measured by the PNSS correlated with severe skin psoriasis as indicated by the percentage of body surface area affected by psoriasis (r = 0.34, P = 0.004) and physician global assessment of psoriasis (r = 0.45, P<0.001). Patients with distal interphalangeal (DIP) joint disease had higher PNSS scores (P = 0.03). The PNSS was also associated with unremitting and progressive arthritis (P<0.001), and correlated with Stanford health assessment questionnaire (HAQ) (r = 0.34, P = 0.004), depression (r = 0.39, P<0.001) and anxiety (r = 0.34, P = 0.004) scores. Compared with dermatology assessment, the rheumatology examination of nail disease had a positive predictive value of 84% and negative predictive value of 83%.Conclusions. In patients with PsA, the severity of nail disease correlates with indicators of severity of both skin and joint disease. Although rheumatologists can adequately screen for nail disease, the management of this aspect of PsA is often overlooked.

Ankylosing spondylitis is a highly heritable, common rheumatic condition, primarily affecting the axial skeleton. The association with HLA-B27 has been demonstrated worldwide, and evidence for a role of HLA-B27 in disease comes from linkage and association studies in humans, and transgenic animal models. However, twin studies indicate that HLA-B27 contributes only 16% of the total genetic risk for disease. Furthermore, there is compelling evidence that non-B27 genes, both within and outwith the major histocompatability complex, are involved in disease aetiology. In this post-genomic era we have the tools to help elicit the genetic basis of disease. This review describes methods for genetic investigation of ankylosing spondylitis, and summarises the status of current research in this exciting area.

Objectives. To determine whether genetic polymorphisms in or near the transforming growth factor β1 (TGFB1) locus were associated with susceptibility to or severity of ankylosing spondylitis (AS).Methods. Five intragenic single-nucleotide polymorphisms (SNP) and three microsatellite markers flanking the TGFB1 locus were genotyped. Seven hundred and sixty-two individuals from 184 multiplex families were genotyped for the microsatellite markers and two of the promoter SNPs. One thousand and two individuals from 212 English and 170 Finnish families with AS were genotyped for all five intragenic SNPs. A structured questionnaire was used to assess the age of symptom onset, disease duration and disease severity scores, including the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index).Results. A weak association was noted between the rare TGFB1 +1632 T allele and AS in the Finnish population (P = 0.04) and in the combined data set (P = 0.03). No association was noted between any other SNPs or SNP haplotype and AS, even among those families with positive non-parametric linkage scores. The TGFB1 +1632 polymorphism was also associated with a younger age of symptom onset (English population, allele 2 associated with age of onset greater by 4.2 yr, P = 0.05; combined data set, allele 2 associated with age of onset greater by 3.2 yr, P = 0.02). A haplotype of coding region SNPs (TGFB1 +869/+915+1632 alleles 2/1/2) was associated with age of symptom onset in both the English parent–case trios and the combined data set (English data set, haplotype 2/1/2 associated with age of onset greater by 4.9 yr, P = 0.03; combined data set, haplotype 2/1/2 associated with greater age of onset by 4.2 yr, P = 0.006). Weak linkage with AS susceptibility was noted and the peak LOD score was 1.3 at distance 2 cM centromeric to the TGFB1 gene. No other linkage or association was found between quantitative traits and the markers.Conclusion. This study suggests that the polymorphisms within the TGFB1 gene play at most a small role in AS and that other genes encoded on chromosome 19 are involved in susceptibility to the disease.

Objective. To determine the frequency and clinical predictors of sacroiliitis diagnosed by magnetic resonance imaging (MRI) in a psoriatic arthritis (PsA) population.Methods. The studied comprised 103 patients with PsA. A careful clinical assessment for sacroiliitis was made from history and examination, and HLA-B27 testing was performed. Sixty-eight patients underwent tilted coronal fat-saturated T1-weighted and STIR MRI of the sacroiliac joints.Results. Clinical features of moderate or severe sacroiliitis were found in 24/68 (35%) patients. MRI features of sacroiliitis were found in 26/68 (38%) patients. Clinical features of sacroiliitis were present in 14/42 (33%) with normal MRI scans and 10/26 (38%) with abnormal scans (normal vs abnormal scans, P = 0.7). The presence of sacroiliitis on MRI was associated with restricted spinal movements (P = 0.004) and the duration of PsA (P = 0.04). There was no correlation between HLA-B27 and sacroiliitis diagnosed by MRI.Conclusion. Sacroiliitis diagnosed by MRI occurs commonly in PsA but is difficult to detect clinically.

HLA–DRB1, a major genetic determinant of susceptibility to rheumatoid arthritis (RA), is located within 1,000 kb of the gene encoding tumor necrosis factor (TNF). Because certain HLA–DRB1*04 subtypes increase susceptibility to RA, investigation of the role of the TNF gene is complicated by linkage disequilibrium (LD) between TNF and DRB1 alleles. By adequately controlling for this LD, we aimed to investigate the presence of additional major histocompatibility complex (MHC) susceptibility genes. We identified 274 HLA–DRB1*04–positive cases of RA and 271 HLA–DRB1*04–positive population controls. Each subject was typed for 6 single-nucleotide polymorphisms within a 4.5-kb region encompassing TNF and lymphotoxin α (LTA). LTA–TNF haplotypes in these unrelated individuals were determined using a combination of family data and the PHASE software program. Significant differences in LTA–TNF haplotype frequencies were observed between different subtypes of HLA–DRB1*04. The LTA–TNF haplotypes observed were very restricted, with only 4 haplotypes constituting 81% of all haplotypes present. Among individuals carrying DRB1*0401, the LTA–TNF 2 haplotype was significantly underrepresented in cases compared with controls (odds ratio 0.5 [95% confidence interval 0.3–0.8], P = 0.007), while in those with DRB1*0404, the opposite effect was observed (P = 0.007). These findings suggest that the MHC contains genetic elements outside the LTA–TNF region that modify the effect of HLA–DRB1 on susceptibility to RA.

Background. Rheumatoid arthritis (RA) is strongly associated with a series of HLA‐DRB1 alleles that encode a conserved sequence of amino acids (70Q/R K/R R A A74) in the DRβ1 chain, known as the shared epitope (SE). However 30% of patients are negative for DRB1*04 and 15% are SE‐negative. Exposure to these alleles as non‐inherited maternal antigens (NIMA) might explain this discrepancy. We undertook a family study to investigate the role of NIMA in RA.Methods. One hundred families, including the RA proband and both parents, were recruited. HLA‐DRB1 genotyping was performed using an allele‐specific polymerase chain reaction by standard methods. The frequencies of NIMA and non‐inherited paternal antigens (NIPA) were compared using contingency tables and a two‐tailed P test. We then reviewed four previously published studies of NIMA in RA and conducted an analysis of the combined dataResults. We identified 36 families in which the proband was DRB1*04‐negative and 13 in which the proband lacked the SE. There was an excess of DRB1*04 and SE NIMA (P=0.05) compared with NIPA. Combined analysis with previous studies showed that 53/231 mothers (23%) versus 25/205 fathers (12%) had a non‐inherited DRB1*04 (P=0.003) and 30/99 mothers versus 18/101 fathers had a non‐inherited SE allele (P=0.03).Conclusion. A role for HLA NIMA in RA is suggested by these results.

OBJECTIVE: To elucidate the relative importance of the HLA-DR and HLA-DQ loci in conferring genetic predisposition to rheumatoid arthritis (RA). METHODS: HLA-DRB1 and HLA-DQB1 alleles were typed in a set of 685 patients with RA using sequence-specific polymerase chain reaction. Allele and phenotype frequencies were compared with those in 2 large sets of historical, ethnically matched healthy controls, using the relative predispositional effect method. RESULTS: Positive association was confirmed with the shared epitope positive HLA-DRB1 alleles associated with RA in Caucasians. A significant susceptibility effect was observed with HLA-DRB1*09, described in other ethnically diverse populations but not in Caucasians. A significant underrepresentation of the HLA-DRB1*0103 variant was noted among the RA cases, supporting the proposed protective role of the DERAA motif at residues 70-74 of the DRbeta molecule. No HLA-DRB1 independent association of the HLA-DQB1 alleles, implicated in predisposing to RA, was evident. CONCLUSION: These data corroborate the shared epitope hypothesis of susceptibility to RA and provide strong evidence for the DRB1 locus as the primary RA susceptibility factor in the HLA region.

While twin studies have previously demonstrated high heritability of susceptibility to ankylosing spondylitis (AS), it is only recently that the involvement of genetic factors in determining the severity of the disease has been demonstrated. The genes involved in determining the rate of ankylosis in AS are likely to be different from those involved in the underlying immunologic events, and represent important potential targets for treatment of AS. This article will describe the progress that has been made in the genetic epidemiology of AS, and in identifying the genes involved.

To investigate the role of the gene NOD2 in susceptibility to, and clinical manifestations of, ankylosing spondylitis (AS). A case–control study of NOD2 polymorphisms known to be associated with Crohn's disease (CD) (Pro²⁶⁸Ser, Arg⁷⁰²Trp, Gly⁹⁰⁸Arg, and Leu¹⁰⁰⁷fsinsC) was performed in 229 cases of primary AS with no diagnosed inflammatory bowel disease (IBD), 197 cases of AS associated with IBD (referred to as colitic spondylarthritis; comprising 78 with CD and 119 with ulcerative colitis [UC]), and 229 ethnically matched, healthy controls. Associations between NOD2 polymorphisms and several clinical features of AS, including disease severity assessed by questionnaire and age at spondylarthritis onset, were also investigated. Exclusion linkage mapping of chromosome 16 was performed in a separate group of 185 multicase families with AS. An association was identified between Gly⁹⁰⁸Arg and UC spondylarthritis (P = 0.016, odds ratio [OR] 4.6, 95% confidence interval [95% CI] 1.3–16), and a nonsignificant trend with a similar magnitude was observed in association with CD spondylarthritis (P = 0.08, OR 3.9, 95% CI 0.8–18). The Pro²⁶⁸Ser variant was inversely associated with UC spondylarthritis (P = 0.003, OR 0.55, 95% CI 0.37–0.82), but not with CD spondylarthritis. No association was demonstrated between NOD2 variants and primary AS, or between other variants of NOD2 and either UC or CD spondylarthritis. Carriage of the Pro²⁶⁸Ser polymorphism was associated with greater disease activity as measured by the Bath Ankylosing Spondylitis Disease Activity Index (P = 0.002). Although patients with CD had a younger age at spondylarthritis onset than did those with UC (22.4 years versus 26.4 years; P = 0.01), no association was noted between the NOD2 variants linked with CD and age at spondylarthritis onset. In primary AS, the presence of a gene with a magnitude of association >2.0 was excluded (exclusion logarithm of odds score less than −2.0), and no association was observed with the microsatellite D16S3136. NOD2 variants do not significantly affect the risk of developing primary AS, but may influence susceptibility to, and clinical manifestations of, colitic spondylarthritis.

To identify T cell epitopes of the human La autoantigen involved in the generation of anti-Ro/La autoantibodies. Molecular techniques were used for HLA typing of 219 white patients with systemic lupus erythematosus and 125 white patients with primary Sjögren's syndrome. Anti-Ro/La antibody levels were measured by enzyme-linked immunosorbent assay. Peripheral blood mononuclear cell responses to an overlapping series of synthetic 15-mer peptides spanning the entire La sequence were examined in pools or individually in conventional 7-day proliferation assays. HLA typing confirmed that the HLA-DR3/DQ2 haplotype is closely associated with the occurrence of anti-Ro/La antibodies, and that the frequency of HLA-DR1 and DR4 haplotypes is reduced among antibody-positive patients. We identified 3 regions of the La sequence likely to contain T cell epitopes and 1 peptide, La 49–63, that generated a low-level but clear-cut T cell proliferative response. The HLA restrictions of these responses mirrored the HLA association data from the cohort study. Among individuals who were HLA-DR3 positive, there was no difference between patients and controls in the proliferative response to the La 49–63 peptide. Our data suggest that these are naive T cell responses, and that the identification of T cell epitopes involved in the generation of anti-Ro/La autoantibodies should focus on alternative candidate antigens.

Background & Aims: The detection of phenotype-determining genes as opposed to disease susceptibility genes requires precise phenotypic characterization of patients. Peripheral arthropathies in inflammatory bowel disease (IBD) are well recognized and are classified with the HLA-B*27-related spondyloarthropathies by the European Spondyloarthropathy Study Group. However, previous HLA studies in IBD have only shown this association with axial disease rather than peripheral arthropathy. We recently reported a clinical classification that describes 2 types of peripheral arthropathy, distinguished by their natural history and articular distribution. We now report the results of immunogenetic studies in these patients and compare them with other spondyloarthropathies. Methods: IBD patients with type 1 (n = 57) and type 2 (n = 45) peripheral arthropathy were identified by case note review and questionnaire. Patients and 603 controls from Oxfordshire were assigned HLA-A, -B, -C, -DR, and -DQ genotypes by sequence-specific primer polymerase chain reaction. Patient results were compared with controls (corrected for multiple comparisons), then with each other in light of existing hypotheses. The results were compared with those of a cohort of 30 patients with postenteric reactive arthritis (ReA) and 16 patients with IBD-associated ankylosing spondylitis (IBD-AS). Results: Type 1 arthropathy was associated with HLA-DRB1*0103 (DR103; a rare subtype of DR1) in 33% (P < 0.0001; relative risk [RR], 12.1), B*35 in 30% (P = 0.01; RR, 2.2), and B*27 in 26% (P = 0.001; RR, 4.0). In contrast, type 2 was associated with HLA-B*44 in 62% (P = 0.01; RR, 2.1). Similar significant associations to type 1 arthropathy were found in ReA, except that the HLA-B*27 association was significantly stronger and an association was found with DRB1*0101 (DR1) in 43% (P = 0.001; RR, 2.2). IBD-AS was associated only with HLA-B*27 and DRB1*0101. Conclusions: These data suggest that the clinical classification into type 1 and type 2 arthropathies describes immunogenetically distinct entities and establish that in polygenic disorders, genes may determine clinical phenotype without conferring overall disease susceptibility (in this case, HLA genes). Type 1 arthropathy is clinically and immunogenetically similar to the spondyloarthropathies, but different HLA associations may define phenotypically distinct groups. Type 2 arthropathy has different HLA associations and may have a different etiology. Further studies are now required to confirm these associations and to elucidate the different pathogenetic mechanisms. GASTROENTEROLOGY 2000;118:274-278

We have investigated the role of 23 candidate genes in the control of bone mineral density (BMD) by linkage studies in families of probands with osteoporosis (lumbar spine [LS] or femoral neck [FN] BMD T score < −2.5) and low BMD relative to an age‐ and gender‐matched cohort (Z score < −2.0). One hundred and fifteen probands (35 male, 80 female) and 499 of their first‐ or second‐degree relatives (223 males and 276 females) were recruited for the study. BMD was measured at the LS and FN using dual‐energy X‐ray absorptiometry and expressed as age‐ and gender‐matched Z scores corrected for body mass index. The candidate genes studied were the androgen receptor, type I collagen A1 (COLIA1), COLIA2, COLIIA1, vitamin D receptor (VDR), colony‐stimulating factor 1, calcium‐sensing receptor, epidermal growth factor (EGF), estrogen receptor 1 (ESR1), fibrillin type 1, insulin‐like growth factor 1, interleukin‐1 alpha (IL‐1α), interleukin‐4 (IL‐4), interleukin‐6 (IL‐6), interleukin‐11 (IL‐11), osteopontin, parathyroid hormone (PTH), PTH‐related peptide, PTH receptor type 1 (PTHR1), transforming growth factor‐beta 1, and tumor necrosis factors alpha and beta. Sixty‐four microsatellites lying close to or within these genes were investigated for linkage with BMD. Using the program MapMaker/Sibs there was suggestive evidence of linkage between BMD and PTHR1 (maximum LOD score obtained [MLS] 2.7–3.5). Moderate evidence of linkage was also observed with EGF (MLS 1.8), COLIA1 (MLS 1.7), COLIIA1/VDR (MLS 1.7), ESR1 (MLS 1.4), IL‐1α (MLS 1.4), IL‐4 (MLS 1.2), and IL‐6 (MLS 1.2). Variance components analysis using the program ACT, correcting for proband‐wise ascertainment, also showed evidence of linkage (p≤ 0.05) at markers close to or within the candidate genes IL‐1α, PTHR1, IL‐6, and COLIIA1/VDR. Further studies will be required to confirm these findings, to refine the location of gene responsible for the observed linkage, and to screen the candidate genes targeted at these loci for mutations.

Primary sclerosing cholangitis (PSC) is an inflammatory disease of the biliary tree associated with an increase in the HLA alleles DR3, DR52a, DR2, Dw2, and a decrease in DR4. However, it is not certain which of these alleles provides the primary associations. Our aim was to establish the primary HLA associations with PSC and to assess the ability of HLA alleles to mark for disease progression.

The role of germline polymorphisms of the T-cell receptor A/D and B loci in susceptibility to ankylosing spondylitis was investigated by linkage studies using microsatellite markers in 215 affected sibling pairs. The presence of a significant susceptibility gene (lambda  1.6) at the TCRA/D locus was excluded (LOD score &lt; -2.0). At the TCRB locus, there was weak evidence of the presence of a susceptibility gene (P = 0.01, LOD score 1.1). Further family studies will be required to determine whether this is a true or false-positive finding. It is unlikely that either the TCRA/D or TCRB loci contain genes responsible for more than a moderate proportion of the non-MHC genetic susceptibility to ankylosing spondylitis.

BACKGROUND: Peripheral arthropathy is a well-recognised complication of inflammatory bowel disease (IBD). Little is known of its natural history, but a variety of joint involvement has been described, from large joint pauciarticular arthropathy to a rheumatoid pattern polyarthropathy. AIMS: To classify the peripheral arthropathies according to pattern of articular involvement, and study their natural history and clinical associations. METHODS: The case notes of all patients attending the Oxford IBD clinic were reviewed, and information on general disease characteristics, extraintestinal features, and arthropathy extracted. This was confirmed by direct patient interview using questionnaires at routine follow up. Patients with recorded joint swelling or effusion were classified as type 1 (pauciarticular) if less than five joints were involved and type 2 (polyarticular) if five or more were involved. Patients without evidence of swelling were classified as arthralgia. RESULTS: In total, 976 patients with ulcerative colitis (UC) and 483 with Crohn's disease (CD) were reviewed. Type 1 occurred in 3.6% of patients with UC (83% acute and self-limiting) and in 6.0% of those with CD (79% self-limiting); 83% and 76%, respectively, were associated with relapsing IBD. Type 2 occurred in 2.5% of patients with UC and 4.0% of those with CD; 87% and 89%, respectively, caused persistent symptoms whereas only 29% and 42%, respectively, were associated with relapsing IBD. CONCLUSION: Enteropathic peripheral arthropathy without axial involvement can be subdivided into a pauciarticular, large joint arthropathy, and a bilateral symmetrical polyarthropathy, each being distinguished by its articular distribution and natural history.

Susceptibility to rheumatoid arthritis (RA) may be due to the presence of shared functional epitopes common to the HLA-DR beta chains of several RA-associated haplotypes. We have obtained direct evidence for this hypothesis by using the polymerase chain reaction and sequencing the DRB1 and DQB1 genes from RA patients. A highly conserved epitope present on DR beta chains of DR4 and DR1 haplotypes was found in 83% of 149 patients with classical or definite RA but was found in only 46% of 100 control individuals (P less than 0.0001). Two Dw subtypes of DR4 (Dw4 and Dw14) were associated with disease susceptibility but two other subtypes (Dw10 and Dw13) were not. Sequence differences between these subtypes implicate those residues around the putative antigen binding site of the DR beta molecule in the pathogenesis of RA. These data provide a basis for understanding host susceptibility to RA at a molecular level.

Ankylosing spondylitis (AS) affects 0.25–1.0% of the population, and its etiology is incompletely understood. Susceptibility to this highly familial disease (λs = 58) is primarily genetically determined. There is a significant sex bias in AS, and there are differences in recurrence risk to the offspring of affected mothers and fathers, suggesting that there may be an X-linked recessive effect. We undertook an X-chromosome linkage study to determine any contribution of the X-chromosome to AS susceptibility. A linkage study of the X-chromosome using 234 affected sibling pairs was performed to investigate this hypothesis. No linkage of the X-chromosome with susceptibility to AS was found. Model-free multipoint linkage analysis strongly excluded any significant genetic contribution (λ ≥1.5) to AS susceptibility encoded on the X-chromosome (logarithm of odds [LOD] &lt;−2.0). Smaller genetic effects (λ ≥1.3) were also found to be unlikely (LOD &lt;−1.0). The sex bias in AS is not explained by X-chromosome–encoded genetic effects. The disease model best explaining the sex bias in occurrence and transmission of AS is a polygenic model with a higher susceptibility threshold in females.

Angiogenesis is an important process in the development of destructive synovial pannus in rheumatoid arthritis (RA). The ITGAV +gene encodes a cell cycle-associated antigen, integrin ανβ 3, which plays a role in RA angiogenesis. Previously, two independent studies identified an association between the major allele of the ITGAV single-nucleotide polymorphism (SNP) rs3738919 and RA. We therefore tested this association in an independent study using New Zealand (NZ) and Oxford (UK) RA case control samples.

&lt;it>Objectives&lt;/it>. To confirm the association of a functional single-nucleotide polymorphism (SNP), C1858T (rs2476601), in the &lt;it>PTPN22&lt;/it> gene of British Caucasian rheumatoid arthritis (RA) patients and to evaluate its influence on the RA phenotype. &lt;it>Methods&lt;/it>. A total of 686 RA patients and 566 healthy volunteers, all of British Caucasian origin, were genotyped for C1858T polymorphism by PCR–restriction fragment length polymorphism assay. Data were analysed using SPSS software and the χ2 test as applicable. &lt;it>Results&lt;/it>. The &lt;it>PTPN22&lt;/it> 1858T risk allele was more prevalent in the RA patients (13.9&percnt;) compared with the healthy controls (10.3&percnt;) (&lt;it>P&lt;/it>&equals;0.008, odds ratio 1.4, 95&percnt; confidence interval 1.09–1.79). The association of the T allele was restricted to those with rheumatoid factor (RF)-positive disease (&lt;it>n&lt;/it>&equals;524, 76.4&percnt;) (&lt;it>P&lt;/it>&equals;0.004, odds ratio 1.5, 95&percnt; confidence interval 1.1–1.9). We found no association between &lt;it>PTPN22&lt;/it> and the presence of the HLA-DRB1 shared epitope or clinical characteristics. &lt;it>Conclusions&lt;/it>. We confirmed the previously reported association of &lt;it>PTPN22&lt;/it> with RF-positive RA, which was independent from the HLA-DRB1 genotype.

&lt;it>Objective&lt;/it>. To identify HLA class II associations with anti &lt;it>β&lt;/it>&lt;inf>2&lt;/inf>&hyphen;glycoprotein I &lpar;&lt;it>β&lt;/it>2GPI&rpar; antibodies in a cohort of Caucasian patients with systemic lupus erythematosus &lpar;SLE&rpar; and to determine whether these &lt;it>HLA&lt;/it> genotypes act as restriction elements for lymphocyte proliferation to native human &lt;it>β&lt;/it>2GPI &lt;it>in vitro&lt;/it>. &lt;it>Methods&lt;/it>. Anti&hyphen;&lt;it>β&lt;/it>2GPI antibodies were detected in patient sera using enzyme&hyphen;linked immunosorbent assays &lpar;ELISAs&rpar;. &lt;it>HLA&lt;/it> class II alleles &lpar;&lt;it>DRB1&lt;/it>, &lt;it>DQB1&lt;/it>&rpar; were determined by polymerase chain reaction&hyphen;based DNA genotyping. &lt;it>In vitro&lt;/it> peripheral blood mononuclear cell &lpar;PBMC&rpar; responses to native human &lt;it>β&lt;/it>2GPI were measured in a 7&hyphen;day proliferation assay. &lt;it>Results&lt;/it>. We identified three groups of Caucasian SLE patients using these ELISAs. In group 1, 16 out of 18 SLE patients &lpar;89&percnt;&rpar; with anti&hyphen;&lt;it>β&lt;/it>2GPI antibodies were positive for HLA&hyphen;DRB1*0401&sol;4&sol;8, DR11 or DRB1*1302 &lpar;&lt;it>P&lt;/it>&equals;0.001 &lt;it>vs&lt;/it> controls&rpar; compared with 23 out of 53 patients &lpar;43&percnt;&rpar; in group 2 with anti&hyphen;cardiolipin antibodies only, 57 out of 151 patients &lpar;38&percnt;&rpar; in group 3 &lpar;SLE patients without anticardiolipin antibodies&rpar; and 109 out of 225 controls &lpar;48&percnt;&rpar;. Fourteen patients with anti&hyphen;&lt;it>β&lt;/it>2GPI antibodies had greater median stimulation indices to &lt;it>β&lt;/it>2GPI &lt;it>in vitro&lt;/it> compared with the 15 controls studied &lpar;&lt;it>P&lt;/it>&equals;0.04&rpar;. &lt;it>Conclusion&lt;/it>. The &lt;it>HLA&lt;/it> class II and PBMC proliferation data suggest that &lt;it>β&lt;/it>2GPI may be both a T&hyphen; and B&hyphen;cell autoantigen in SLE.