Alternative titles; symbols
DO: 0080603;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p21.33 | {Spondyloarthropathy, susceptibility to, 1} | 106300 | Multifactorial | 3 | HLA-B | 142830 |
A number sign (#) is used with this entry because of evidence that susceptibility to spondyloarthropathy-1 (SPDA1) can be conferred by variation in the HLA-B27 allele (142830.0001) on chromosome 6p21.3.
Spondyloarthropathy (SpA), one of the commonest chronic rheumatic diseases, includes a spectrum of related disorders comprising the prototype ankylosing spondylitis (AS), a subset of psoriatic arthritis (PsA), reactive arthritis (ReA), arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthropathy (Miceli-Richard et al., 2004). These phenotypes are difficult to differentiate because they may occur simultaneously or sequentially in the same patient. Studies have suggested that a predominant shared component, including HLA-B27, predisposes to all phenotypic subsets, and that these subsets should be considered as various phenotypic expressions of the same disease (Said-Nahal et al., 2000, Said-Nahal et al., 2001).
Braun and Sieper (2007) provided a detailed review of ankylosing spondylitis, including clinical features, pathogenesis, and management.
Genetic Heterogeneity of Susceptibility to Spondyloarthropathy
Additional susceptibility loci for spondyloarthropathy have been identified on chromosome 9q31-q34 (SPDA2; 183840) and chromosome 2q36 (SPDA3; 613238).
Kidd et al. (1995) described a family in which 7 of 12 members had early onset oligo- or polyarthritis, enthesitis, or both, and fulfilled established criteria for spondyloarthropathy, although none had radiologic evidence of sacroiliitis. The mean age at first symptom was 22 years, with only 1 individual having the first symptom beyond the age of 30 years. All subjects were rheumatoid factor negative. Histocompatibility showed association with HLA-B7. None had psoriasis or inflammatory bowel disease.
Monnet et al. (2004) analyzed the ocular and extraocular manifestations in 175 consecutive patients with HLA-B27-associated uveitis. The male-to-female ratio was 1.3:1. The median age at first attack of uveitis was 31 years. An HLA-B27-associated extraocular disorder was seen in 136 (77.7%) patients. Ankylosing spondylitis was diagnosed in 81 (46.3%) patients and presumed in 17 (9.7%); undifferentiated spondyloarthropathy was seen in 21 (12%) patients and other HLA-B27-associated diseases in 17 (9.7%). Monnet et al. (2004) concluded that uveitis is frequently the first indication of a previously undiagnosed HLA-B27-associated extraocular disease.
Karten et al. (1962) demonstrated familial aggregation. Rheumatoid arthritis and positive tests for rheumatoid factor were found no more often in the relatives of spondylitics than in those of controls, suggesting that rheumatoid arthritis and ankylosing spondylitis are distinct entities. De Blecourt et al. (1961) found spondylitis 22.6 times more frequently in the relatives of spondylitic patients than in the relatives of controls. They suggested autosomal dominant inheritance with greater penetrance in males than in females. O'Connell (1959) arrived at the same conclusion. The familial incidence was higher when the proband was female. Kornstad and Kornstad (1960) described 2 families in which only females were affected. Emery and Lawrence (1967) presented data that they interpreted as indicating multifactorial inheritance, however. Linkage data were published by Kornstad and Kornstad (1960) and earlier by Riecker et al. (1950). Schlosstein et al. (1973) found HLA specificity w27 in 35 of 40 cases (87.5%) of ankylosing spondylitis and in only 8% of normal controls. The HLA findings brought thinking about the genetics full-circle. Autosomal dominant inheritance with reduced penetrance seemed to be established.
Calin and Elswood (1989) analyzed 42 sib pairs concordant for ankylosing spondylitis. They found that the correlation coefficient was not significant for age at onset but was much higher, reaching a level of significance at the 0.01 level, for calendar year of onset. This was interpreted as consistent with environmental factors playing a greater role in the timing of onset. Concordance with the presence or absence of uveitis was only 43%, again suggesting that genetic factors are less significant than environment. Conversely, genetic factors appeared to be more important than environment in influencing prognosis as measured by a disability and pain index and by the severity of radiologic findings.
Brown et al. (1997) found that 6 of 8 monozygotic twin pairs (75%) were concordant for ankylosing spondylitis, compared with 4 of 15 B27-positive dizygotic twin pairs (27%) and 4 of 32 dizygotic twin pairs overall (12.5%). The twins with ankylosing spondylitis had been identified in the database maintained at the Royal National Hospital for Rheumatic Diseases in Bath, England.
Gu et al. (2009) conducted a genomewide scan followed by fine mapping analysis in a 4-generation Han Chinese family with ankylosing spondylitis and obtained a maximum lod score of 4.02 at D6S273 (theta = 0.0) on chromosome 6, verifying the HLA-B locus.
Linkage Heterogeneity
To identify major loci controlling clinical manifestations of AS, Brown et al. (2003) performed genomewide linkage analysis on 188 affected sib-pair families containing 454 affected individuals. Heritabilities of the traits studied were as follows: age at symptom onset, 0.33 (p = 0.005); disease activity assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), 0.49 (p = 0.0001); and functional impairment assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI), 0.76 (p = 0.0000001). No linkage was observed between the MHC and any of the traits studied. Significant linkage (lod = 4.0) was observed between a region on chromosome 18p and the BASDAI. Age at symptom onset showed suggestive linkage to chromosome 11p (lod = 3.3). Maximum linkage with the BASFI was seen at chromosome 2q (lod = 2.9; see SPDA3, new). Brown et al. (2003) concluded that these clinical manifestations are largely determined by a small number of genes not encoded within the MHC.
In a multistage study involving 12,701 SNPs and patients with autoimmune diseases, including ankylosing spondylitis, the Wellcome Trust Case Control Consortium and the Australo-Anglo-American Spondylitis Consortium (2007) identified significant association with SNPs in the ARTS1 gene (ERAP1; 606832) (combined results, p = 1.2 x 10(-8) to 3.4 x 10(-10)) on chromosome 5q15. Association was also found with SNPs in the IL23R gene (607562) on chromosome 1p31.3: in combined analysis, the strongest association was at rs11209032 (odds ratio, 1.3; p = 7.5 x 10(-9)). The association remained strong when only individuals who self-reported as not having inflammatory bowel disease (see IBD17, 612261) were considered, and was still strongest at rs11209032 (p = 6.9 x 10(-7)).
The Australo-Anglo-American Spondyloarthritis Consortium (2010) undertook a genomewide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; p less than 10(-800)), The Australo-Anglo-American Spondyloarthritis Consortium (2010) found association with SNPs in 2 gene deserts at 2p15 (rs10865331; combined p = 1.9 x 10(-19)) and 21q22 (rs2242944; p = 8.3 x 10(-20)), as well as in the genes ANTXR2 (608041) (rs4333130; p = 9.3 x 10(-8)), and IL1R2 (147811) (rs2310173; p = 4.8 x 10(-7)). The Australo-Anglo-American Spondyloarthritis Consortium (2010) also replicated previously reported associations at IL23R (607562) (rs11209026; p = 9.1 x 10(-14)) and ERAP1 (606832) (rs27434; p = 5.3 x 10(-12)). The Australo-Anglo-American Spondyloarthritis Consortium (2010) concluded that their study identified a major role for the IL23 and IL1 cytokine pathways in ankylosing spondylitis disease susceptibility.
The Australo-Anglo-American Spondyloarthritis Consortium and Wellcome Trust Case Control Consortium 2 (2011) reported the identification of 3 variants in the RUNX3 (600210), LTBR-TNFRSF1A (600979, 191190), and IL12B (161561) regions convincingly associated with ankylosing spondylitis (p less than 5 x 10(-8) in the combined discovery and replication datasets) and a further 4 loci at PTGER4 (601586), TBKBP1 (608476), ANTXR2, and CARD9 (607212) that showed strong association across all their datasets (p less than 5 x 10(-6) overall, with support in each of the 3 datasets studied). This group also showed that polymorphisms of ERAP1 (rs30187, combined p = 1.8 x 10(-27)), which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, affect ankylosing spondylitis risk only in HLA-B27-positive individuals. The authors concluded that their findings provided strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.
Nuki (1998) summarized the hypotheses put forward to explain the association between HLA-B27 and the spondyloarthropathies, as well the evidence supporting these hypotheses.
Luthra-Guptasarma and Singh (2004) reviewed hypotheses concerning the mechanism by which HLA-B27 predisposes to ankylosing spondylitis. They proposed that beta-2-microglobulin (B2M; 109700)-free, peptide-free heavy chains support a helix-coil transition in the segment leading from the alpha-2 domain to the alpha-3 domain, facilitating rotation of backbone angles around residues 167/168, and allowing residues 169-181 (identical to a known B27 ligand) to loop around and occupy the molecule's own peptide-binding cleft. They suggested that this 'auto-display,' occurring either within or between B27 molecules, could provoke autoimmune attack.
Gran and Husby (1995) expressed the view that the HLA-B27 test is of limited usefulness and cannot be used for confirming a diagnosis of spondyloarthropathy or predicting the prognosis in patients with an established diagnosis of inflammatory rheumatic disease. The test can be used in 3 ways: first, if the likelihood of spondyloarthropathy based on symptoms and signs is greater than 50%, a B27-positive test result significantly increases the chance for correct diagnosis. A high pretest likelihood, however, required reliable diagnostic criteria. Second, in patients with back pain and stiffness, a negative B27 test result very strongly indicates that the complaints are caused by disorders other than AS. In the absence of concurrent psoriasis or inflammatory bowel disease, a negative B27 test result virtually excludes a diagnosis of AS. Third, a positive B27 test in children with established inflammatory joint disease may help the physician focus on the possible development of seronegative spondyloarthropathy.
The finding of B27 in 16 of 17 AS cases in India and in 2 of 60 controls (Sengupta et al., 1977) appeared to exclude genetic linkage as the basis of the association.
Calin et al. (1983) studied 499 available first-degree relatives of 79 HLA-B27-positive patients with ankylosing spondylitis and 69 HLA-B27-positive healthy blood donors. The rate of ankylosing spondylitis cases was estimated to be 10.6% as compared with 1.9% in B27-positive relatives of healthy persons (p less than 0.025). This suggested a genetic difference between B27-positive diseased persons and B27-positive healthy persons. It was thought that complete sequencing of HLA-B27 cDNA might help identify whether this polymorphic marker is directly related in the etiology of AS and, if so, what the mechanism of that involvement is (Szots et al., 1986).
Despite the strong association between HLA-B27 and ankylosing spondylitis, linkage of this phenotype to the major histocompatibility complex region had not been established before the study of Rubin et al. (1992, 1994) involving 15 multiplex AS families. Among affected family members, 13 of 15 females and 46 of 49 males were B27 positive, as compared with 22 of 43 unaffected females and 16 of 40 unaffected males. The linkage analysis was based on a genetic model with a frequency of the AS gene of 1.8%; the risk of AS for homozygotes was placed at 99.5% and for heterozygotes at 43% with a sporadic risk of 0.1%. Analysis showed linkage with the MHC region, with a lod score of 3.36 at no recombination. The B27 haplotype did not consistently segregate with disease in 2 families, but both families still supported linkage. In a second analysis in which the population association of HLA-B27 with AS was taken into account, the maximum lod score was 7.5 at theta = 0.05. Identity-by-descent analyses showed a significant departure from random segregation among affected avuncular (uncle/nephew-niece) and cousin pairs. The presence of HLA-B40 in HLA-B27 positive individuals increased the risk for disease more than 3-fold, confirming previous reports. Disease susceptibility modeling suggested an autosomal dominant pattern of inheritance with penetrance of approximately 20%. In this study, which involved families from Toronto and Newfoundland, B27 alleles were detected by hybridization with sequence-specific oligonucleotide probes (SSOP) after amplification of genomic DNA by PCR.
Scofield et al. (1993) used protein sequence databases to test a series of hypotheses: first, they asked whether the primary amino acid sequence of the hypervariable regions of HLA-B27 shares short sequences with the proteins of gram-negative enteric bacteria. They found that, unique among the HLA-B molecules, the hypervariable regions of HLA-B27 shared short peptide sequences with proteins from these bacteria, indicating the possibility of antigen mimicry. Second, they asked whether the enteric proteins satisfy the structural requirements for peptide binding to B27. This hypothesis also tended to be true. Scofield et al. (1993) concluded that HLA-B27 and enteric gram-negative bacteria have undergone convergent evolution. The regions of the enteric bacterial proteins that are contiguous with the short sequences shared with B27 tend to have structures that are also predicted to bind B27. The observation suggested a mechanism for autoimmunity and led to the prediction that the B27-associated diseases are mediated by a subset of T-cell receptors, B27, and the peptides bound by B27.
HLA-B27 shares sequence with proteins from enteric bacteria. Scofield et al. (1995) pointed out that the B*2705 sequence contains a nonapeptide (LRRYLENGK) predicted to bind in the binding cleft of B27. Some nonapeptides from enteric organisms that share sequence with this nonapeptide of B27 also bind B27. Thus, peptides that both mimic and bind B27 may constitute the molecular components of a mechanism for spondyloarthropathies.
Brown et al. (2000) performed a linkage study of chromosome 22 in 200 families with AS-affected sib pairs. Association of alleles of the debrisoquine hydroxylase gene (CYP2D6; 124030) was examined by both case-control and within-family means. While homozygosity for poor-metabolizer alleles was found to be associated with AS, heterozygosity for the most frequent poor-metabolizer allele (CYP2D6*4) was not associated with increased susceptibility to AS. Significant within-family association of CYP2D6*4 alleles and AS was demonstrated. Weak linkage was also demonstrated between CYP2D6 and AS. The authors hypothesized that altered metabolism of a natural toxin or antigen by the CYP2D6 gene may increase susceptibility to AS.
Spondyloarthropathy Unassociated with HLA-B27
Gaucher et al. (1989) described a French family in which 18 members in 4 generations had spondyloarthropathy, radiologically proved in 16. The disease started during the third decade of life as an asymmetric, destructive arthropathy, predominantly affecting the wrists. Six patients had sacroiliitis. Rheumatoid serologic tests were all negative. After a destructive phase, repair took the form of ossification. Superti-Furga et al. (1990) stated that HLA-B27 antigen was not found in any members of the family and the disease did not segregate with the HLA locus. Because of the evidence that familial osteoarthrosis is sometimes linked genetically (and presumably etiologically) to the type II collagen gene (COL2A1; 120140), Superti-Furga et al. (1990) tested for linkage of COL2A1 and the arthropathy in this family. Linkage analysis excluded COL2A1 as the disease-causing locus in this family. It was significant that the Finnish families in which linkage to the cartilage collagen gene was demonstrated had no clinical or other evidence of inflammation, whereas in this French family the arthritis was inflammatory in nature and often asymmetric.
Associations Pending Confirmation
For discussion of a possible association between ankylosing spondylitis and variation in the ANKDD1B gene, see 619920.
James (1991) suggested an ingenious explanation for the fact that, in conditions suspected of multifactorial inheritance, the sex ratio (proportion of males) of randomly ascertained probands is more extreme than that of their affected relatives. He used a simple model, based on multifactorial inheritance with liability varying by sex, and the following assumptions: (1) the variances of male and female liability are equal; (2) the variances of liability in male and female sibs of probands take the same value; and (3) the difference between the mean liabilities of males and females in the general population is equal to the difference between the mean liabilities of male and female sibs of cases. With a pair of diagrams, one for the male and female distributions in the general population and one for the relatives of probands, he demonstrated that the proportion of males above the threshold is less markedly different from the proportion of females in the case of relatives. The conditions with unusual sex ratio that were studied included ankylosing spondylitis, infantile pyloric stenosis (179010), otosclerosis (166800), congenital dislocation of the hip (142700), and systemic lupus erythematosus (152700).
The overall prevalence of ankylosing spondylitis is between 0.1% and 1.4%, with most of these data coming from Europe. In mid-Europe, the prevalence is about 0.3 to 0.5% for ankylosing spondylitis and 1 to 2% for the whole group of spondyloarthritides. The incidence of ankylosing spondylitis is between 0.5 and 14 per 100,000 people per year in studies from different countries (Braun and Sieper, 2007).
Mahowald et al. (1988) analyzed the features of murine progressive ankylosis, an autosomal recessive mutation first described by Sweet and Green (1981). Peripheral joints were inflamed initially, then became ankylosed in a predictable sequence from distal to proximal. Axial joint involvement produced severe spinal ankylosis. Vertebral syndesmophytes produced a 'bamboo' spine. Mahowald et al. (1988) suggested that this is a useful animal model for study of the human spondyloarthropathies.
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