The effect of HLA-DR genes on susceptibility to and severity of ankylosing spondylitis

Brown, Matthew A.; Kennedy, L G; Darke, C.; Gibson, Karen J.; Pile, K; Shatford, J; Taylor, Andrew; Calin, Andrei; Wordsworth, B P

doi:10.1002/1529-0131(199803)41:3<460::aid-art12>3.0.co;2-x

Cited by 87 publications

(37 citation statements)

References 27 publications

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“…This might lead some to postulate that HLA-DRB1 forms a separate locus for AS predisposition. Other studies have suggested this (6). However, the tight linkage disequilibrium known to exist between MHC genes makes it impossible to assign a definite and dominant role for any 1 MHC locus in this study.…”

Section: Discussionmentioning

confidence: 64%

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Genetic studies in familial ankylosing spondylitis susceptibility

Zhang¹,

Luo²,

Brückel³

et al. 2004

Arthritis & Rheumatism

104

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Objective. To define the genetic basis of susceptibility to ankylosing spondylitis (AS), especially nonmajor histocompatibility complex (MHC) genes.Methods. The study group comprised 244 affected sibling pairs from 180 pedigrees of primarily European ancestry. Sibling pairs were concordant for AS by the modified New York criteria and had available sacroiliac radiographs. The subjects were genotyped for 400 markers in ABI PRISM linkage map MD-10 and for 17 additional markers on chromosomes 6p, 6q, and 11q (including HLA-B, DRB1, DQA1, DQB1, and DPB1 alleles). Two-point and multipoint nonparametric linkage (NPL) analyses were conducted using the NPL statistic and 1-parameter allele-sharing model logarithm of odds (LOD) scores, calculated using the AlleleSharing Model (ASM) computer program.Results. Linkage of the MHC region was supported by both 2-point and multipoint analyses, with the strongest peak (45.90 cM) in the MHC at the HLA-DRB1 locus (NPL score 8.720, ASM LOD score 20.49; P ‫؍‬ 6.8 ؋ 10 ؊20 for 2-point analysis). A second region was found to have positive linkage at the q arm of chromosome 6 (D6S441) in 2-point analysis; this was supported by a 39.13-cM region (135.58-174.71 cM) in multipoint analysis, with the smallest P value (4.2 ؋ 10 ؊3 ) at 166.39 cM. A third region was found on chromosome 11q, with the strongest evidence for linkage for D11S4094 at 123 cM (NPL score 2.235, ASM LOD score 1.939) and, on transmission disequilibrium test analysis, D11S4090 at 105.74 cM (P ‫؍‬ 6.2 ؋ 10 ؊5 ). Linkage in this area was supported by multipoint analysis, spanning 22.19 cM continuously from 101.68 cM to 123.87 cM, with the strongest peak at 112.33 cM (P ‫؍‬ 0.014); this was confirmed by subsequent fine mapping studies.Conclusion. Thus, this genome-wide scan implicates, in addition to the MHC, regions outside the MHC in AS susceptibility, especially on chromosomes 6q and 11q.Ankylosing spondylitis (AS) is a common chronic inflammatory disorder primarily affecting the spine, although the peripheral joints and the attachments of ligaments and tendons to joints (the entheses) are also frequently involved, as well as the eyes, and, less com-

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Section: Discussionmentioning

confidence: 64%

“…Although the MHC is likely the primary mediator of genetic susceptibility to AS, it explains Ͻ50% of the total genetic risk for AS (6,7). Genome-wide linkage scans have implicated numerous non-MHC genomic regions, including 1p, 2p, 2q, 3p, 9q, 10q, 11p, 19q, and 16q (9,10).…”

mentioning

confidence: 99%

Genetic studies in familial ankylosing spondylitis susceptibility

Zhang¹,

Luo²,

Brückel³

et al. 2004

Arthritis & Rheumatism

104

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“…Finally, the specificity of the staining also could not be completely explained by the presence of the SE in RA. Indeed, half of the control patients who were tested for HLA-DR turned out to be SE positive, especially in the group with SpA (24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

Detection of major histocompatibility complex/human cartilage gp‐39 complexes in rheumatoid arthritis synovitis as a specific and independent histologic marker

Baeten¹,

Steenbakkers²,

Rijnders³

et al. 2004

Arthritis & Rheumatism

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Clinically, there were no correlations between mAb 12A staining and clinical or biologic parameters in RA. However, positive staining was observed in 61.5% of the inflamed RA synovial samples compared with only 3.0% of the control samples (P < 0.001). This mAb 12A staining was not related to intracellular citrullinated peptides, which are another specific histologic marker for RA.Conclusion. Presentation by synovial dendritic cells of the immunodominant epitope of HC gp-39, in the context of the shared epitope, is associated with characteristic histologic features of follicular synovitis and is highly specific for RA. This suggests a contribution to the autoimmune-related tissue inflammation and provides a new and independent tool for the immunopathologic diagnosis of RA.

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“…66 HLA-B60 shows association with both B27-positive and negative AS, and this association has been replicated in a Chinese population. 67 The MHC class II gene HLA-DRB1 has been found to be associated with AS in B27 matched case control studies 68 and twin studies. 12 A study of non-B27 MHC associations of AS using B27-matched haplotypes in cases and controls has shown that HLA-DRB1 is associated with AS irrespective of whether the haplotype contained HLA-B27.…”

Section: Other Mhc Genesmentioning

confidence: 99%

The genomics and genetics of ankylosing spondylitis

Kenna¹,

Davidson²,

Thomas³

2011

AGG

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Abstract:The spondyloarthropathies are a group of arthritides which specifically target the spine and pelvis with ankylosing spondylitis (AS) being the most prevalent and debilitating of these conditions. Unique to AS is the progression to excessive uncontrolled bone formation following an initial inflammatory phase that can result in joint fusion and significant disability. Spondyloarthritis is estimated to affect 1%-2% of the population, twice as many as rheumatoid arthritis and thus constitutes a significant health problem. Currently AS pathogenesis is very poorly understood but recent large-scale genetics and gene expression profiling studies have identified some of the underlying mechanisms and pathways contributing to the disease. Genome-wide association studies have identified a number of candidate genes associated with AS sharing the same pathways which are now being targeted for therapeutic intervention. However, although such approaches can identify genes contributing to the disease process and are very informative as to disease aetiopathogenesis, they cannot profile the actual changes in gene/cell activity at any point in the disease process or possibly more importantly at specific sites. Such information is generated using expression profiling. A number of expression profiling studies have been undertaken in AS, looking at both circulating cells and tissues from affected joints. Although some common genes/pathways have been identified, overall the results to date have been somewhat disappointing due to differences in experimental design and tissue source as well as the low power of the studies. More recent better powered studies have shown some potential in developing gene expression profiling as a diagnostic tool in AS. True future success will rely on larger genetic and genomic studies and the combination of these datasets in eQTL studies requiring significant collaborative efforts. Such larger-scale approaches will also generate sufficient power to target specific disease stages and sites.

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The effect of HLA-DR genes on susceptibility to and severity of ankylosing spondylitis

Cited by 87 publications

References 27 publications

Genetic studies in familial ankylosing spondylitis susceptibility

Genetic studies in familial ankylosing spondylitis susceptibility

Detection of major histocompatibility complex/human cartilage gp‐39 complexes in rheumatoid arthritis synovitis as a specific and independent histologic marker

The genomics and genetics of ankylosing spondylitis

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