Susceptibility to ankylosing spondylitis in twins the role of genes, HLA, and the environment

Brown, Matthew A.; Kennedy, L G; Macgregor, Alexander; Darke, C.; Duncan, Emma L.; Shatford, J; Taylor, Andrew; Calin, Andrei; Wordsworth, P

doi:10.1002/art.1780401015

Cited by 566 publications

(309 citation statements)

References 17 publications

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“…Of note, however, this is the first study to examine the HLA-DPB1 locus in AS susceptibility. Overall, the MHC contributed less than half the susceptibility to AS, as has been reported elsewhere (5).…”

Section: Discussionsupporting

confidence: 70%

“…The prevalence of AS in European Caucasoid populations ranges from 0.2% to 0.9% (2,3). Disease susceptibility is clearly attributable to genetic factors, because the sibling recurrence risk ratio is 82 (4), and twin-based studies estimate that disease heritability exceeds 90% (5). HLA-B27, which is encoded in the class I major histocompatibility complex (MHC) region, confers the greatest known susceptibility to AS, and up to 95% of patients of European ancestry are HLA-B27 positive (1,5).…”

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confidence: 99%

“…Disease susceptibility is clearly attributable to genetic factors, because the sibling recurrence risk ratio is 82 (4), and twin-based studies estimate that disease heritability exceeds 90% (5). HLA-B27, which is encoded in the class I major histocompatibility complex (MHC) region, confers the greatest known susceptibility to AS, and up to 95% of patients of European ancestry are HLA-B27 positive (1,5). In addition to HLA-B27, other MHC genes have also been implicated in AS, including HLA-DRB1 (6), tumor necrosis factor ␣ (TNF␣) (1), transporter-associated protein 1 (7), and low molecular weight protein 1 (8).…”

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confidence: 99%

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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: Discussionsupporting

confidence: 70%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Genetic studies in familial ankylosing spondylitis susceptibility

Zhang¹,

Luo²,

Brückel³

et al. 2004

Arthritis & Rheumatism

104

View full text Add to dashboard Cite

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“…contribution from non-HLA genes (1,2). The component of the increased risk in siblings that is attributable to non-HLA loci ( non-HLA ) has been estimated to be 14, which is approximately equivalent to the entire genetic component of insulin-dependent diabetes mellitus ( S ϭ 15) and greater than that of rheumatoid arthritis ( S ϭ 6).…”

mentioning

confidence: 99%

High‐throughput single‐nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondylitis by matrix‐assisted laser desorption ionization‐time‐of‐flight mass spectrometry

Maksymowych¹,

Reeve²,

Reveille³

et al. 2003

Arthritis & Rheumatism

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Objective. To examine single-nucleotide polymorphisms (SNPs) in the 3 region of the IL1RN gene in a large Caucasoid case-control series and in ankylosing spondylitis (AS) families from Western Canada by use of high-throughput MassArray matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry SNP typing.Methods. An association analysis was performed in a case-control cohort of 394 AS cases and 500 controls. Family-based association analysis was performed in 58 simplex and 13 multiplex families. Three SNPs located in the 3 region of the IL1RN gene (T/C at position 27810 in exon 4, T/C at position 30735 in exon 6, and G/C at position 31017 in exon 6) were examined by high-throughput MassArray MALDI-TOF mass spectrometry. Haplotype inference software programs were used to infer the most likely haplotypes and to compare haplotype frequencies, which were then further analyzed in family-based association studies by transmission disequilibrium tests.Results. The frequency of allele C at SNP position 30735 in exon 6 was significantly increased in AS cases (35.1%) versus controls (27.8%), as was the phenotype frequency (61.7% versus 48.6%). A significantly increased frequency of SNP allele G at position 31017 in exon 6 in cases (32.9%) versus controls (28.3%) was also noted. A highly significant difference in the overall distribution of haplotype frequencies was evident between cases and controls, with significant increases in the frequencies of the 27810C/30735C/31017C and 27810C/30735T/31017G haplotypes, but a significant reduction in the estimated frequency of the 27810C/ 30735T/31017C haplotype, in the AS cases. Estimation of haplotype frequencies based on 2 SNP markers indicated a highly significant increase in the 30735C/ 31017C haplotype and a highly significant decrease in the 30735T/31017C haplotype in cases compared with controls. Preliminary evidence for reduced transmission of the 27810C/30735T/31017C 3-marker haplotype was also found in family-based association analyses. Conclusion. Our data establish a highly significant disease association with markers in the IL1RN gene. In the absence of nonsynonymous coding sequence substitutions, it is possible that the primary diseaseassociated locus regulates gene expression. Association with specific haplotypes raises the possibility that the primary disease locus is in linkage disequilibrium with a specific combination(s) of markers in the IL1RN gene.Genetic modeling studies in twins have suggested that 97% of the population variance for developing ankylosing spondylitis (AS) can be explained by additive genetic effects, while comparison of disease concordance in identical twins (75%) versus HLA-B27-concordant dizygotic twins (27%) points to an important Dr. Maksymowych is a Senior Scholar with the Alberta

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“…1 The endoplasmic reticulum aminopeptidase 1 (ERAP1) gene is strongly associated with AS; only the class I major histocompatibility complex allele, HLA-B27 (human leukocyte antigen B27) shows stronger association. 2 ERAP1 (formerly known as ARTS-1) is an aminopeptidase with a ubiquitous tissue distribution, which is expressed in the endoplasmic reticulum (ER).…”

Section: Introductionmentioning

confidence: 99%

Disease-associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis

et al. 2014

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Susceptibility to ankylosing spondylitis in twins the role of genes, HLA, and the environment

Abstract: Susceptibility to AS is largely genetically determined, and the environmental trigger for the disease is probably ubiquitous. HLA-B27 accounts for a minority of the overall genetic susceptibility to AS.

Cited by 566 publications

References 17 publications

Genetic studies in familial ankylosing spondylitis susceptibility

Genetic studies in familial ankylosing spondylitis susceptibility

High‐throughput single‐nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondylitis by matrix‐assisted laser desorption ionization‐time‐of‐flight mass spectrometry

Disease-associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis

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