The Interleukin 1 Gene Cluster Contains a Major Susceptibility Locus for Ankylosing Spondylitis

Timms, Andrew E.; Crane, Alison M.; Sims, A. M.; Cordell, Heather J.; Bradbury, L.; Abbott, Aaron; Coyne, M.; Beynon, O.; Herzberg, I.; Duff, Gordon W.; Calin, Andrei; Cardon, Lon R.; Wordsworth, B P; Brown, Matthew A.

doi:10.1086/424695

Cited by 124 publications

(88 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It is highly associated with HLA-B27, but analyses of recurrence risk among family members suggest that at least 3 other genetic loci in addition to HLA-B27 are required to confer full susceptibility to AS (2). Despite several large genome-wide linkage studies of AS families (3)(4)(5)(6), the IL1 locus is the only significant non-major histocompatibility complex (non-MHC) susceptibility locus that has thus far emerged (7,8). However, 2 family-based association studies, 1 of which examined 244 affected sibpairs, showed no evidence of linkage to genes in the IL1 cluster (9,10).…”

Section: Conclusion Our Results Indicate That the Tnap Haplotype Rs3mentioning

confidence: 99%

Association of a TNAP haplotype with ankylosing spondylitis

Tsui¹,

Inman²,

Reveille³

et al. 2007

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. To use a candidate gene approach to the identification of genetic markers that are significantly associated with ankylosing spondylitis (AS).Methods. We genotyped 201 multiplex AS families with 1 exonic and 5 intronic single-nucleotide polymorphisms (SNPs) in TNAP, the gene that encodes tissuenonspecific alkaline phosphatase, and performed family-based association analyses.Results. In our cohort of 201 multiplex AS families, the TNAP haplotype rs3767155 (G)/rs3738099 (G)/ rs1780329 (T) was significantly associated with AS (P ‫؍‬ 0.032 by additive model). Haplotype-Based Association Testing (HBAT) analyses of AS families in which both men and women were affected showed that the same TNAP haplotype was significantly associated with AS (P ‫؍‬ 0.002 by additive model). Using setafftrait code 1 0 0 in the HBAT program, testing specifically for affected men in AS families containing affected individuals of both sexes, this TNAP haplotype was also significantly associated with AS (P ‫؍‬ 0.001 by additive model). The HBAT -p option (haplotype permutation test) was used to compute the "exact" P value via a Monte Carlo method for each haplotype (haplotype permutation test) and for the minimum observed P value among the haplotypes (whole marker permutation using the minimal P test), and both P values were statistically significant (2-sided P value for haplotype rs3767155[G]/rs3738099 [G]/rs1780329 [T] ‫؍‬ 0.00059, the smallest observed P value among all the individual haplotype scores ‫؍‬ 0.003). Interestingly, this haplotype was not associated with AS in affected women from the same families.Conclusion. Our results indicate that the TNAP haplotype rs3767155 (G)/rs3738099 (G)/rs1780329 (T) is a novel genetic marker in men that is significantly associated with AS in multiplex families containing affected individuals of both sexes.

show abstract

Section: Conclusion Our Results Indicate That the Tnap Haplotype Rs3mentioning

confidence: 99%

Association of a TNAP haplotype with ankylosing spondylitis

Tsui¹,

Inman²,

Reveille³

et al. 2007

Arthritis & Rheumatism

View full text Add to dashboard Cite

show abstract

“…The IL1 molecule has extensive biological effects, among which is its ability to partly or entirely activate and enhance the function of mononuclear cells, neutrophils and phagocytes and promote them to release inflammatory mediators; it also mediates immune response and inflammation reactions. A genomewide scan has identified that a region including IL1 family gene cluster is linked to ankylosing spondylitis (AS) susceptibility (Miceli-Richard et al 2004, Timms et al 2004. This linkage finding was later confirmed by one family-based association study in western Canadian family population (Zhang et al 2004).…”

Section: Introductionmentioning

confidence: 91%

Polymorphism of IL37 gene as a protective factor for autoimmune thyroid disease

Ni¹,

Meng²,

Song³

et al. 2015

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Autoimmune thyroid disease (AITD) comprises Graves' disease (GD) and Hashimoto's thyroiditis (HT). IL37 has been recently proved to be a natural suppressor for innate immunity and acquired immunity. Therefore, this study was conducted to identify the association of IL37 genetic polymorphisms with AITD in Chinese Han population. Polymorphisms of rs3811046/rs3811047/rs2723176/rs272186 in the IL37 gene were assessed in a case-control study comprising 701 GD patients, 301 HT patients and 939 controls. Genetic variants were genotyped by multiplex polymerase chain reaction and ligase detection reaction. The frequencies of the minor allele A of rs2723176 and A of rs2723186 were significantly lower in the GD patients than in the controls (PZ0.014, ORZ0.774; PZ0.014, ORZ0.777). After gender stratification, the rs3811046 G allele and the rs3811047/rs2723186 A allele were both significantly associated with a decreased risk of GD in female patients (PZ0.030, ORZ0.777; PZ0.023, ORZ0.774; PZ0.029, ORZ0.761). However, none of the four single nucleotide polymorphisms of IL37 gene showed any significant association with HT. Moreover, haplotype analysis revealed the GCG haplotype conferred increased risk for GD as a whole and in female GD patients (ORZ1.213; ORZ1.320). The ACG haplotype was associated with an increased risk of HT as a whole (ORZ1.567) and in male GD patients (ORZ1.820). In contrast, the AAA haplotype showed a protective role for GD as a whole (ORZ0.760) and in female GD patients (ORZ0.765). Our study strongly supports that the IL37 gene variants are associated with the susceptibility to AITD.

show abstract

“…The interleukin-1 (IL-1) cluster on chromosome 2q has emerged as a robust non-MHC susceptibility locus for AS in multiple AS populations (3,4). Genome-wide scans have demonstrated several areas of suggestive or significant linkage in non-MHC regions, including 1p, 1q, 2p, 2q, 3p, 5q, 6q, 9q, 10q, 11p, 11q, 16q, 17p, 17q, and 19q (1,5).…”

mentioning

confidence: 99%

Association of interleukin‐23 receptor variants with ankylosing spondylitis

Rahman¹,

Inman²,

Gladman³

et al. 2008

Arthritis & Rheumatism

161

View full text Add to dashboard Cite

Objective. Recent studies have shown that a nonsynonymous single-nucleotide polymorphism (SNP) (Arg381Gln; rs11209026) in the interleukin-23 receptor (IL-23R) gene on chromosome 1p31 is associated with Crohn's disease and psoriasis. Given the clinical and immunologic overlap between ankylosing spondylitis (AS) and these diseases, and the potential function of this candidate SNP, this study was undertaken to examine the association of IL-23R variants with AS in multiple Canadian populations.Methods. We examined 3 cohorts of AS patients from established rheumatic disease centers in Canada. The majority of AS patients were Caucasians of northern European descent, and all patients satisfied the modified New York classification criteria for AS or for juvenile spondylarthritis. We examined 424 AS probands and 401 controls from Alberta, 251 AS probands and 122 controls from Toronto, and 121 AS probands and 219 controls from Newfoundland. Ten IL-23R SNPs were genotyped, 9 of which were incorporated in the haplotype analysis. Allele and haplotype associations were calculated using the WHAP software package. P values for haplotype associations were calculated using a permutation test.Results. The primary SNP of interest in a previous study of inflammatory bowel disease (IBD) (Arg381Gln; rs11209026) was found to be protective against AS in the Newfoundland population (P ‫؍‬ 0.04) and in the Toronto population (P ‫؍‬ 0.04) in singlemarker univariate analysis. The strongest association, however, was with SNP rs11465804 (P ‫؍‬ 0.007 for the Newfoundland population and P ‫؍‬ 0.0007 for the Toronto population). A 3-marker sliding window omnibus test revealed a significant association with markers rs10489629, rs2201841, and rs11465804 in both the Newfoundland population (P ‫؍‬ 0.04) and the Alberta population (P ‫؍‬ 0.034). Our results were independent of the IBD and psoriasis status of the AS patients.Conclusion. This concurrent analysis of 3 distinct AS populations and their regional controls demonstrates a disease association with the IL-23R locus and implicates the same polymorphisms associated with IBD and psoriasis.Spondylarthritis (SpA) is a group of inflammatory conditions of which the main clinical feature is inflammation of the spine. Ankylosing spondylitis (AS) is regarded as the prototypic SpA and is a complex multifactorial disease resulting from gene-environment interaction. Genetic factors have a substantive role in AS susceptibility and expression (1). AS is highly heritable, as evidenced by the results of population-based epidemiologic studies. The sibling recurrence risk ( s ) in AS is Ͼ80, and heritability of Ն90% for AS has been estimated from twin studies (for review, see ref. 1). HLA-B27 is the major gene associated with AS and is present in Ͼ95% of Caucasians of northern European ancestry. Despite the prominence of HLA-B27 in genetic susceptibility to AS, its contribution to overall genetic predisposition is only ϳ16-40% (1). Furthermore, since the genetic contribution of the entire major histocompatibilit...

show abstract

The Interleukin 1 Gene Cluster Contains a Major Susceptibility Locus for Ankylosing Spondylitis

Cited by 124 publications

References 28 publications

Association of a TNAP haplotype with ankylosing spondylitis

Association of a TNAP haplotype with ankylosing spondylitis

Polymorphism of IL37 gene as a protective factor for autoimmune thyroid disease

Association of interleukin‐23 receptor variants with ankylosing spondylitis

Contact Info

Product

Resources

About