Association of the IL1 gene cluster with susceptibility to ankylosing spondylitis: An analysis of three Canadian populations

Abstract

Objective. To examine the association between the IL1 gene cluster and susceptibility to ankylosing spondylitis (AS) in 3 independent case-control cohorts.Methods. We analyzed 394 patients and 446 controls from Alberta, Newfoundland, and Toronto, Canada. Samples were genotyped using a panel of 38 single-nucleotide polymorphism (SNP) markers within the IL1 gene cluster. Data from 20 informative and nonredundant SNP markers were analyzed using several association test strategies. First, we used the program WHAP to identify single-marker associations. Second, we used WHAP to analyze "sliding windows" of 3 contiguous markers along the entire extent of the IL1 gene cluster in order to identify haplotypic associations. Third, we used the linkage disequilibrium mapping program DMLE to estimate the posterior probability distribution of a disease locus.Results. A total of 14 SNP markers showed significant single-locus disease associations, the most significant being rs3783526 (IL1A) (P ‫؍‬ 0.0009 in the Alberta cohort, P ‫؍‬ 0.04 in the Newfoundland cohort) and rs1143627 (IL1B) (P ‫؍‬ 0.0005 in the Alberta cohort, P ‫؍‬ 0.02 in the Newfoundland cohort). Analysis of 3-marker sliding windows revealed significant and consistent associations with all of the haplotypes in the IL1A and IL1B loci in the Alberta cohort and with IL1B in the Newfoundland cohort, especially haplotypes rs1143634/rs1143630/rs3917356 and rs1143630/ rs3917356/rs3917354 (P ‫؍‬ 0.006-0.0001). With DMLE, a strong peak in the probability distribution was estimated near IL1A in both the Alberta and the Newfoundland populations.Conclusion. These results indicate that the IL1 locus, or a locus close to IL1, is associated with susceptibility to AS.

Association of a TNAP haplotype with ankylosing spondylitis

“…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).…”

Genetics in Ankylosing Spondylitis – Beyond HLA-B*27

“…A significant difference of the distribution of haplotypes was found between the AS affected and healthy individuals. On the contrary, in earlier studies no association between AS and IL1-F3 gene was found Jin, et al, 2004;Kim, et al, 2005;Maksymowych, W. P., et al, 2006;Timms, A. E., et al, 2004). These findings were also observed in the genome scan carried out by North American Spondylitis Consortium (NASC) (Jin, et al, 2004).…”

“…In nine IL-1 genes, were identified SNPs showing significant association with AS (Timms, A. E., et al, 2004). Maksymowych et al identified 14 SNPs with high association in at least one cohort (Maksymowych, W. P., et al, 2006). The most significant cohorts were in IL1-F1 and IL1-F2.…”

Association between IL-1RN gene polymorphisms and susceptibility to ankylosing spondylitis: a large Human Genome Epidemiology review and meta-analysis

“…According to the inclusion criteria, 13 studies (McGarry et al, 2001;van der Paardt et al, 2002;Maksymowych et al, 2003;Timms et al, 2004;Kim et al, 2005;Chou et al, 2006;Lin et al, 2006;Maksymowych et al, 2006;Yang et al, 2007;Agrawal et al, 2008;Liu et al, 2008;Sims et al, 2008;Guo et al, 2010) were included and 53 were excluded. A flow chart of the study selection process is shown in Figure 1.…”