Association between the interleukin‐1 family gene cluster and psoriatic arthritis

Abstract

Objective. The interleukin-1 (IL-1) cytokine elicits a wide variety of biologic activities that initiate and promote an inflammatory response. The loci in the IL1 gene cluster have recently been associated with ankylosing spondylitis (AS). Since there is clinical and immunologic overlap between psoriatic arthritis (PsA) and AS, we wanted to examine the association between a panel of single-nucleotide polymorphisms (SNPs) in the IL1 gene family cluster and chromosome 2q12-13 in a PsA cohort.Methods. Two hundred twelve PsA patients and 150 ethnically matched controls were genotyped with 11 SNPs in IL1A, 9 SNPs in IL1B, and 9 SNPs in IL1F5-10. Univariate analyses of the 29 single markers and short intragenic haplotypes identified several associated regions. Seventeen markers of interest were noted and further investigated to determine which markers or short haplotypes independently predict case-control status, using a stepwise logistic model.Results. Two regions contributing independently to risk of disease in PsA were noted: a region spanned by markers rs3783547, rs3783543, and rs17561 in IL1A, and a region near the end of IL1B, through IL1F7, IL1F8, and into IL1F10. The best model contained markers rs3811047, rs1562304, and rs3811058, and 1 haplotype constructed from the 3 markers in region 1, with a likelihood ratio of 25.34 (4 degrees of freedom).Conclusion. The IL1 locus appears to be a highpriority susceptibility locus in PsA, with at least 2 independent regions that confer increased risk.Psoriatic arthritis (PsA) is a heterogeneous inflammatory arthritis associated with psoriasis. Although the etiology of PsA is not fully elucidated, epidemiologic and immunogenetic studies convincingly demonstrate a strong genetic predisposition to PsA (1). Various cytokines, including tumor necrosis factor ␣ (TNF␣), interleukin-1 (IL-1), and IL-10, are postulated to play a pivotal role in the pathogenesis of PsA and have been studied with respect to genetic association (2-4). A recent meta-analysis of TNF␣ promoter polymorphisms in PsA by our group noted a significant association between the Ϫ238 variant of the TNF␣ promoter and PsA (5).The IL-1 cytokine elicits a wide variety of biologic activities that initiate and promote an inflammatory response. With respect to PsA, an increased expression of IL-1␣ and IL-1␤ has been noted in the serum, synovial fluid, and skin of PsA patients (6,7). There are 2 structurally distinct forms of IL-1 (IL-1␣ and IL-1␤), both of which are potent mediators of inflammation. Both IL-1␣ and IL-1␤ are synthesized by a variety of cell types, including activated macrophages, keratinocytes, and fibroblasts, and stimulate osteoclast activity, thus promoting bone-resorbing factors (8). The biologic activity of IL1A and IL1B is initiated by binding with IL-1 receptor type I and is inhibited by IL-1 receptor antagonist (9).The loci for the IL1 gene cluster are found on chromosome 2q12-13 and span a 360-kb region. Within this region, the following IL1-related genes are noted: IL1A, IL1B, as well as IL1F...

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

“…Furthermore, there were no obvious differences in disease severity (as assessed by the Bath AS Disease Activity Index and the Bath AS Functional Index [37,38]) between the 3 population cohorts in the present study (data not shown). A preliminary report has also implicated a locus in IL1A/B in susceptibility to psoriatic arthritis (35), while a family study has suggested familial aggregation of 2 distinct phenotypes differentiated by the presence of peripheral inflammation, psoriasis, and IBD (39). However, there was no significant difference in the prevalence of peripheral arthritis or concomitant psoriasis or IBD between the AS cohorts in our study (data not shown).…”

“…Thus, detection of a significant signal in the Toronto population is more challenging since modest genetic signals may be overlooked. This notion is further supported by the recent identification of a disease association in the Newfoundland psoriatic arthritis population that was not replicated in the Toronto psoriatic arthritis cohort (35). Thus, there appear to be population-specific differences between Toronto and the other 2 white populations.…”

IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist

“…The allele combinations that include IL-38 polymorphisms are associated with psoriatic arthritis and ankylosing spondylitis (13)(14)(15). These reports suggest that IL-38 plays a role in the pathogenesis of these inflammatory diseases.…”

Absence of a classically activated macrophage cytokine signature in peripheral spondylarthritis, including psoriatic arthritis

“…Polymorphisms in the gene encoding IL-1␣, which is mostly a cell-associated cytokine but can also be found in the extracellular space, has been reported to show a strong association with SpA (23,24). Whereas this cytokine was clearly detectable in RA SF, it was almost completely absent from SpA SF (mean Ϯ SEM 0.3 Ϯ 0.2 pg/ml in SpA versus 67.9 Ϯ 34.1 pg/ml in RA; P Ͻ 0.001).…”