Prospective meta-analysis of interleukin 1 gene complex polymorphisms confirms associations with ankylosing spondylitis

Objectives: The aim of the current study is to determine the contribution of IL-1 gene cluster polymorphisms previously implicated in susceptibility to ankylosing spondylitis (AS), to AS susceptibility in different populations worldwide. Methods: Nine polymorphisms in the IL-1 gene cluster members IL1A (rs2856836, rs17561, and rs1894399), IL1B (rs16944), IL1F10 (rs3811058) and IL1RN (rs419598, the IL-1RA VNTR, rs315952 and rs315951) were genotyped in 2675 AS cases and 2592 healthy controls recruited in 12 different centres in 10 countries. Association of variants with AS was tested by Mantel-Haenszel random effects analysis. Results: Strong association was observed with three SNPs in the IL1A gene (rs2856836, rs17561, rs1894399, P=0.0036, 0.000019, 0.0003 respectively). There was no evidence of significant heterogeneity of effects between centres, and no evidence of non-combinability of findings. The population attributable risk fraction of these variants in Caucasians is estimated at 4-6%. Conclusions: This study confirms that IL1A is associated with susceptibility to AS. Association of the other IL-1 gene complex members could not be excluded in specific populations. Prospective meta-analysis is a useful tool in confirmation studies of genes associated with complex genetic disorders such as AS, providing sufficiently large sample sizes to produce robust findings often not achieved in smaller individual cohorts.