A common haplotype of the IL-31 gene influencing gene expression is associated with nonatopic eczema

Background IL-31 is a novel cytokine that, when overexpressed in transgenic mice, induces severe itching dermatitis resembling human eczema. Objective We aimed to evaluate the importance of polymorphisms in the human IL-31 gene ( IL31 ) in the genetic susceptibility to eczema. Methods We sequenced the entire IL-31 gene, including the promoter region, and determined the haplotypestructure. Single nucleotide polymorphisms tagging the main haplotypeswere genotyped in 3 independent European populations comprising 690 affected families. An association analysis of IL31 gene variants with atopic and nonatopic eczema was performed. Results We found significant association of a common IL31 haplotypewith the nonatopic type of eczema in all 3 study populations (combined P = 4.5 × 10 −5 ). Analysis of PBMCs in healthy individuals revealed a strong induction IL31 mRNA expression on stimulation with anti-CD3 and anti- CD28that was 3.8-fold higher in individuals homozygous for the risk haplotype(AA) in contrast to non-A haplotypecarriers, suggesting that altered regulation of IL-31 gene expression is the disease-causing factor. Conclusion Our results lend strong support to an important role of IL-31 in the pathogenesis of nonatopic eczema. Clinical implications This study presents the first genetic risk factor for the nonatopic type of eczema and indicates a primary role of IL-31–induced pruritus in the initiation of this disease, thus proposing a new target for the prevention and therapy of eczema.