title: Genetic analysis of the interleukin-1 receptor antagonist and its homologue IL-1L1 in alopecia areata: strong severity association and possible gene interaction.
abstract: Alopecia areata is an inflammatory hair loss disease with a major genetic component. The presence of focal inflammatory lesions with perifollicular T-cell infiltrates reflects the importance of local cytokine production in the pathogenesis. In addition to its fundamental pro-inflammatory role, the interleukin-1 (IL-1) system has major effects on hair growth regulation in vitro, with the inhibitory actions of IL-1alpha and IL-1beta being opposed by the receptor antagonist IL-1ra. The novel interleukin-1 like molecule 1 (IL-1L1) which has greatest gene sequence homology with IL1RN, the gene encoding IL-1ra, is another potential IL-1 antagonist. In view of previous studies suggesting a significant role for IL1RN polymorphisms in the pathogenesis of autoimmune/inflammatory disease, we have analysed polymorphisms of IL-1ra (IL1RN+2018) and its homologue IL-1L1 (IL1L1+4734) in a case-control association study on 165 patients and a large number of matched controls. Homozygosity for the rare allele of IL1RN (IL1RN*2) was significantly associated with alopecia areata [odds ratio (OR) = 1.89, 95% CI (1.09, 3.28); P = 0.02], confirming our previous findings of significant association with the IL1RN variable number tandem repeat (VNTR). The results also revealed a novel association involving a polymorphism of the interleukin-1 receptor antagonist homologue IL1L1 at position + 4734, IL1RN+2018, and alopecia areata. The effect of a genotype combining three copies of the rare alleles at the IL1RN and IL1L1 loci conferred a more than additive increase in the risk of disease compared to IL1RN+2018 or IL1L1+4734 alone [OR 3.37 (1.60, 7.06); P = 0.002], suggesting possible synergy between the IL1RN and IL1L1 genes. This effect was stronger in patients with severe disease (alopecia totalis/universalis) [OR 4.62 (1.87, 11.40), P = 0.0022], and in those with early age at onset (< 20 years) [OR = 6.38 (2.64, 15.42), P = 0.0002]. Our results suggest that these polymorphisms within IL1RN and IL1L1 themselves or a gene in linkage disequilibrium with IL1RN and IL1L1 predispose to the more severe forms of alopecia areata.
authors.affiliation: Division of Genomic Medicine, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JF, UK. r.taziahnini@sheffield.ac.uk
authors.forename: R
authors.initials: R
authors.lastname: Tazi-Ahnini
authors.forename: A
authors.initials: A
authors.lastname: Cox
authors.forename: A J G
authors.initials: AJ
authors.lastname: McDonagh
authors.forename: M J H
authors.initials: MJ
authors.lastname: Nicklin
authors.forename: F S
authors.initials: FS
authors.lastname: di Giovine
authors.forename: J M
authors.initials: JM
authors.lastname: Timms
authors.forename: A G
authors.initials: AG
authors.lastname: Messenger
authors.forename: P
authors.initials: P
authors.lastname: Dimitropoulou
authors.forename: G W
authors.initials: GW
authors.lastname: Duff
authors.forename: M J
authors.initials: MJ
authors.lastname: Cork
mesh_terms: D000328:Adult; D000506:Alopecia Areata / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007378:Interleukins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017422:Sequence Analysis, DNA; D017385:Sequence Homology; D012795:Sialoglycoproteins / Q000235:genetics*
chemical_list: C507763:IL1RN protein, human; C122187:IL36RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007378:Interleukins; D012795:Sialoglycoproteins