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We and others have shown that the minor, nonconserved allele Gln381 of the Arg381Gln single-nucleotide polymorphism (rs11209026G>A) of the IL-23 receptor gene (IL23R) protects against psoriasis. Moreover, we have recently shown impaired IL-23-induced IL-17A production and STAT-3 phosphorylation in Th17 cells generated in vitro from healthy individuals heterozygous for the protective A allele (GA). However, the biological effect of this variant has not been determined in homozygous carriers of the protective A allele (AA), nor in psoriatic patients. Here we expand our functional investigation of the IL23R Arg381Gln gene variant to include AA homozygous individuals. By using isolated memory CD4+ T cells, we found attenuated IL-23-induced Th17 response in heterozygous individuals. Moreover, we found that AA homozygous individuals were strikingly unresponsive to IL-23, with minimal or no IL-17A and IL-17F production and failure of human memory Th17 cell survival/expansion. Finally, IL-23-induced Th17 response was also attenuated in age- and sex-matched GA versus GG psoriatic patients undergoing systemic treatment. Taken together, our data provide evidence for an allele-dosage effect for IL-23R Gln381 and indicate that common gene alleles associated with complex diseases might have biological effects of considerable magnitude in homozygous carriers.

Original publication

DOI

10.1038/jid.2013.170

Type

Journal article

Journal

The Journal of investigative dermatology

Publication Date

10/2013

Volume

133

Pages

2381 - 2389

Addresses

St John's Institute of Dermatology, NIHR Biomedical Research Centre, King's College London, London, UK. Electronic address: pdimegl@nimr.mrc.ac.uk.

Keywords

Humans, Psoriasis, Receptors, Interleukin, Immunologic Memory, Heterozygote, Homozygote, Polymorphism, Single Nucleotide, Alleles, Adult, Aged, Middle Aged, Female, Male, Interleukin-23, Young Adult, Th17 Cells