Genome-wide association scan yields new insights into the immunopathogenesis of psoriasis

Abstract

Psoriasis is a common, immunologically mediated, inflammatory and hyperproliferative disease of the skin and joints, with a multifactorial genetic basis. We earlier mapped PSORS1, the major psoriasis susceptibility gene in the major histocompatibility complex (MHC), to within or very near HLA-Cw6. In an effort to identify non-MHC psoriasis genes, we carried out a collaborative genome-wide association study. After the initial follow-up genotyping of 21 single nucleotide polymorphisms from 18 loci, showing strong evidence of association in the initial scan, we confirmed evidence of association at seven loci. Three of these loci confirm earlier reports of association (HLA-C, IL12B, IL23R) and four identify novel signals located near plausible candidate genes (IL23A, IL4/IL13, TNFAIP3 and TNIP1). In other work, we have also shown that interferon-gamma (IFN-gamma) treatment induces interleukin (IL)-23 mRNA and protein in antigen-presenting cells (APC), leading to the proliferation of CD4+ and CD8+ memory T cells expressing IL-17. Although functional variants remain to be identified, we speculate that genetic variants at the IL4/IL13 locus contribute to the Th1 bias that is characteristic of psoriasis, that Th1-derived IFN-gamma supports expansion of IL-17+ T cells through APC-derived IL-23 and that negative regulation of inflammatory signaling through the NF-kappaB axis is impaired because of genetic variants of TNFAIP3 and TNIP1.

Figure 1

Interplay between IFN-γ producing Th1 cells and IL-17-producing T-cells in psoriatic lesions. Interferon-γ produced by Th1 cells stimulates myeloid APCs and/or macrophages to produce IL-23, which together with IL-1, stimulates the survival and expansion of T-cells expressing IL-17 and/or IL-22. The entry of CD8+ T-cells expressing these cytokines into the epidermis is associated with increased epidermal hyperplasia and the production of innate immune peptides such as human β—defensin 2 (HBD-2). From , with permission.

Figure 2

CASP GWAS results plotted against chromosomal position; the inset presents quantile-quantile plots. Loci that were followed up and showed convincing evidence of association in the replication study are labeled in green. In the inset, red represents all the SNPs; blue symbols represent results after excluding SNPs at replicated loci and the gray area corresponds to the 90% confidence region for a null distribution of p-values. All panels are truncated at -log₁₀(p-value) = 20, markers near HLA-C exceed this threshold. Adapted from , with permission.

Figure 3

Multi-stage model integrating genetics and immunology of psoriasis. See text for details.