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New immune system genetic polymorphisms associated with moderate‐to‐severe plaque psoriasis: a case–control study

DEAR EDITOR, Genes for factors such as interleukin-23 receptor (IL-23R), IL-12B and tumour necrosis factor (TNF)-a have been widely associated with psoriasis and related diseases [rheumatoid arthritis (RA), psoriatic arthritis (PsA) and Crohn disease (CD)]. These genes are therapeutic targets to treat psoriasis. However, results with other candidate genes are controversial. Therefore, large-scale studies are needed to verify the genetic factors that trigger psoriasis. We evaluated the possible association between 192 single-nucleotide polymorphisms (SNPs) and moderate-to-severe chronic plaque psoriasis. This approach may help us to find new targets for safer and more effective drugs. We recruited 197 healthy volunteers without a personal or family history of psoriasis, and 198 patients with moderateto-severe plaque psoriasis between 16 October 2007 and 17 December 2012, in four hospitals in Madrid, Spain. All patients were white. The protocol fulfilled Spanish law on biomedical research. DNA was obtained from peripheral blood samples (MagNA Pure System; Roche, Pleasanton, CA, U.S.A.). All samples were sent to the Human Genotyping Unit (CEGEN, Madrid, Spain), except two samples that had insufficient volume, to genotype 192 SNPs (VeraCode genotyping platform; Illumina, San Diego, CA, U.S.A.). The SNPs were preselected based on reports of psoriasis and other autoimmune diseases (RA, PsA and CD; 449 articles). We finally selected SNPs based on minor allele frequency ≥ 0 05, and on the results of studies performed in white patients with psoriasis (Table S1; see Supporting Information). We calculated the Hardy–Weinberg equilibrium (HWE; P > 0 05), and allele and genotype frequencies (snpStats R). The SNPs that did not fulfil the HWE in controls were removed from the subsequent analysis. Univariate analysis was performed using R version 3.0.2 (SNPassoc; http://www. r-project.org/). We constructed logistic regression models (codominant, dominant, recessive and additive). We then repeated these analyses in stratified populations: patients with psoriasis without and with PsA. The results were adjusted for rs12191877, which was strongly associated with the human leucocyte antigen (HLA)-C*0602 allele with high prevalence in our population. The optimal model was selected by the Akaike information criterion. We also calculated the haplotype frequencies and the association with psoriasis (snpStats). SNPs with P < 0 1 in the univariate analysis (adjusted for rs12191877) were included in a multivariate logistic regression model (SPSS 15 0; IBM, Armonk, NY, U.S.A.). Our population included 197 controls (98 men and 99 women; aged 24 5 4 3 years) and 191 patients (111 men and 80 women; aged 50 1 15 4 years). We evaluated the effect of sex on our results and did not find any significant association. CEGEN quality criteria were not met in 19 SNPs and five patients, and nine SNPs in the controls were not in HWE (Table S1). Sixty-four SNPs with P < 0 1 were included in the multivariate analysis (Table S2; see Supporting Information), and only nine SNPs maintained their associations with psoriasis (Table 1). We provide the first description of the following SNPs in psoriasis (Tables 1 and 2). 1 rs2476601 (PTPN22; AA/AG decreased the risk of psoriasis 3 80-fold). The minor allele only has been associated with CD, RA and PsA. 2 rs3783543 (IL1A; TT/CT increased the risk 1 94-fold). The haplotype analysis showed an association between psoriasis and the TGC haplotype (rs3783543, rs17561 and rs1143634, respectively) in the IL1A and IL1B genes (P = 0 0072) (Table S3; see Supporting Information). Only one study has associated PsA with a region including rs3783543. 3 rs12188300 (IL12B; TT/AT increased the risk 5 54-fold). Only one genome-wide association study (GWAS) has associated this SNP (T allele) with susceptibility to PsA. The p40 subunit of IL-12 (encoded by IL12B) is used as a target in the treatment of psoriasis (ustekinumab). Thus this cytokine is clearly involved in the immunopathogenesis of psoriasis. 4 rs10499194 (TNFAIP3; CT increased the risk 2 50-fold). In a GWAS, this SNP has been associated only with RA. 5 rs11986055 (IKBKB; AC decreased the risk 4 85-fold). rs11986055 (C allele) has been associated only with a more pronounced response to anti-TNF drugs after 6 months of treatment in RA. 6 rs3792876 (SLC22A4; TT/CT increased the risk 4 01-fold). rs3792876 has been associated more with paediatric-onset CD than with adult-onset CD. One meta-analysis showed a significant association between RA and rs3792876 in a Japanese population, although not in white patients.