Psoriasis is a common immune mediated disorder that affects the skin, nails, and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 European ancestry psoriasis cases and 1,436 controls. Twenty-one promising SNPs were followed-up in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with p < 5×10−8 overall). Loci with confirmed association encode HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R, IL12B), two genes that act downstream of TNF-α and regulate NF-κB signaling (TNIP1, TNFAIP3), and two genes involved in the modulation of Th2 immune responses (IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.

Background-Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin

Summary To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of three genome-wide association studies (GWAS) and two independent datasets genotyped on the Immunochip, involving 10,588 cases and 22,806 controls in total. We identified 15 new disease susceptibility regions, increasing the number of psoriasis-associated loci to 36 for Caucasians. Conditional analyses identified five independent signals within previously known loci. The newly identified shared disease regions encompassed a number of genes whose products regulate T-cell function (e.g. RUNX3, TAGAP and STAT3). The new psoriasis-specific regions were notable for candidate genes whose products are involved in innate host defense, encoding proteins with roles in interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C), and NF-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBRTNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10−8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10−6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27–positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

McInnes, I. B. et al. (2015) Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 386(9999), pp. 1137Lancet, 386(9999), pp. -1146 This is the accepted version.

A randomized, double-blind, placebo-controlled, multicenter study of secukinumab to demonstrate the efficacy at 24 weeks and to assess the long term safety, tolerability and efficacy up to 2 years in patients with active psoriatic arthritis List of tables List of figures Glossary of termsAssessment A procedure used to generate data required by the study Control drug A study drug used as a comparator to reduce assessment bias, preserve blinding of investigational drug, assess internal study validity, and/or evaluate comparative effects of the investigational drug Enrollment Point/time of patient entry into the study; the point at which informed consent must be obtained (i.e. prior to starting any of the procedures described in the protocol)Inadequate response to TNFα Active disease despite stable treatment with anti-TNFa for at least 3 months at a stable dose or for at least one dose in the case of lack of tolerance Investigational drugThe study drug whose properties are being tested in the study; this definition is consistent with US CFR 21 Section 312.3 and is synonymous with "investigational new drug."Medication number A unique identifier on the label of each study drug package in studies that dispense study drug using an IVR systemPatient number A number assigned to each patient who enrolls in the study. When combined with the center number, a unique identifier is created for each patient in the study. PeriodA minor subdivision of the study timeline; divides phases into smaller functional segments such as screening, baseline, titration, washout, etc.Phase A major subdivision of the study timeline; begins and ends with major study milestones such as enrollment, randomization, completion of treatment, etc.Premature patient withdrawal Point/time when the patient exits from the study prior to the planned completion of all study drug administration and assessments; at this time all study drug administration is discontinued and no further assessments are plannedRandomization number A unique identifier assigned to each randomized patient, corresponding to a specific treatment arm assignment Stop study participation Point/time at which the patient came in for a final evaluation visit or when study drug was discontinued whichever is later Study drug Any drug administered to the patient as part of the required study procedures; includes investigational drug and any control drugs Study drug discontinuation Point/time when patient permanently stops taking study drug for any reason; may or may not also be the point/time of premature patient withdrawal Variable Information used in the data analysis; derived directly or indirectly from data collected using specified assessments at specified timepointsThis document (090095a88362b521 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Protocol synopsisTitle of study: A randomized, double-blind, placebo-controlled, multicenter study of secukinumab to demonstrate the efficacy at 24 weeks and to assess the safety, tolerability and...

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Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis–associated haplotypes at 11 loci. Two ankylosing spondylitis–associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.