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BackgroundPsoriatic disease (psoriasis and psoriatic arthritis) is a common inflammatory disease associated with obesity. However, recent studies suggest that lipid changes, rather than obesity, may independently drive psoriatic disease [1]. Mendelian randomization (MR) can assess the causal effect of modifiable exposure by measuring the variation of genes of known function.ObjectivesIn this study, we perform a two-sample mendelian randomization to investigate the possible causal relationship between polygenic hyperlipidemia and psoriatic disease (psoriasis and psoriatic arthritis).MethodsThe study cohorts (psoriasis, psoriatic arthritis, hyperlipidemia, and controls of European ancestry) were identified from the FinnGen biobank, an academia/industry collaboration aiming to identify genotype-phenotype correlations in the Finnish founder population. Hyperlipidemia was identified by code E4_HYPERLIPNAS, which represents disorders of lipoprotein metabolism and other lipidaemias [2]. The L12_psoriasis code and psoriatic arthritis by M13_PSORIARTH code identified psoriatic arthritis. The control population was selected after excluding E4_MEABOLIA, psoriasis, and psoriatic arthritis when appropriate. Genome-wide association studies (GWAS) and summarized data were extracted from public IEU datasets. The single-nucleotide polymorphisms (SNPs) were used as instrumental variables (IV) to identify the potential causal effect. The SNP selection was performed by considering the genome-wide significance, clumping, linkage disequilibrium, and minor allele frequency. The effect alleles were harmonized for exposures and outcomes. An inverse variance weighted (IVW) model was used to estimate causality for each IV in this two-sample MR study. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for causal estimations. The MR was performed in both directions to explore the possibility of reverse causality.Results4535 patients with hyperlipidemia, 4510 with psoriasis, and 1553 patients with psoriatic arthritis (PsA) were identified from the FinnGenn biobank based on their id as noted above. The control patients ranged from 147,221 to 212,242, depending on the cohort being compared. Genetic instruments comprising 5 SNPs for hyperlipidemia, 16 SNPs for psoriasis and 4 SNPs for PsA were used for this two-sample MR. A significant causal effect was noted in hyperlipidemia and psoriasis (OR 1.26 (95% CI 1.097-1.439; p < 0.00009) and hyperlipidemia and PsA (OR 1.35 (95% CI 1.08-1.68; p=0.007) but no causal effect was noted in the reverse direction with psoriasis leading to hyperlipidemia OR 1.02 (95% CI 0.977-1.07; p=0.31) and PsA leading to hyperlipidemia OR 1.03 (95% CI 0,987 to 1.08; p=0.15).ConclusionOur two-sample MR study genetically predicted that hyperlipidemia has a potential causal association with psoriatic disease, which leads to a higher risk of psoriasis and PsA. Further validation and molecular studies are required to understand this relationship. If these results were to be validated, targeted reduction of hyperlipidemia may help modify the expression of psoriatic disease.References[1]Snekvik, I., et al. Metabolic syndrome and risk of incident psoriasis: prospective data from the HUNT Study, Norway. Br. J. Dermatol. 2019; 180, 94–99[2]https://risteys.finngen.fi/endpoints/E4_HYPERLIPNASAcknowledgements:NIL.Disclosure of InterestsQuan Li: None declared, Amanda Dohey: None declared, Dianne Codner: None declared, Proton Rahman Speakers bureau: Abbott, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, and Pfizer, Consultant of: Abbott, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, and Pfizer, Grant/research support from: Janssen and Novartis.

Ankylosing Spondylitis (AS) and psoriatic arthritis (PsA) are chronic inflammatory diseases of undetermined etiology. Both entities exhibit features of autoimmunity (exhibited by clonal expansion of T cell populations) and autoinflammation, as noted by the aberrant activity of innate and innate-like cells [1]. In this study, we screen for genetic variants associated with known autoinflammatory disease in patients with AS, PsA, and compare it to rheumatoid arthritis (RA) and psoriasis (Ps). The UK genome biobank identified exomes of AS, PsA, RA, and Ps patients. Autoinflammatory genes were selected from the blueprint autoinflammatory syndrome panel [2]. Twenty thousand nine hundred five missense mutations were identified from the 47 autoinflammatory genes in the blueprint panel and screened in these four cohorts. Mutational burden, mutation number, and mutation rate in these 47 genes were calculated. Exonic mutations of 1264 in AS, 886 in PsA, 5361 in RA and 5567 in Ps patients from the UK biobank were enrolled and analyzed in this study. The number of autoinflammatory variants identified was 937 in AS, 780 in PsA, 2081 in RA and 2015 in Ps. The average mutation rate in 47 genes is around 0.26 for these four diseases. The autoinflammatory panel's average mutation burden was not significantly different between these diseases (116 in AS and PsA, 118 in RA and Ps). However, when we accounted for the number of individuals screened, AS and PsA had a higher mean number of autoinflammatory variants than RA and Ps. Specifically, AS and PsA patients had a mean number of 0.741 and 0.880 variants per individual, respectively, compared to 0.388 and 0.362 for RA and Ps, respectively. This study strengths the role of autoinflammation in AS and PsA as we report an overabundance of autoinflammatory variants in AS and PsA compared to RA and psoriasis. Consideration of autoinflammatory etiology may impact current diagnostic and therapeutic approaches. [1]Mauro D, Thomas R, Guggino G, Lories R, Brown MA, Ciccia F. Ankylosing spondylitis: an autoimmune or autoinflammatory disease? Nat Rev Rheumatol. 2021 Jul;17(7):387-404. doi: 10.1038/s41584-021-00625-y. Epub 2021 Jun 10. PMID: 34113018. [2]https://blueprintgenetics.com/tests/panels/immunology/autoinflammatory-syndrome-panel/ NIL. Quan Li: None declared, Amanda Dohey: None declared, Dianne Codner: None declared, Proton Rahman Speakers bureau: Abbott, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, and Pfizer, Consultant of: Abbott, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, and Pfizer, Grant/research support from: Janssen and Novartis. Table 1Autoinflammatory variants in AS, PsA, RA and PsDiseaseNo. of PatientsNo. of Autoinflammatory VariantsAverage No. of Autoinflammatory Variants per patientAS12649370.741PsA8867800.880RA536120810.388Ps556720150.362

Background and aimsColorectal cancer (CRC) is the second most frequent cancer in developed countries. Newfoundland has the highest incidence of CRC in Canada and the highest rate of familial CRC yet reported in the world. To determine the impact of mutations in known CRC susceptibility genes and the contribution of the known pathways to the development of hereditary CRC, an incident cohort of 750 patients with CRC (708 different families) from the Newfoundland population was studied. MethodsMicrosatellite instability (MSI) testing was performed on tumours, together with immunohistochemistry analysis for mismatch repair (MMR) genes. Where indicated, DNA sequencing and multiplex ligation-dependent probe amplifications of MMR genes and APC was undertaken. DNA from all patients was screened for MUTYH mutations. The presence of the BRAF variant, p.V600E, and of MLH1 promoter methylation was also tested in tumours.Results4.6% of patients fulfilled the Amsterdam criteria (AC), and an additional 44.6% fulfilled the revised Bethesda criteria. MSI-high (MSI-H) was observed in 10.7% (n=78) of 732 tumours. In 3.6% (n=27) of patients, CRC was attributed to 12 different inherited mutations in six known CRC-related genes associated with chromosomal instability or MSI pathways. Seven patients (0.9%) carried a mutation in APC or biallelic mutations in MUTYH. Of 20 patients (2.7%) with mutations in MMR genes, 14 (70%) had one of two MSH2 founder mutations. 17 of 28 (61%) AC families did not have a genetic cause identified, of which 15 kindreds fulfilled the criteria for familial CRC type X (FCCTX).ConclusionsFounder mutations accounted for only 2.1% of cases and this was insufficient to explain the high rate of familial CRC. Many of the families classified as FCCTX may have highly penetrant mutations segregating in a Mendelian-like manner. These families will be important for identifying additional CRC susceptibility loci.

BackgroundSeveral studies have demonstrated excessive paternal transmission of psoriasis and psoriatic arthritis (PsA). This phenomenon is thought to be mediated by genomic imprinting. We previously compared whole blood methylation patterns among PsA patients from Newfoundland, Canada and identified 90 significant CpG sites that differentiate patients with paternally and maternally-transmitted disease.ObjectivesTo validate previously-identified CpG sites in an independent sample of PsA patients with paternally and maternally-transmitted disease from Toronto, Canada.MethodsAll PsA patients included in the study satisfied the CASPAR criteria and had a parent with either psoriasis or PsA. Forty-six (46) PsA patients with paternally-transmitted disease were compared to 48 PsA patients with maternally-transmitted disease at 136 CpG sites on 10 different chromosomes. Percent methylation was measured at each CpG site by Sequenom EpiTyper technology, which involves bisulfite conversion followed by mass spectrometric analysis. Generated β values ranging from 0% (fully unmethylated) to 100% (fully methylated) were compared between groups using the nonparametric Mann-Whitney U test. Logistic regression models adjusting for age and sex were run to confirm the unadjusted results.ResultsPsA patients with paternally-transmitted disease were 52% female, and at the time of sample collection had a mean (SD) age of 47.7 (12.6) years, psoriasis duration of 23.7 (13.3) years, PsA duration of 14.1 (9.7) years, PASI score of 5.3 (7.2) and tender joint count of 4.9 (7.8). Patients with maternally-transmitted disease were 53% female, and had a mean age of 50.3 (11.1) years, psoriasis duration of 23.1 (12.2) years, PsA duration of 14.9 (12.0) years, PASI score of 4.5 (5.3) and tender joint count of 6.8 (8.5). Three CpG sites were significantly differentially methylated in the Toronto patients with paternally and maternally-transmitted disease. The most significant site was located within an intron of the CROCC (rootelin) gene on 1p36.13 and was hypomethylated in paternally-transmitted disease (p=0.014). Two sites within the 5' UTR of the PACSIN1 gene on chromosome 6p21.3 were also significantly hypomethylated in paternally-transmitted disease (p=0.040 and p=0.047). After adjustment for age and sex, CpG methylation at CROCC remained significantly associated with paternally-transmitted disease (OR=0.77, 95% CI 0.60-0.99, p=0.04).ConclusionsCpG methylation at the CROCC locus on chromosome 1p36.13 differentiates PsA patients with paternally and maternally-transmitted disease. Although CROCC is not known to be imprinted in humans, these data suggest it may play some role in the excessive paternal transmission of psoriatic disease. Further validation of these results in somatic and germ line cells are necessary.Disclosure of InterestNone declared

BackgroundThe variability in the rate of radiographic progression in ankylosing spondylitis (AS) and the role of smoking, as an independent risk factor for radiographic progression, has been well documented. We have recently identified multiple epigenetic variants associated with ankylosis in AS using a genome-wide epigenetic approach. In this study, we examined the recently identified epigenetic markers in an independent AS cohort to assess radiographic progression and determine if an interaction exists with smoking status.MethodsOur replication cohort consisted of 76 AS patients (16 females; 32 smokers; 56 HLA-B27+) that had serial radiographs on average 3 years apart (range 1.2 to 7.5 yrs). Of the 76 patients, 35 patients exhibited radiographic progression (change in mSASSS score >0). The mean radiographic progression for the entire group was 0.99 mSASSS/yr. The DNA methylation experiments on 17 CpG sites were designed using EpiTyper and performed on a Sequenom MassArray 4 system. The association between methylation score and radiographic progression rate was examined by multiple linear regressions after controlling for age of onset and gender. An interaction between methylation score and smoking status was introduced into the model to examine the association in the smokers and non-smokers, respectively. The Akaike information criterion (AIC) was used to assess the goodness of fit. Methylation sites with more than 15% of data missing were excluded from the analysis. The total methylation score of 7 CpG sites had the best goodness of fit.ResultsIn the univariate analysis, high total methylation score was significantly associated with less radiographic progression (β=-0.97; 95%CI=-1.91:-0.02; p=0.04). Smokers demonstrated worse radiographic progression than non-smokers, but it was not statistically significant (p=0.62). In the multivariate analysis, the interaction between methylation score and smoke status was statistically significant (p=0.008). Among smokers, high total methylation score was significantly associated with less radiographic progression (β=-2.01; 95%CI=-3.26:-0.75; p=0.0017). No such association was observed among non-smokers.ConclusionsThis is the first study to demonstrate how epigenetic factors can influence radiographic progression in AS. Specifically, the results from this study reveal a significant association between smoking, methylation status and radiographic progression in AS.Disclosure of InterestNone declared

Using transcriptomic data at initiation of therapy, we recently identified differentially expressed genes (DEGs) that separated IL-17Ai response from non-response1. Integration of cell-type-specific DEGs with protein-protein interactions (PPIs) and further comprehensive pathway enrichment analysis revealed Rho GTPase signaling pathway exhibited a strong signal specific to IL-17Ai response and particularly the genes, RAC1 and ROCKs. To characterize microRNA (miR) profiles among IL-17Ai responders and non-responders, as it relates to RHO GTPase pathway. We interrogated 20 psoriatic arthritis (PsA) patients initiating IL-17Ai. Patients achieving at least low disease activity according to the Disease Activity Index for PsA (DAPSA) at three months were classified as responders. There were seven responders (35%) and thirteen non-responders (65%) in the IL-17Ai group, with biologic treatment naïve (bio-naïve) and previously-exposed (bio-exposed) patients exhibiting a 50% (4/8) and a 25% (3/12) response rate, respectively. For the miR analysis, CD4 positive T cells were isolated from peripheral blood mononuclear cells using DynabeadsTM CD4 beads (ThermoFisher). Total RNA was extracted from the CD4+ T cells using Lexogen's Split RNA Extraction Kit (D-Mark Biosciences). Libraries were prepared from 200ng total RNA with the NEXTFLEX Small RNA-Seq Kit v3 with UDIs (Bioo Scientific) and sequenced on the Illumina NovaSeq 6000. Raw sequencing fastq data assessed the quality using FastQC. The miRDeep2 was used to trim the adapter, align and quantify human mature miRs from miRbase (Release 22). The abundance of miRs was converted to read counts per million, normalized and limma R package was used to identify pre- and post-differentially expressed miRs. We obtained 2,889 miRs. After removing miRs with low reads in >90% of samples, 1902 high quality miRs remained for further analysis. Using mirDIP v4.1 we identified gene targets for differential miRs, and focused on recently identified DEGs related to RHO GTPase pathway. The miRs on the left of the figure 1 are those deregulated in pre-treatment, and the miRs on the right of the figure 1 show the post-treatment deregulated miRs. hsa-miR-3691-5p and hsa-miR-3161 represent the miRs that were deregulated in both conditions. The red highlighted nodes represent the most connected miRs and genes; thus, representing miRs that are the most RHO-pathway centric regulators (hsa-miR-495-3p, 16-5p, 129-5p, 520h, 520g-3p), and genes representing the most strongly regulated RHO-pathway gene products (ROCK1, RHOQ, PFN2, TAOK1, DYNC1L12, MAPRE1, PAFAH1B1, ARHGAP5, MAPK1, CALM1, DIAPH2, PKN2, ITSN1). Pre- and post-treatment differential miRs related to IL-17Ai response regulate multiple genes from RHO GTPase pathway. [1]Rahmati S, O'Rielly DD, Li Q, Codner D, Dohey A, Jenkins K, Jurisica I, Gladman DD, Chandran V, Rahman P. Rho-GTPase pathways may differentiate treatment response to TNF-alpha and IL-17A inhibitors in psoriatic arthritis. Sci Rep. 2020 Dec 10;10(1):21703. Proton Rahman Speakers bureau: AbbVie, Amgen, BMS, Celgene, Eli Lily, Janssen, Merck, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, BMS, Celgene, Eli Lily, Janssen, Merck, Novartis, Pfizer, UCB, Grant/research support from: Janssen, Novartis, Quan Li: None declared, Dianne Codner: None declared, Darren O'Rielly: None declared, Amanda Dohey: None declared, Kari Jenkins: None declared, Dafna D Gladman Speakers bureau: AbbVie, Amgen, BMS, Eli Lily, Galapagos, Gilead, Janssen, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, BMS, Eli Lily, Galapagos, Gilead, Janssen, Novartis, Pfizer, UCB, Grant/research support from: AbbVie, Amgen, Eli Lily, Janssen, Novartis, Pfizer, UCB, Vinod Chandran Speakers bureau: AbbVie, Amgen, BMS, Eli Lily, Janssen, Novartis, Pfizer, UCB, Paid instructor for: AbbVie, Amgen, BMS, Eli Lily, Janssen, Novartis, Pfizer, UCB, Grant/research support from: AbbVie, Amgen, Eli Lily, Employee of: Spousal Employment Eli Lilly, Igor Jurisica: None declared [Display omitted]

BackgroundAlthough tumor necrosis factor-α inhibitors TNFi are well established treatment for psoriatic arthritis (PsA), the efficacy can vary greatly between patients. In this study, we examined the genome-wide epigenetic changes among TNFi responders and TNFi secondary failures in PsA patientsMethodsTwenty-one PsA patients (15 males; 6 females) were considered TNFi responders of which 13 were treated with etanercept and 8 with adalumimab. The median follow up duration was 18 months. Twenty patients (5 males; 15 females) were secondary TNFi failures of which 15 were treated with etanercept and 5 with adalumimab. The median follow up duration was 36 months. Genome-wide DNA methylation profiling was performed using the Illumina HumanMethylation450k Beadchip, which measures ∼480,000 different CpG sites per sample and covers 96% of RefSeq genes. The methylation level at each CpG site was measured by β values varying from 0 (no methylation) to 1 (100% methylation). Analysis was performed using a t-test after a Bonferroni-Holm correction was applied. Regions of interest were selected based on β value (β diff>5%) and p-value (p<0.01).ResultsAfter quality control filtering, 384,599 and 368,863 CpG sites were evaluated for TNFi responders and TNFi failures, respectively. Analysis revealed 72 and 91 CpG sites of interest in the TNFi responder group and in the TNFi failure group, respectively. Top gene candidates for TNFi responders included TRAPPC9 (β diff=0.056; p=3.42x10-6 - functions as an activator of NFkB); CCR6 (β diff=0.053; p=0.0028 - regulates the migration and recruitment of dentritic and T cells); and PSORSC13 (β diff=0.035; p=0.003). Top candidate genes for TNFi secondary failures included CD70 (encoded protein is a ligand for TNFRSF27/CD27), and TNFRSF1B (a member of the TNF receptor superfamily, that mediates most of the metabolic effects of TNFα).ConclusionsThese preliminary results demonstrate that the global DNA methylation pattern differs between TNFi responders and secondary failures. They also serve to highlight the possible importance of epigenetic (methylation) changes with respect to the TNFα signaling pathway. High priority candidate regions and genes identified in this study warrant further validation.Disclosure of InterestNone declared

Background Although tumor necrosis factor-α inhibitors TNFi are well established treatment for psoriatic arthritis (PsA), the efficacy can vary greatly between patients. In this study, we examined the genome-wide epigenetic changes among TNFi responders and TNFi secondary failures in PsA patients Methods Twenty-one PsA patients (15 males; 6 females) were considered TNFi responders of which 13 were treated with etanercept and 8 with adalumimab. The median follow up duration was 18 months. Twenty patients (5 males; 15 females) were secondary TNFi failures of which 15 were treated with etanercept and 5 with adalumimab. The median follow up duration was 36 months. Genome-wide DNA methylation profiling was performed using the Illumina HumanMethylation450k Beadchip, which measures ∼480,000 different CpG sites per sample and covers 96% of RefSeq genes. The methylation level at each CpG site was measured by β values varying from 0 (no methylation) to 1 (100% methylation). Analysis was performed using a t-test after a Bonferroni-Holm correction was applied. Regions of interest were selected based on β value (β diff>5%) and p-value (p<0.01). Results After quality control filtering, 384,599 and 368,863 CpG sites were evaluated for TNFi responders and TNFi failures, respectively. Analysis revealed 72 and 91 CpG sites of interest in the TNFi responder group and in the TNFi failure group, respectively. Top gene candidates for TNFi responders included TRAPPC9 (β diff=0.056; p=3.42x10-6 - functions as an activator of NFkB); CCR6 (β diff=0.053; p=0.0028 - regulates the migration and recruitment of dentritic and T cells); and PSORSC13 (β diff=0.035; p=0.003). Top candidate genes for TNFi secondary failures included CD70 (encoded protein is a ligand for TNFRSF27/CD27), and TNFRSF1B (a member of the TNF receptor superfamily, that mediates most of the metabolic effects of TNFα). Conclusions These preliminary results demonstrate that the global DNA methylation pattern differs between TNFi responders and secondary failures. They also serve to highlight the possible importance of epigenetic (methylation) changes with respect to the TNFα signaling pathway. High priority candidate regions and genes identified in this study warrant further validation. Disclosure of Interest None declared