Replication of a distinct psoriatic arthritis risk variant at the<i>IL23R</i>locus

Budu-Aggrey, Ashley; Loehr, Sabine; Uebe, Steffen; Zervou, Maria I.; Helliwell, Philip S.; Ryan, Anthony W.; Kane, David; Korendowych, Eleanor; Giardina, Emiliano; Packham, Jon; McManus, Ross; FitzGerald, Oliver; McHugh, Neil; Behrens, Frank; Burkhardt, Harald; Hüffmeier, Ulrike; Ho, Pauline; Martín, Javier; Castañeda, Santos; Goulielmos, George N.; Reis, André; Barton, Anne

doi:10.1136/annrheumdis-2016-209290

Cited by 10 publications

(2 citation statements)

References 9 publications

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“…Although gene mapping is consistent across different studies, resolution to a precise allelic variant is conflicting when the reported index associations point to amino acid positions 45 or 97 ( Table 1 ). Outside the HLA region, there is convincing evidence for a PsA-specific effect at the IL23R locus independent of the known psoriasis risk variant [ 32 , 33 , 34 ]. Other genes associated with PsA but not psoriasis include KIR2D [ 35 ], IL4 and KIF3A [ 36 ], B3GNT2 [ 37 ] and PTPN22 [ 25 ].…”

Section: Genomicsmentioning

confidence: 99%

Omics and Multi-Omics Analysis for the Early Identification and Improved Outcome of Patients with Psoriatic Arthritis

Bendes

Koehm

Twyman³

et al. 2022

Biomedicines

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The definitive diagnosis and early treatment of many immune-mediated inflammatory diseases (IMIDs) is hindered by variable and overlapping clinical manifestations. Psoriatic arthritis (PsA), which develops in ~30% of people with psoriasis, is a key example. This mixed-pattern IMID is apparent in entheseal and synovial musculoskeletal structures, but a definitive diagnosis often can only be made by clinical experts or when an extensive progressive disease state is apparent. As with other IMIDs, the detection of multimodal molecular biomarkers offers some hope for the early diagnosis of PsA and the initiation of effective management and treatment strategies. However, specific biomarkers are not yet available for PsA. The assessment of new markers by genomic and epigenomic profiling, or the analysis of blood and synovial fluid/tissue samples using proteomics, metabolomics and lipidomics, provides hope that complex molecular biomarker profiles could be developed to diagnose PsA. Importantly, the integration of these markers with high-throughput histology, imaging and standardized clinical assessment data provides an important opportunity to develop molecular profiles that could improve the diagnosis of PsA, predict its occurrence in cohorts of individuals with psoriasis, differentiate PsA from other IMIDs, and improve therapeutic responses. In this review, we consider the technologies that are currently deployed in the EU IMI2 project HIPPOCRATES to define biomarker profiles specific for PsA and discuss the advantages of combining multi-omics data to improve the outcome of PsA patients.

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Section: Genomicsmentioning

confidence: 99%

Omics and Multi-Omics Analysis for the Early Identification and Improved Outcome of Patients with Psoriatic Arthritis

Bendes

Koehm

Twyman³

et al. 2022

Biomedicines

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“…Only a limited number of studies have evaluated genetic loci specifically associated with PsA, PsC and the differences between PsA and PsC. To date only 15 polymorphisms in twelve genes outside the MHC region have been reported to render differences in susceptibility between the two phenotypes, including IL23R (rs2201841, rs12044149) [ 11 , 12 , 15 ], FBXL19 (rs10782001) [ 16 ], IL12B (rs2082412) [ 11 , 17 ], ZNF816A (rs9304742) [ 17 ], CCR2 (rs1799864) [ 18 ], CSF2 (rs715285) [ 19 ], PTPN22 (rs2476601) [ 12 , 20 ], IL13 (rs1800925, rs20541, rs848) [ 21 – 23 ], TNFRSF9 (rs4908742) [ 12 ], LCE3A (rs10888503) [ 12 ], TNFAIP3 (rs9321623) [ 12 ], and KIR2DS2 [ 24 ]. Among these, only associations to PTPN22 (rs2476601) [ 12 , 20 ], IL23R (rs2201841, rs12044149) [ 11 , 12 , 15 ], IL12B (rs2082412) [ 11 , 17 ], and IL13 (rs1800925, rs20541, rs848) [ 21 – 23 ] have been replicated, while a large scale genome wide association study (GWAS) failed to reproduce the associations for the polymorphisms in IL13 and IL12B [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic polymorphisms associated with psoriasis and development of psoriatic arthritis in patients with psoriasis

et al. 2018

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BackgroundPsoriasis (PsO) is a chronic inflammatory disease with predominantly cutaneous manifestations. Approximately one third of patients with PsO develop psoriatic arthritis (PsA), whereas the remaining proportion of patients has isolated cutaneous psoriasis (PsC). These two phenotypes share common immunology, but with different heredity that might in part be explained by genetic variables.MethodsUsing a candidate gene approach, we studied 53 single nucleotide polymorphisms (SNPs) in 37 genes that regulate inflammation. In total, we assessed 480 patients with PsO from DERMBIO, of whom 151 had PsC for 10 years or more (PsC10), 459 patients with PsA from DANBIO, and 795 healthy controls. Using logistic regression analysis, crude and adjusted for age and gender, we assessed associations between genetic variants and PsO, PsC10, and PsA, as well as associations between genetic variants and development of PsA in PsO.ResultsEleven polymorphisms in 10 genes were nominally associated with PsO and/or PsC and/or PsA (P < 0.05). After correction for multiple testing with a false discovery rate of 5%, two SNPs remained significant: TNF (rs361525) was associated with PsO, PsC10, and PsA; and IL12B (rs6887695) was associated with PsO.ConclusionAmong a cohort of Danish patients with moderate-to-severe psoriasis, two SNPs in the IL12B and TNF genes were associated with susceptibility of psoriasis. None of the SNPs were specifically associated with isolated cutaneous psoriasis or psoriatic arthritis.

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Comparative Genetic Analysis of Psoriatic Arthritis and Psoriasis for the Discovery of Genetic Risk Factors and Risk Prediction Modeling

Soomro

Stadler

Dand

et al. 2022

Arthritis & Rheumatology

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Objectives. Psoriatic arthritis (PsA) has a strong genetic component, and the identification of genetic risk factors could help identify the ~30% of psoriasis patients at high risk of developing PsA. Our objectives were to identify genetic risk factors and pathways that differentiate PsA from cutaneous-only psoriasis (PsC) and to evaluate the performance of PsA risk prediction models.Methods. Genome-wide meta-analyses were conducted separately for 5,065 patients with PsA and 21,286 healthy controls and separately for 4,340 patients with PsA and 6,431 patients with PsC. The heritability of PsA was calculated as a single-nucleotide polymorphism (SNP)-based heritability estimate (h 2 SNP ) and biologic pathways that differentiate PsA from PsC were identified using Priority Index software. The generalizability of previously published PsA risk prediction pipelines was explored, and a risk prediction model was developed with external validation.Results. We identified a novel genome-wide significant susceptibility locus for the development of PsA on chromosome 22q11 (rs5754467; P = 1.61 × 10 −9 ), and key pathways that differentiate PsA from PsC, including NF-κB signaling (adjusted P = 1.4 × 10 −45 ) and Wnt signaling (adjusted P = 9.5 × 10 −58 ). The heritability of PsA in this cohort was found to be moderate (h 2 SNP = 0.63), which was similar to the heritability of PsC (h 2 SNP = 0.61). We observed modest performance of published classification pipelines (maximum area under the curve 0.61), with similar performance of a risk model derived using the current data.Conclusion. Key biologic pathways associated with the development of PsA were identified, but the investigation of risk classification revealed modest utility in the available data sets, possibly because many of the PsC patients included in the present study were receiving treatments that are also effective in PsA. Future predictive models of 1535

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Replication of a distinct psoriatic arthritis risk variant at theIL23Rlocus

Cited by 10 publications

References 9 publications

Omics and Multi-Omics Analysis for the Early Identification and Improved Outcome of Patients with Psoriatic Arthritis

Omics and Multi-Omics Analysis for the Early Identification and Improved Outcome of Patients with Psoriatic Arthritis

Genetic polymorphisms associated with psoriasis and development of psoriatic arthritis in patients with psoriasis

Comparative Genetic Analysis of Psoriatic Arthritis and Psoriasis for the Discovery of Genetic Risk Factors and Risk Prediction Modeling

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