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

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 cutane...

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Autores principales: Soomro, Mehreen, Stadler, Michael, Dand, Nick, Bluett, James, Jadon, Deepak, Jalali‐najafabadi, Farideh, Duckworth, Michael, Ho, Pauline, Marzo‐Ortega, Helena, Helliwell, Philip S., Ryan, Anthony W., Kane, David, Korendowych, Eleanor, Simpson, Michael A., Packham, Jonathan, McManus, Ross, Gabay, Cem, Lamacchia, Céline, Nissen, Michael J., Brown, Matthew A., Verstappen, Suzanne M. M., Van Staa, Tjeerd, Barker, Jonathan N., Smith, Catherine H., FitzGerald, Oliver, McHugh, Neil, Warren, Richard B., Bowes, John, Barton, Anne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wiley Periodicals, Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9539852/
https://www.ncbi.nlm.nih.gov/pubmed/35507331
http://dx.doi.org/10.1002/art.42154
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author Soomro, Mehreen
Stadler, Michael
Dand, Nick
Bluett, James
Jadon, Deepak
Jalali‐najafabadi, Farideh
Duckworth, Michael
Ho, Pauline
Marzo‐Ortega, Helena
Helliwell, Philip S.
Ryan, Anthony W.
Kane, David
Korendowych, Eleanor
Simpson, Michael A.
Packham, Jonathan
McManus, Ross
Gabay, Cem
Lamacchia, Céline
Nissen, Michael J.
Brown, Matthew A.
Verstappen, Suzanne M. M.
Van Staa, Tjeerd
Barker, Jonathan N.
Smith, Catherine H.
FitzGerald, Oliver
McHugh, Neil
Warren, Richard B.
Bowes, John
Barton, Anne
author_facet Soomro, Mehreen
Stadler, Michael
Dand, Nick
Bluett, James
Jadon, Deepak
Jalali‐najafabadi, Farideh
Duckworth, Michael
Ho, Pauline
Marzo‐Ortega, Helena
Helliwell, Philip S.
Ryan, Anthony W.
Kane, David
Korendowych, Eleanor
Simpson, Michael A.
Packham, Jonathan
McManus, Ross
Gabay, Cem
Lamacchia, Céline
Nissen, Michael J.
Brown, Matthew A.
Verstappen, Suzanne M. M.
Van Staa, Tjeerd
Barker, Jonathan N.
Smith, Catherine H.
FitzGerald, Oliver
McHugh, Neil
Warren, Richard B.
Bowes, John
Barton, Anne
author_sort Soomro, Mehreen
collection PubMed
description 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 PsA should be tested in PsC patients recruited from primary care.
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spelling pubmed-95398522022-10-14 Comparative Genetic Analysis of Psoriatic Arthritis and Psoriasis for the Discovery of Genetic Risk Factors and Risk Prediction Modeling Soomro, Mehreen Stadler, Michael Dand, Nick Bluett, James Jadon, Deepak Jalali‐najafabadi, Farideh Duckworth, Michael Ho, Pauline Marzo‐Ortega, Helena Helliwell, Philip S. Ryan, Anthony W. Kane, David Korendowych, Eleanor Simpson, Michael A. Packham, Jonathan McManus, Ross Gabay, Cem Lamacchia, Céline Nissen, Michael J. Brown, Matthew A. Verstappen, Suzanne M. M. Van Staa, Tjeerd Barker, Jonathan N. Smith, Catherine H. FitzGerald, Oliver McHugh, Neil Warren, Richard B. Bowes, John Barton, Anne Arthritis Rheumatol Psoriatic Arthritis 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 PsA should be tested in PsC patients recruited from primary care. Wiley Periodicals, Inc. 2022-08-04 2022-09 /pmc/articles/PMC9539852/ /pubmed/35507331 http://dx.doi.org/10.1002/art.42154 Text en © 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Psoriatic Arthritis
Soomro, Mehreen
Stadler, Michael
Dand, Nick
Bluett, James
Jadon, Deepak
Jalali‐najafabadi, Farideh
Duckworth, Michael
Ho, Pauline
Marzo‐Ortega, Helena
Helliwell, Philip S.
Ryan, Anthony W.
Kane, David
Korendowych, Eleanor
Simpson, Michael A.
Packham, Jonathan
McManus, Ross
Gabay, Cem
Lamacchia, Céline
Nissen, Michael J.
Brown, Matthew A.
Verstappen, Suzanne M. M.
Van Staa, Tjeerd
Barker, Jonathan N.
Smith, Catherine H.
FitzGerald, Oliver
McHugh, Neil
Warren, Richard B.
Bowes, John
Barton, Anne
Comparative Genetic Analysis of Psoriatic Arthritis and Psoriasis for the Discovery of Genetic Risk Factors and Risk Prediction Modeling
title Comparative Genetic Analysis of Psoriatic Arthritis and Psoriasis for the Discovery of Genetic Risk Factors and Risk Prediction Modeling
title_full Comparative Genetic Analysis of Psoriatic Arthritis and Psoriasis for the Discovery of Genetic Risk Factors and Risk Prediction Modeling
title_fullStr Comparative Genetic Analysis of Psoriatic Arthritis and Psoriasis for the Discovery of Genetic Risk Factors and Risk Prediction Modeling
title_full_unstemmed Comparative Genetic Analysis of Psoriatic Arthritis and Psoriasis for the Discovery of Genetic Risk Factors and Risk Prediction Modeling
title_short Comparative Genetic Analysis of Psoriatic Arthritis and Psoriasis for the Discovery of Genetic Risk Factors and Risk Prediction Modeling
title_sort comparative genetic analysis of psoriatic arthritis and psoriasis for the discovery of genetic risk factors and risk prediction modeling
topic Psoriatic Arthritis
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9539852/
https://www.ncbi.nlm.nih.gov/pubmed/35507331
http://dx.doi.org/10.1002/art.42154
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