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Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Title: Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
Author: Saevarsdottir, Saedis   orcid.org/0000-0001-9392-6184
Stefansdottir, Lilja
Sulem, Patrick   orcid.org/0000-0001-7123-6123
Thorleifsson, Gudmar   orcid.org/0000-0003-4623-9087
Ferkingstad, Egil   orcid.org/0000-0001-8090-7988
Rutsdottir, Gudrun
Glintborg, Bente
Westerlind, Helga
Grondal, Gerdur
Loft, Isabella C.
... 69 more authors Show all authors
Date: 2022-08-01
Language: English
Scope: 11
School: Health Sciences
Department: Faculty of Medicine
Office of Division of Diagnostic and Support Services
Faculty of Industrial Engineering, Mechanical Engineering and Computer Science
Internal Medicine and Emergency Services
Clinical Laboratory Services, Diagnostics and Blood Bank
Other departments
Series: Annals of the Rheumatic Diseases; 81(8)
ISSN: 0003-4967
DOI: https://doi.org/10.1136/annrheumdis-2021-221754
Subject: autoantibodies; polymorphism, genetic; rheumatoid arthritis; Genome-Wide Association Study; Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics; Interferon-alpha; Humans; Signal Transduction/genetics; Arthritis, Rheumatoid/genetics; Genetic Predisposition to Disease/genetics; Janus Kinases/genetics; Proteomics; STAT Transcription Factors/genetics; Biochemistry, Genetics and Molecular Biology (all); Rheumatology; Immunology and Allergy; Immunology
URI: https://hdl.handle.net/20.500.11815/3514

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Saevarsdottir , S , Stefansdottir , L , Sulem , P , Thorleifsson , G , Ferkingstad , E , Rutsdottir , G , Glintborg , B , Westerlind , H , Grondal , G , Loft , I C , Sorensen , S B , Lie , B A , Brink , M , Arlestig , L , Arnthorsson , A O , Baecklund , E , Banasik , K , Bank , S , Bjorkman , L I , Ellingsen , T , Erikstrup , C , Frei , O , Gjertsson , I , Gudbjartsson , D F , Gudjonsson , S A , Halldorsson , G H , Hendricks , O , Hillert , J , Hogdall , E , Jacobsen , S , Jensen , D V , Jonsson , H , Kastbom , A , Kockum , I , Kristensen , S , Kristjansdottir , H , Larsen , M H , Linauskas , A , Hauge , E M , Loft , A G , Ludviksson , B R , Lund , S H , Markusson , T , Masson , G , Melsted , P , Moore , K H S , Munk , H , Nielsen , K R , Norddahl , G L , Oddsson , A , Olafsdottir , T A , Olason , P I , Olsson , T , Ostrowski , S R , Hørslev-Petersen , K , Rognvaldsson , S , Sanner , H , Silberberg , G N , Stefansson , H , Sørensen , E , Sørensen , I J , Turesson , C , Bergman , T , Alfredsson , L , Kvien , T K , Brunak , S , Steinsson , K , Andersen , V , Andreassen , O A , Rantapää-Dahlqvist , S , Hetland , M L , Klareskog , L , Askling , J , Padyukov , L , Pedersen , O B V , Thorsteinsdottir , U , Jonsdottir , I , Stefansson , K & Saevarsdottir , S 2022 , ' Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset ' , Annals of the Rheumatic Diseases , vol. 81 , no. 8 , pp. 1085-1095 . https://doi.org/10.1136/annrheumdis-2021-221754


Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ∼1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-Alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1×10-9), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3×10-160). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6×10-11). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10-9-10-27) and decreased plasma levels of interferon-Alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.


Funding Information: Funding The study was funded by NORDFORSK (grant agreement no. 90825, project NORA), the Swedish Research Council (2018-02803), the Swedish innovation Agency (Vinnova), Innovationsfonden and The Research Council of Norway, Region Stockholm-Karolinska Institutet and Region Västerbotten (ALF), the Danish Rheumatism Association (R194-A6956), the Swedish Brain Foundation, Nils and Bibbi Jensens Foundation, the Knut and Alice Wallenberg Foundation, Margaretha af Ugglas Foundation, the South-Eastern Heath Region of Norway, the Health Research Fund of Central Denmark Region, Region of Southern Denmark, the A.P. Moller Foundation for the Advancement of Medical Science, the Colitis-Crohn Foreningen, the Novo Nordisk Foundation (NNF15OC0016932), Aase og Ejnar Danielsens Fond, Beckett-Fonden, Augustinus Fonden, Knud and Edith Eriksens Mindefond, Laege Sofus Carl Emil Friis and Hustru Olga Doris Friis’ Legat, the Psoriasis Forskningsfonden, the University of Aarhus, the Danish Rheumatism Association (R194-A6956, A1923, A3037 and A3570 – www. gigtforeningen.dk), Region of Southern Denmark’s PhD Fund, 12/7725 (www.regionsyddanmark.dk) and the Department of Rheumatology, Frederiksberg Hospital (www.frederiksberghospital. dk). MoBa Genetics has been funded by the Research Council of Norway (#229624, #223273), South East and Western Norway Health Authorities, ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Novo Nordisk Foundation and the University of Bergen. KB and SB acknowledge the Novo Nordisk Foundation (grant NNF14CC0001). Funding Information: competing financial interests as employees. OAA is a consultant to HealthLytix. The following coauthors report the following but unrelated to the current report: Karolinska Institutet, with JA as principal investigator, has entered into agreements with the following entities, mainly but not exclusively for safety monitoring of rheumatology immunomodulators: Abbvie, BMS, Eli Lilly, Janssen, MSD, Pfizer, Roche, Samsung Bioepis and Sanofi, unrelated to the present study. SB has ownerships in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S and managing board memberships in Proscion A/S and Intomics A/S. BG has received research grants from AbbVie, Bristol Myers-Squibb and Pfizer; OH has received research grants from AbbVie, Novartis and Pfizer, DVJ has received speaker and consultation fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB, AGL has received speaking and/or consulting fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB; and CT has received consulting fees from Roche, speaker fees from Abbvie, Bristol Myers-Squibb, Nordic Drugs, Pfizer and Roche, and an unrestricted grant from Bristol Myers-Squibb. Publisher Copyright: ©

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