Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
Autor: | Saedis, Saevarsdottir, Lilja, Stefansdottir, Patrick, Sulem, Gudmar, Thorleifsson, Egil, Ferkingstad, Gudrun, Rutsdottir, Bente, Glintborg, Helga, Westerlind, Gerdur, Grondal, Isabella C, Loft, Signe Bek, Sorensen, Benedicte A, Lie, Mikael, Brink, Lisbeth, Ärlestig, Asgeir Orn, Arnthorsson, Eva, Baecklund, Karina, Banasik, Steffen, Bank, Lena I, Bjorkman, Torkell, Ellingsen, Christian, Erikstrup, Oleksandr, Frei, Inger, Gjertsson, Daniel F, Gudbjartsson, Sigurjon A, Gudjonsson, Gisli H, Halldorsson, Oliver, Hendricks, Jan, Hillert, Estrid, Hogdall, Søren, Jacobsen, Dorte Vendelbo, Jensen, Helgi, Jonsson, Alf, Kastbom, Ingrid, Kockum, Salome, Kristensen, Helga, Kristjansdottir, Margit H, Larsen, Asta, Linauskas, Ellen-Margrethe, Hauge, Anne G, Loft, Bjorn R, Ludviksson, Sigrun H, Lund, Thorsteinn, Markusson, Gisli, Masson, Pall, Melsted, Kristjan H S, Moore, Heidi, Munk, Kaspar R, Nielsen, Gudmundur L, Norddahl, Asmundur, Oddsson, Thorunn A, Olafsdottir, Pall I, Olason, Tomas, Olsson, Sisse Rye, Ostrowski, Kim, Hørslev-Petersen, Solvi, Rognvaldsson, Helga, Sanner, Gilad N, Silberberg, Hreinn, Stefansson, Erik, Sørensen, Inge J, Sørensen, Carl, Turesson, Thomas, Bergman, Lars, Alfredsson, Tore K, Kvien, Søren, Brunak, Kristján, Steinsson, Vibeke, Andersen, Ole A, Andreassen, Solbritt, Rantapää-Dahlqvist, Merete Lund, Hetland, Lars, Klareskog, Johan, Askling, Leonid, Padyukov, Ole Bv, Pedersen, Unnur, Thorsteinsdottir, Ingileif, Jonsdottir, Kari, Stefansson |
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Jazyk: | angličtina |
Rok vydání: | 2022 |
Předmět: |
Proteomics
rheumatoid arthritis autoantibodies Janus Kinases/genetics Immunology polymorphism genetic General Biochemistry Genetics and Molecular Biology polymorphism Protein Tyrosine Phosphatase Non-Receptor Type 22/genetics Arthritis Rheumatoid Rheumatology genetic Immunology and Allergy Humans Genetic Predisposition to Disease Medicinsk genetik Rheumatology and Autoimmunity Janus Kinases Reumatologi och inflammation Genetic Predisposition to Disease/genetics Biochemistry and Molecular Biology Interferon-alpha Protein Tyrosine Phosphatase Non-Receptor Type 22 Arthritis Rheumatoid/genetics STAT Transcription Factors/genetics STAT Transcription Factors Signal Transduction/genetics Medical Genetics Biokemi och molekylärbiologi Genome-Wide Association Study Signal Transduction |
Zdroj: | 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, Ärlestig, 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, Ostrowski, S R, Sørensen, E, Sørensen, I J, Brunak, S, Andersen, V, Hetland, M L, Askling, J, Pedersen, O B & Members of the DBDS Genomic Consortium 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 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, DBDS Genomic Consortium, The Danish RA Genetics Working Group & The Swedish Rheumatology Quality Register Biobank Study Group (SRQb) 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 Annals of the Rheumatic Diseases 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, Ärlestig, 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, Thorsteinsdottir, U, Jonsdottir, I, Stefansson, K, Members of the DBDS Genomic Consortium & Nyegaard, M 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, 221754, pp. 1085-1095 . https://doi.org/10.1136/annrheumdis-2021-221754 |
ISSN: | 0003-4967 |
Popis: | 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 similar to 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=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-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=6.6x10(-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 Agencies|NORDFORSK [90825]; Swedish Research Council [2018-02803]; Swedish innovation Agency (Vinnova); Innovationsfonden; The Research Council of Norway; Region Stockholm-Karolinska Institutet; Region Vasterbotten (ALF); Danish Rheumatism Association [R194-A6956, A1923, A3037, A3570]; Swedish Brain Foundation; Nils and Bibbi Jensens Foundation; Knut and Alice Wallenberg Foundation; Margaretha af Ugglas Foundation; South-Eastern Heath Region of Norway; Health Research Fund of Central Denmark Region; Region of Southern Denmark; A.P. Moller Foundation for the Advancement of Medical Science; Colitis-Crohn Foreningen; 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; Psoriasis Forskningsfonden; University of Aarhus; Region of Southern Denmarks PhD Fund [12/7725]; Department of Rheumatology, Frederiksberg Hospital; Research Council of Norway [229624, 223273]; South East and Western Norway Health Authorities; ERC AdG project SELECTionPREDISPOSED; Stiftelsen Kristian Gerhard Jebsen; Trond Mohn Foundation; Novo Nordisk Foundation; University of Bergen |
Databáze: | OpenAIRE |
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