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1. Genome-wide association study identifies Sjögrens risk loci with functional implications in immune and glandular cells.

Author

Khatri, Bhuwan, Tessneer, Kandice, Rasmussen, Astrid, Aghakhanian, Farhang, Reksten, Tove, Adler, Adam, Alevizos, Ilias, Anaya, Juan-Manuel, Aqrawi, Lara, Baecklund, Eva, Brun, Johan, Bucher, Sara, Eloranta, Maija-Leena, Engelke, Fiona, Forsblad-dElia, Helena, Glenn, Stuart, Hammenfors, Daniel, Imgenberg-Kreuz, Juliana, Jensen, Janicke, Johnsen, Svein, Jonsson, Malin, Kvarnström, Marika, Kelly, Jennifer, Li, He, Mandl, Thomas, Martín, Javier, Nocturne, Gaétane, Norheim, Katrine, Palm, Øyvind, Skarstein, Kathrine, Stolarczyk, Anna, Taylor, Kimberly, Teruel, Maria, Theander, Elke, Venuturupalli, Swamy, Wallace, Daniel, Grundahl, Kiely, Hefner, Kimberly, Radfar, Lida, Lewis, David, Stone, Donald, Kaufman, C, Brennan, Michael, Guthridge, Joel, James, Judith, Scofield, R, Gaffney, Patrick, Criswell, Lindsey, Jonsson, Roland, Eriksson, Per, Bowman, Simon, Omdal, Roald, Rönnblom, Lars, Warner, Blake, Rischmueller, Maureen, Witte, Torsten, Farris, A, Mariette, Xavier, Alarcon-Riquelme, Marta, Shiboski, Caroline, Wahren-Herlenius, Marie, Ng, Wan-Fai, Sivils, Kathy, Adrianto, Indra, Nordmark, Gunnel, and Lessard, Christopher

Subjects
Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Sjogrens Syndrome
Abstract

Sjögrens disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögrens cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands.

Published
2022

2. Author Correction: Genome-wide association study identifies Sjögren’s risk loci with functional implications in immune and glandular cells

Author

Khatri, Bhuwan, Tessneer, Kandice L., Rasmussen, Astrid, Aghakhanian, Farhang, Reksten, Tove Ragna, Adler, Adam, Alevizos, Ilias, Anaya, Juan-Manuel, Aqrawi, Lara A., Baecklund, Eva, Brun, Johan G., Bucher, Sara Magnusson, Eloranta, Maija-Leena, Engelke, Fiona, Forsblad-d’Elia, Helena, Glenn, Stuart B., Hammenfors, Daniel, Imgenberg-Kreuz, Juliana, Jensen, Janicke Liaaen, Johnsen, Svein Joar Auglænd, Jonsson, Malin V., Kvarnström, Marika, Kelly, Jennifer A., Li, He, Mandl, Thomas, Martín, Javier, Nocturne, Gaétane, Norheim, Katrine Brække, Palm, Øyvind, Skarstein, Kathrine, Stolarczyk, Anna M., Taylor, Kimberly E., Teruel, Maria, Theander, Elke, Venuturupalli, Swamy, Wallace, Daniel J., Grundahl, Kiely M., Hefner, Kimberly S., Radfar, Lida, Lewis, David M., Stone, Donald U., Kaufman, C. Erick, Brennan, Michael T., Guthridge, Joel M., James, Judith A., Scofield, R. Hal, Gaffney, Patrick M., Criswell, Lindsey A., Jonsson, Roland, Eriksson, Per, Bowman, Simon J., Omdal, Roald, Rönnblom, Lars, Warner, Blake, Rischmueller, Maureen, Witte, Torsten, Farris, A. Darise, Mariette, Xavier, Alarcon-Riquelme, Marta E., Shiboski, Caroline H., Wahren-Herlenius, Marie, Ng, Wan-Fai, Sivils, Kathy L., Adrianto, Indra, Nordmark, Gunnel, and Lessard, Christopher J.

Published
2023
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3. Addressing the clinical unmet needs in primary Sjögren’s Syndrome through the sharing, harmonization and federated analysis of 21 European cohorts

Author

Pezoulas, Vasileios C., Goules, Andreas, Kalatzis, Fanis, Chatzis, Luke, Kourou, Konstantina D., Venetsanopoulou, Aliki, Exarchos, Themis P., Gandolfo, Saviana, Votis, Konstantinos, Zampeli, Evi, Burmeister, Jan, May, Thorsten, Marcelino Pérez, Manuel, Lishchuk, Iryna, Chondrogiannis, Thymios, Andronikou, Vassiliki, Varvarigou, Theodora, Filipovic, Nenad, Tsiknakis, Manolis, Baldini, Chiara, Bombardieri, Michele, Bootsma, Hendrika, Bowman, Simon J., Soyfoo, Muhammad Shahnawaz, Parisis, Dorian, Delporte, Christine, Devauchelle-Pensec, Valérie, Pers, Jacques-Olivier, Dörner, Thomas, Bartoloni, Elena, Gerli, Roberto, Giacomelli, Roberto, Jonsson, Roland, Ng, Wan-Fai, Priori, Roberta, Ramos-Casals, Manuel, Sivils, Kathy, Skopouli, Fotini, Torsten, Witte, A. G. van Roon, Joel, Xavier, Mariette, De Vita, Salvatore, Tzioufas, Athanasios G., and Fotiadis, Dimitrios I.

Published
2022
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4. Author Correction: Genome-wide association study identifies Sjögren’s risk loci with functional implications in immune and glandular cells

Author

Khatri, Bhuwan, Tessneer, Kandice L., Rasmussen, Astrid, Aghakhanian, Farhang, Reksten, Tove Ragna, Adler, Adam, Alevizos, Ilias, Anaya, Juan-Manuel, Aqrawi, Lara A., Baecklund, Eva, Brun, Johan G., Bucher, Sara Magnusson, Eloranta, Maija-Leena, Engelke, Fiona, Forsblad-d’Elia, Helena, Glenn, Stuart B., Hammenfors, Daniel, Imgenberg-Kreuz, Juliana, Jensen, Janicke Liaaen, Johnsen, Svein Joar Auglænd, Jonsson, Malin V., Kvarnström, Marika, Kelly, Jennifer A., Li, He, Mandl, Thomas, Martín, Javier, Nocturne, Gaétane, Norheim, Katrine Brække, Palm, Øyvind, Skarstein, Kathrine, Stolarczyk, Anna M., Taylor, Kimberly E., Teruel, Maria, Theander, Elke, Venuturupalli, Swamy, Wallace, Daniel J., Grundahl, Kiely M., Hefner, Kimberly S., Radfar, Lida, Lewis, David M., Stone, Donald U., Kaufman, C. Erick, Brennan, Michael T., Guthridge, Joel M., James, Judith A., Scofield, R. Hal, Gaffney, Patrick M., Criswell, Lindsey A., Jonsson, Roland, Eriksson, Per, Bowman, Simon J., Omdal, Roald, Rönnblom, Lars, Warner, Blake, Rischmueller, Maureen, Witte, Torsten, Farris, A. Darise, Mariette, Xavier, Alarcon-Riquelme, Marta E., Shiboski, Caroline H., Wahren-Herlenius, Marie, Ng, Wan-Fai, Sivils, Kathy L., Adrianto, Indra, Nordmark, Gunnel, and Lessard, Christopher J.

Published
2022
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7. The HLA region in ANCA-associated vasculitis : characterisation of genetic associations in a Scandinavian patient population

Author

Lundtoft, Christian, Knight, Ann, Meadows, Jennifer, Karlsson, Åsa, Rantapää-Dahlqvist, Solbritt, Berglin, Ewa, Palm, Øyvind, Haukeland, Hilde, Gunnarsson, Iva, Bruchfeld, Annette, Segelmark, Mårten, Ohlsson, Sophie, Mohammad, Aladdin J., Eriksson, Per, Söderkvist, Peter, Rönnblom, Lars, Omdal, Roald, Jonsson, Roland, Lindblad-Toh, Kerstin, Dahlqvist, Johanna, Lundtoft, Christian, Knight, Ann, Meadows, Jennifer, Karlsson, Åsa, Rantapää-Dahlqvist, Solbritt, Berglin, Ewa, Palm, Øyvind, Haukeland, Hilde, Gunnarsson, Iva, Bruchfeld, Annette, Segelmark, Mårten, Ohlsson, Sophie, Mohammad, Aladdin J., Eriksson, Per, Söderkvist, Peter, Rönnblom, Lars, Omdal, Roald, Jonsson, Roland, Lindblad-Toh, Kerstin, and Dahlqvist, Johanna

Abstract

Objective: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci in the human leucocyte antigen (HLA) region. While the association between MPO-AAV and HLA has been well characterised in East Asian populations where MPO-AAV is more common, studies in populations of European descent are limited. The aim of this study was to thoroughly characterise associations to the HLA region in Scandinavian patients with PR3-AAV as well as MPO-AAV. Methods: Genotypes of single-nucleotide polymorphisms (SNPs) located in the HLA region were extracted from a targeted exome-sequencing dataset comprising Scandinavian AAV cases and controls. Classical HLA alleles were called using xHLA. After quality control, association analyses were performed of a joint SNP/classical HLA allele dataset for cases with PR3-AAV (n=411) and MPO-AAV (n=162) versus controls (n=1595). Disease-associated genetic variants were analysed for association with organ involvement, age at diagnosis and relapse, respectively. Results: PR3-AAV was significantly associated with both HLA-DPB1*04:01 and rs1042335 at the HLA-DPB1 locus, also after stepwise conditional analysis. MPO-AAV was significantly associated with HLA-DRB1*04:04. Neither carriage of HLA-DPB1*04:01 alleles in PR3-AAV nor of HLA-DRB1*04:04 alleles in MPO-AAV were associated with organ involvement, age at diagnosis or relapse. Conclusions: The association to the HLA region was distinct in Scandinavian cases with MPO-AAV compared with cases of East Asian descent. In PR3-AAV, the two separate signals of association to the HLD-DPB1 region mediate potentially different functional effects.

Published
2024
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8. The IRF5–TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share

Author

Kottyan, Leah C, Zoller, Erin E, Bene, Jessica, Lu, Xiaoming, Kelly, Jennifer A, Rupert, Andrew M, Lessard, Christopher J, Vaughn, Samuel E, Marion, Miranda, Weirauch, Matthew T, Namjou, Bahram, Adler, Adam, Rasmussen, Astrid, Glenn, Stuart, Montgomery, Courtney G, Hirschfield, Gideon M, Xie, Gang, Coltescu, Catalina, Amos, Chris, Li, He, Ice, John A, Nath, Swapan K, Mariette, Xavier, Bowman, Simon, Rischmueller, Maureen, Lester, Sue, Brun, Johan G, Gøransson, Lasse G, Harboe, Erna, Omdal, Roald, Cunninghame-Graham, Deborah S, Vyse, Tim, Miceli-Richard, Corinne, Brennan, Michael T, Lessard, James A, Wahren-Herlenius, Marie, Kvarnström, Marika, Illei, Gabor G, Witte, Torsten, Jonsson, Roland, Eriksson, Per, Nordmark, Gunnel, Ng, Wan-Fai, Anaya, Juan-Manuel, Rhodus, Nelson L, Segal, Barbara M, Merrill, Joan T, James, Judith A, Guthridge, Joel M, Scofield, R Hal, Alarcon-Riquelme, Marta, Bae, Sang-Cheol, Boackle, Susan A, Criswell, Lindsey A, Gilkeson, Gary, Kamen, Diane L, Jacob, Chaim O, Kimberly, Robert, Brown, Elizabeth, Edberg, Jeffrey, Alarcón, Graciela S, Reveille, John D, Vilá, Luis M, Petri, Michelle, Ramsey-Goldman, Rosalind, Freedman, Barry I, Niewold, Timothy, Stevens, Anne M, Tsao, Betty P, Ying, Jun, Mayes, Maureen D, Gorlova, Olga Y, Wakeland, Ward, Radstake, Timothy, Martin, Ezequiel, Martin, Javier, Siminovitch, Katherine, Sivils, Kathy L Moser, Gaffney, Patrick M, Langefeld, Carl D, Harley, John B, and Kaufman, Kenneth M

Subjects
Biological Sciences, Genetics, Autoimmune Disease, Biotechnology, Lupus, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Autoimmune Diseases, Bayes Theorem, Case-Control Studies, Cohort Studies, DNA-Binding Proteins, Haplotypes, Humans, Interferon Regulatory Factors, Lupus Erythematosus, Systemic, Male, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, beta Karyopherins, UK Primary Sjögren's Syndrome Registry, Medical and Health Sciences, Genetics & Heredity
Abstract

Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.

Published
2015

9. NCR3/NKp30 Contributes to Pathogenesis in Primary Sjögren’s Syndrome

Author

Rusakiewicz, Sylvie, Nocturne, Gaetane, Lazure, Thierry, Semeraro, Michaela, Flament, Caroline, Caillat-Zucman, Sophie, Sène, Damien, Delahaye, Nicolas, Vivier, Eric, Chaba, Kariman, Poirier-Colame, Vichnou, Nordmark, Gunnel, Eloranta, Maija-Leena, Eriksson, Per, Theander, Elke, Forsblad-d’Elia, Helena, Omdal, Roald, Wahren-Herlenius, Marie, Jonsson, Roland, Rönnblom, Lars, Nititham, Joanne, Taylor, Kimberly E, Lessard, Christopher J, Sivils, Kathy L Moser, Gottenberg, Jacques-Eric, Criswell, Lindsey A, Miceli-Richard, Corinne, Zitvogel, Laurence, and Mariette, Xavier

Subjects
Autoimmune Disease, Rare Diseases, Genetics, Clinical Research, Digestive Diseases, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Adult, Aged, Cell Line, Cells, Cultured, Female, Genotype, Humans, Interferon-gamma, Male, Middle Aged, Natural Cytotoxicity Triggering Receptor 3, Polymorphism, Genetic, Reverse Transcriptase Polymerase Chain Reaction, Sjogren's Syndrome, Biological Sciences, Medical and Health Sciences
Abstract

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease characterized by a lymphocytic exocrinopathy. However, patients often have evidence of systemic autoimmunity, and they are at markedly increased risk for the development of non- Hodgkin's lymphoma. Similar to other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, although the precise etiology remains uncertain. NCR3/NKp30 is a natural killer (NK)-specific activating receptor regulating the cross talk between NK and dendritic cells and type II IFN secretion. We performed a case-control study of genetic polymorphisms of the NCR3/NKp30 gene and found that rs11575837 (G>A) residing in the promoter was associated with reduced gene transcription and function as well as protection to pSS. We also demonstrated that circulating levels of NCR3/NKp30 were significantly increased among pSS patients compared with controls and correlated with higher NCR3/NKp30 but not CD16-dependent IFN-γ secretion by NK cells. Excess accumulation of NK cells in minor salivary glands correlated with the severity of the exocrinopathy. B7H6, the ligand of NKp30, was expressed by salivary epithelial cells. These findings suggest that NK cells may promote an NKp30-dependent inflammatory state in salivary glands and that blockade of the B7H6/NKp30 axis could be clinically relevant in pSS.

Published
2013

10. Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland

Author

Wiley, Mandi M, primary, Khatri, Bhuwan, additional, Joachims, Michelle L, additional, Tessneer, Kandice L, additional, Stolarczyk, Anna M, additional, Rasmussen, Astrid, additional, Anaya, Juan-Manuel, additional, Aqrawi, Lara A, additional, Bae, Sang-Cheol, additional, Baecklund, Eva, additional, Bjork, Albin, additional, Brun, Johan G, additional, Bucher, Sara Magnusson, additional, Dand, Nick, additional, Eloranta, Maija-Leena, additional, Engelke, Fiona, additional, Forsblad-d'Elia, Helena, additional, Fugmann, Cecilia, additional, Glenn, Stuart B, additional, Gong, Chen, additional, Gottenberg, Jacques-Eric, additional, Hammenfors, Daniel, additional, Imgenberg-Kreuz, Juliana, additional, Jensen, Janicke Liaaen, additional, Johnsen, Svein Joar Auglaend, additional, Jonsson, Malin V, additional, Kelly, Jennifer A, additional, Khanam, Sharmily, additional, Kim, Kwangwoo, additional, Kvarnstrom, Marika, additional, Mandl, Thomas, additional, Martin, Javier, additional, Morris, David L, additional, Nocturne, Gaetane, additional, Norheim, Katrine Braekke, additional, Olsson, Peter, additional, Palm, Oyvind, additional, Pers, Jacques-Olivier, additional, Rhodus, Nelson L, additional, Sjowall, Christopher, additional, Skarstein, Kathrine, additional, Taylor, Kimberly E, additional, Tombleson, Phil, additional, Thorlacius, Gudny Ella, additional, Venuturupalli, Swamy, additional, Vital, Edward M, additional, Wallace, Daniel J., additional, Grundahl, Kiely M, additional, Radfar, Lida, additional, Brennan, Michael T, additional, James, Judith A, additional, Scofield, R. Hal, additional, Gaffney, Patrick M, additional, Criswell, Lindsey A, additional, Jonsson, Roland, additional, Appel, Silke, additional, Eriksson, Per, additional, Bowman, Simon J, additional, Omdal, Roald, additional, Ronnblom, Lars, additional, Warner, Blake M., additional, Rischmueller, Maureen, additional, Witte, Torsten, additional, Farris, A. Darise, additional, Mariette, Xavier, additional, Shiboski, Caroline H, additional, Wahren-Herlenius, Marie, additional, Alarcon-Riquelme, Marta E, additional, Ng, Wan-Fai, additional, Sivils, Kathy L., additional, Guthridge, Joel M, additional, Adrianto, Indra, additional, Vyse, Timothy J, additional, Tsao, Betty P, additional, Nordmark, Gunnel, additional, and Lessard, Christopher J, additional

Published
2023
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14. Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome

Author

Harris, Valerie M., Sharma, Rohan, Cavett, Joshua, Kurien, Biji T., Liu, Ke, Koelsch, Kristi A., Rasmussen, Astrid, Radfar, Lida, Lewis, David, Stone, Donald U., Kaufman, C. Erick, Li, Shibo, Segal, Barbara, Wallace, Daniel J., Weisman, Michael H., Venuturupalli, Swamy, Kelly, Jennifer A., Alarcon-Riquelme, Marta E., Pons-Estel, Bernardo, Jonsson, Roland, Lu, Xianglan, Gottenberg, Jacques-Eric, Anaya, Juan-Manuel, Cunninghame-Graham, Deborah S., Huang, Andrew J.W., Brennan, Michael T., Hughes, Pamela, Alevizos, Ilias, Miceli-Richard, Corinne, Keystone, Edward C., Bykerk, Vivian P., Hirschfield, Gideon, Xie, Gang, Ng, Wan-Fai, Nordmark, Gunnel, Bucher, Sara Magnusson, Eriksson, Per, Omdal, Roald, Rhodus, Nelson L., Rischmueller, Maureen, Rohrer, Michael, Wahren-Herlenius, Marie, Witte, Torsten, Mariette, Xavier, Lessard, Christopher J., Harley, John B., Sivils, Kathy L., and Scofield, R. Hal

Published
2016
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15. Stratified genetic analysis reveals sex differences in MPO-ANCA-associated vasculitis

Author

Ekman, Diana, Sennblad, Bengt, Knight, Ann, Karlsson, Åsa, Rantapää-Dahlqvist, Solbritt, Berglin, Ewa, Stegmayr, Bernd, Baslund, Bo, Palm, Øyvind, Haukeland, Hilde, Gunnarsson, Iva, Bruchfeld, Annette, Segelmark, Mårten, Ohlsson, Sophie, Mohammad, Aladdin J, Svärd, Anna, Pullerits, Rille, Herlitz, Hans, Söderbergh, Annika, Omdal, Roald, Jonsson, Roland, Rönnblom, Lars, Eriksson, Per, Lindblad-Toh, Kerstin, Dahlqvist, Johanna, Ekman, Diana, Sennblad, Bengt, Knight, Ann, Karlsson, Åsa, Rantapää-Dahlqvist, Solbritt, Berglin, Ewa, Stegmayr, Bernd, Baslund, Bo, Palm, Øyvind, Haukeland, Hilde, Gunnarsson, Iva, Bruchfeld, Annette, Segelmark, Mårten, Ohlsson, Sophie, Mohammad, Aladdin J, Svärd, Anna, Pullerits, Rille, Herlitz, Hans, Söderbergh, Annika, Omdal, Roald, Jonsson, Roland, Rönnblom, Lars, Eriksson, Per, Lindblad-Toh, Kerstin, and Dahlqvist, Johanna

Abstract

Objective: To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype. Methods: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems. Results: rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 x 10(-4), OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619. Conclusions: Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.

Published
2023
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16. Identification of new candidate drugs for primary Sjögren's syndrome using a drug repurposing transcriptomic approach.

Author

Felten, Renaud, Ye, Tao, Schleiss, Cedric, Schwikowski, Benno, Sibilia, Jean, Monneaux, Fanny, Dumortier, Hélène, Jonsson, Roland, Lessard, Christopher, Ng, Fai, Takeuchi, Tsutomu, Mariette, Xavier, and Gottenberg, Jacques-Eric

Subjects
PHOSPHOTRANSFERASES, INTERFERONS, GENE expression profiling, INFORMATION resources, RESEARCH funding, SJOGREN'S syndrome, HISTONE deacetylase, LONGITUDINAL method
Abstract

Objectives To date, no immunomodulatory drug has demonstrated its efficacy in primary SS (pSS). We sought to analyse potential commonalities between pSS transcriptomic signatures and signatures of various drugs or specific knock-in or knock-down genes. Methods Gene expression from peripheral blood samples of patients with pSS was compared with that of healthy controls in two cohorts and three public databases. In each of the five datasets, we analysed the 150 most up- and downregulated genes between pSS patients and controls with regard to the differentially expressed genes resulting from the biological action on nine cell lines of 2837 drugs, 2160 knock-in and 3799 knock-down genes in the Connectivity Map database. Results We analysed 1008 peripheral blood transcriptomes from five independent studies (868 patients with pSS and 140 healthy controls). Eleven drugs could represent potential candidate drugs, with histone deacetylases and PI3K inhibitors among the most significantly associated. Twelve knock-in genes were associated with a pSS-like profile and 23 knock-down genes were associated with a pSS-revert profile. Most of those genes (28/35, 80%) were interferon-regulated. Conclusion This first drug repositioning transcriptomic approach in SS confirms the interest of targeting interferons and identifies histone deacetylases and PI3K inhibitors as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Published
2023
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17. Stratified genetic analysis reveals sex differences in MPO-ANCA-associated vasculitis

Author

Ekman, Diana, primary, Sennblad, Bengt, additional, Knight, Ann, additional, Karlsson, Åsa, additional, Rantapää-Dahlqvist, Solbritt, additional, Berglin, Ewa, additional, Stegmayr, Bernd, additional, Baslund, Bo, additional, Palm, Øyvind, additional, Haukeland, Hilde, additional, Gunnarsson, Iva, additional, Bruchfeld, Annette, additional, Segelmark, Mårten, additional, Ohlsson, Sophie, additional, Mohammad, Aladdin J, additional, Svärd, Anna, additional, Pullerits, Rille, additional, Herlitz, Hans, additional, Söderbergh, Annika, additional, Omdal, Roald, additional, Jonsson, Roland, additional, Rönnblom, Lars, additional, Eriksson, Per, additional, Lindblad-Toh, Kerstin, additional, and Dahlqvist, Johanna, additional

Published
2023
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24. Variability of Primary Sjögren's Syndrome Is Driven by Interferon α and Interferon α Blood Levels Are Associated With the Class II HLA–DQ Locus

Author

Trutschel, Diana, Bost, Pierre, Mariette, Xavier, Bondet, Vincent, Llibre, Alba, Posseme, Celine, Charbit, Bruno, Thorball, Christian W., Jonsson, Roland, Lessard, Christopher J., Felten, Renaud, Ng, Wan Fai, Chatenoud, Lucienne, Dumortier, Hélène, Sibilia, Jean, Fellay, Jacques, Brokstad, Karl A., Appel, Silke, Tarn, Jessica R., Quintana‐Murci, Lluis, Mingueneau, Michael, Meyer, Nicolas, Duffy, Darragh, Schwikowski, Benno, Gottenberg, Jacques Eric, Dernis, Emmanuelle, Devauchelle‐Pensec, Valerie, Dieude, Philippe, Dubost, Jean‐Jacques, Fauchais, Anne‐Laure, Goeb, Vincent, Hachulla, Eric, Hatron, Pierre Yves, Larroche, Claire, Le Guern, Véronique, Morel, Jacques, Perdriger, Aleth, Salliot, Carinne, Rist, Stephanie, Saraux, Alain, Vittecoq, Olivier, Nocturne, Gaétane, Ravaud, Philippe, Seror, Raphaèle, Abel, Laurent, Alcover, Andres, Aschard, Hugues, Astrom, Kalla, Bousso, Philippe, Bruhns, Pierre, Cumano, Ana, Demangel, Caroline, Deriano, Ludovic, Di Santo, James, Dromer, Françoise, Eberl, Gérard, Enninga, Jost, Gelpi, Odile, GompertsBoneca, Ivo, Hasan, Milena, Hercberg, Serge, Lantz, Olivier, Leclerc, Claude, Mouquet, Hugo, Pellegrini, Sandra, Pol, Stanislas, Rausell, Antonio, Rogge, Lars, Sakuntabhai, Anavaj, Schwartz, Olivier, Shorte, Spencer, Soumelis, Vassili, Tangy, Frédéric, Tartour, Eric, Toubert, Antoine, Touvier, Mathilde, Ungeheuer, Marie‐Noëlle, Albert, Matthew L., Biomédecine computationelle des systèmes / Computational systems biomedicine, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Universität Zürich [Zürich] = University of Zurich (UZH), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Service de Rhumatologie [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Projet NECESSITY (PN), Hôpitaux Universitaires Paris Sud [AP-HP] (HUPS)-Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Immunologie Translationnelle - Translational Immunology lab, Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Ecole Polytechnique Fédérale de Lausanne (EPFL), Université de Lausanne = University of Lausanne (UNIL), Lausanne University Hospital, University of Bergen (UiB), Oklahoma Medical Research Foundation (OMRF), University of Oklahoma Health Sciences Center (OUHSC), Université de Strasbourg (UNISTRA), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Immunologie, Immunopathologie et Chimie Thérapeutique (I2CT), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Biogen Inc. [Cambridge, MA, USA], Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Supported by the Innovative Medicines Initiative 2 Joint Undertaking (JU) (grant 806975). The JU receives support from the European Union’s Horizon 2020 research and innovation program and the European Unionand the European Federation of Pharmaceutical Industries and Associations. This work was also supported by the National Institutes of Health (National Institute of Arthritis and Musculoskeletal Skin Disease grant R01-AR-065953). The Assessment of Systemic Signs and Evolution in Sjögren’s Syndrome(ASSESS) national multicenter prospective cohort was formed in 2006 with aFrench Ministry of Health grant (Programme Hospitalier de Recherche Clinique 2005 P060228). The ASSESS cohort is promoted by the French Society of Rheumatology and receives research grants from the French Society of Rheumatology. Dr. Gottenberg’s work was supported by Bristol Myers Squibbfor transcriptomic analysis of the ASSESS and Norwegian cohorts and by Geneviève Garnier (Association Française du Syndrome de Gougerot-Sjögrenet des syndromes secs). Drs. Trutschel’s and Schwikowski’s work was supported by Geneviève Garnier (Association Française du Syndrome de Gougerot-Sjögren et des syndromes secs)., Milieu Intérieur Consortium, ASSESS study investigators, and NECESSITY Consortium: Emmanuelle Dernis, Valerie Devauchelle-Pensec, Philippe Dieude, Jean-Jacques Dubost, Anne-Laure Fauchais, Vincent Goeb, Eric Hachulla, Pierre Yves Hatron, Claire Larroche, Véronique Le Guern, Jacques Morel, Aleth Perdriger, Carinne Salliot, Stephanie Rist, Alain Saraux, Jean Sibilia, Olivier Vittecoq, Gaétane Nocturne, Philippe Ravaud, Raphaèle Seror, Laurent Abel, Andres Alcover, Hugues Aschard, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Odile Gelpi, Ivo GompertsBoneca, Milena Hasan, Serge Hercberg, Olivier Lantz, Claude Leclerc, Hugo Mouquet, Sandra Pellegrini, Stanislas Pol, Antonio Rausell, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis, Frédéric Tangy, Eric Tartour, Antoine Toubert, Mathilde Touvier, Marie-Noëlle Ungeheuer, Matthew L Albert, Darragh Duffy, Lluis Quintana-Murci., European Project: 806975,NECESSITY, Clauss, Isabelle, and NEw Clinical Endpoints in primary Sjögren’s Syndrome: an Interventional Trial based on stratifYing patients - NECESSITY - 0000-00-00 - 0000-00-00 - 806975 - VALID

Subjects
Proteomics, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Sjogren's Syndrome, Rheumatology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, HLA-DQ Antigens, Immunology, Humans, Interferon-alpha, Immunology and Allergy, Prospective Studies
Abstract

Objective: Primary Sjögren's syndrome (SS) is the second most frequent systemic autoimmune disease, affecting 0.1% of the general population. To characterize the molecular and clinical variabilities among patients with primary SS, we integrated transcriptomic, proteomic, cellular, and genetic data with clinical phenotypes in a cohort of 351 patients with primary SS. Methods: We analyzed blood transcriptomes and genotypes of 351 patients with primary SS who were participants in a multicenter prospective clinical cohort. We replicated the transcriptome analysis in 3 independent cohorts (n = 462 patients). We determined circulating interferon-α (IFNα) and IFNγ protein concentrations using digital single molecular arrays (Simoa). Results: Transcriptome analysis of the prospective cohort showed a strong IFN gene signature in more than half of the patients; this finding was replicated in the 3 independent cohorts. Because gene expression analysis did not discriminate between type I IFN and type II IFN, we used Simoa to demonstrate that the IFN transcriptomic signature was driven by circulating IFNα and not by IFNγ protein levels. IFNα protein levels, detectable in 75% of patients, were significantly associated with clinical and immunologic features of primary SS disease activity at enrollment and with increased frequency of systemic complications over the 5-year follow-up. Genetic analysis revealed a significant association between IFNα protein levels, a major histocompatibility (MHC) class II haplotype, and anti-SSA antibody. Additional cellular analysis revealed that an MHC class II HLA–DQ locus acts through up-regulation of HLA class II molecules on conventional dendritic cells. Conclusion: We identified the predominance of IFNα as a driver of primary SS variability, with IFNα demonstrating an association with HLA gene polymorphisms., Arthritis & Rheumatology, 74 (12), ISSN:2326-5191, ISSN:2326-5205

Published
2022
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25. Brief Report: Rare X Chromosome Abnormalities in Systemic Lupus Erythematosus and Sjögrenʼs Syndrome

Author

Sharma, Rohan, Harris, Valerie M., Cavett, Joshua, Kurien, Biji T., Liu, Ke, Koelsch, Kristi A., Fayaaz, Anum, Chaudhari, Kaustubh S., Radfar, Lida, Lewis, David, Stone, Donald U., Kaufman, C. Erick, Li, Shibo, Segal, Barbara, Wallace, Daniel J., Weisman, Michael H., Venuturupalli, Swamy, Kelly, Jennifer A., Pons‐Estel, Bernardo, Jonsson, Roland, Lu, Xianglan, Gottenberg, Jacques‐Eric, Anaya, Juan‐Manuel, Cunninghame‐Graham, Deborah S., Huang, Andrew J. W., Brennan, Michael T., Hughes, Pamela, Alevizos, Ilias, Miceli‐Richard, Corinne, Keystone, Edward C., Bykerk, Vivian P., Hirschfield, Gideon, Nordmark, Gunnel, Bucher, Sara Magnusson, Eriksson, Per, Omdal, Roald, Rhodus, Nelson L., Rischmueller, Maureen, Rohrer, Michael, Wahren‐Herlenius, Marie, Witte, Torsten, Alarcón‐Riquelme, Marta, Mariette, Xavier, Lessard, Christopher J., Harley, John B., Ng, Wan‐Fai, Rasmussen, Astrid, Sivils, Kathy L., and Scofield, R. Hal

Published
2017
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26. H1N1 vaccination in Sjögren’s syndrome triggers polyclonal B cell activation and promotes autoantibody production

Author

Brauner, Susanna, Folkersen, Lasse, Kvarnström, Marika, Meisgen, Sabrina, Petersen, Sven, Franzén-Malmros, Michaela, Mofors, Johannes, Brokstad, Karl A, Klareskog, Lars, Jonsson, Roland, Westerberg, Lisa S, Trollmo, Christina, Malmström, Vivianne, Ambrosi, Aurelie, Kuchroo, Vijay K, Nordmark, Gunnel, and Wahren-Herlenius, Marie

Published
2017
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29. Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA

Author

Dahlqvist, Johanna, Ekman, Diana, Sennblad, Bengt, Kozyrev, Sergey V, Nordin, Jessika, Karlsson, Åsa, Meadows, Jennifer R. S., Hellbacher, Erik, Rantapää-Dahlqvist, Solbritt, Berglin, Ewa, Stegmayr, Bernd, Baslund, Bo, Palm, Oyvind, Haukeland, Hilde, Gunnarsson, Iva, Bruchfeld, Annette, Segelmark, Mårten, Ohlsson, Sophie, Mohammad, Aladdin J., Svärd, Anna, Pullerits, Rille, Herlitz, Hans, Söderbergh, Annika, Pielberg, Gerli Rosengren, Rosenberg, Lina Hultin, Bianchi, Matteo, Murén, Eva, Omdal, Roald, Jonsson, Roland, Eloranta, Maija-Leena, Rönnblom, Lars, Söderkvist, Peter, Knight, Ann, Eriksson, Per, Lindblad-Toh, Kerstin, Dahlqvist, Johanna, Ekman, Diana, Sennblad, Bengt, Kozyrev, Sergey V, Nordin, Jessika, Karlsson, Åsa, Meadows, Jennifer R. S., Hellbacher, Erik, Rantapää-Dahlqvist, Solbritt, Berglin, Ewa, Stegmayr, Bernd, Baslund, Bo, Palm, Oyvind, Haukeland, Hilde, Gunnarsson, Iva, Bruchfeld, Annette, Segelmark, Mårten, Ohlsson, Sophie, Mohammad, Aladdin J., Svärd, Anna, Pullerits, Rille, Herlitz, Hans, Söderbergh, Annika, Pielberg, Gerli Rosengren, Rosenberg, Lina Hultin, Bianchi, Matteo, Murén, Eva, Omdal, Roald, Jonsson, Roland, Eloranta, Maija-Leena, Rönnblom, Lars, Söderkvist, Peter, Knight, Ann, Eriksson, Per, and Lindblad-Toh, Kerstin

Abstract

Objective To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). Methods Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. Results PR3-ANCA+ AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 x 10-61, odds ratio (OR) 0.10; rs9277341, P = 1.5 x 10-44, OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 x 10-10, OR 2.9). MPO-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 x 10-25, OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 x 10-7, OR 3.0), the latter a novel susceptibility locus for MPO-ANCA+ granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. Conclusion We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types., Funding Agencies: Swedish Society for Medical Research; Swedish Research Council; Swedish Society of Medicine; Swedish Rheumatism Association; Knut and Alice Wallenberg Foundation; AstraZeneca-Science for Life Laboratory (SciLifeLab) Research Collaboration Grant

Published
2022
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30. Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases

Author

Lundtoft, Christian, Pucholt, Pascal, Martin, Myriam, Bianchi, Matteo, Lundstrom, Emeli, Eloranta, Maija-Leena, Sandling, Johanna K., Sjöwall, Christopher, Jonsen, Andreas, Gunnarsson, Iva, Rantapaa-Dahlqvist, Solbritt, Bengtsson, Anders A., Leonard, Dag, Baecklund, Eva, Jonsson, Roland, Hammenfors, Daniel, Forsblad-dElia, Helena, Eriksson, Per, Mandl, Thomas, Bucher, Sara Magnusson, Norheim, Katrine B., Johnsen, Svein Joar Auglaend, Omdal, Roald, Kvarnstrom, Marika, Wahren-Herlenius, Marie, Notarnicola, Antonella, Andersson, Helena, Molberg, Oyvind, Diederichsen, Louise Pyndt, Almlof, Jonas, Syvanen, Ann-Christine, Kozyrev, Sergey V, Lindblad-Toh, Kerstin, Nilsson, Bo, Blom, Anna M., Lundberg, Ingrid E., Nordmark, Gunnel, Diaz-Gallo, Lina Marcela, Svenungsson, Elisabet, Ronnblom, Lars, Lundtoft, Christian, Pucholt, Pascal, Martin, Myriam, Bianchi, Matteo, Lundstrom, Emeli, Eloranta, Maija-Leena, Sandling, Johanna K., Sjöwall, Christopher, Jonsen, Andreas, Gunnarsson, Iva, Rantapaa-Dahlqvist, Solbritt, Bengtsson, Anders A., Leonard, Dag, Baecklund, Eva, Jonsson, Roland, Hammenfors, Daniel, Forsblad-dElia, Helena, Eriksson, Per, Mandl, Thomas, Bucher, Sara Magnusson, Norheim, Katrine B., Johnsen, Svein Joar Auglaend, Omdal, Roald, Kvarnstrom, Marika, Wahren-Herlenius, Marie, Notarnicola, Antonella, Andersson, Helena, Molberg, Oyvind, Diederichsen, Louise Pyndt, Almlof, Jonas, Syvanen, Ann-Christine, Kozyrev, Sergey V, Lindblad-Toh, Kerstin, Nilsson, Bo, Blom, Anna M., Lundberg, Ingrid E., Nordmark, Gunnel, Diaz-Gallo, Lina Marcela, Svenungsson, Elisabet, and Ronnblom, Lars

Abstract

Objective Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to investigate whether C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjogrens syndrome (SS), or myositis. Methods Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterized Scandinavian patients with SLE, primary SS, or myositis and 1,251 healthy controls. Results A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the 3 diseases. The strongest association was detected in patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (odds ratio [OR] 18.0 [95% confidence interval (95% CI) 10.2-33.3]), whereas a weaker association was seen in patients without SSA/SSB autoantibodies (OR 3.1 [95% CI 1.7-5.5]). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss-of-function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A. Functionally, we showed that absence of C4A reduced the individuals capacity to deposit C4b on immune complexes. Conclusion We show that a low C4A copy number is more strongly associated with the autoantibody repertoire than with the clinically defined disease entities. These findings may have implications for understanding the etiopathogenetic mechanisms of systemic inflammatory autoimmune diseases and for patient stratification when taking the genetic profile into account., Funding Agencies|Swedish Research Council for Medicine and Health; Swedish Rheumatism Association; Swedish Society of Medicine; Swedish Heart Lung Foundation; Stockholm County; Karolinska Institutet; Wallenberg Scholarship; King Gustav Vs 80-Year Foundation

Published
2022
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31. Strong Association of Combined Genetic Deficiencies in the Classical Complement Pathway With Risk of Systemic Lupus Erythematosus and Primary Sjögren's Syndrome

Author

Lundtoft, Christian, Sjöwall, Christopher, Rantapää‐Dahlqvist, Solbritt, Bengtsson, Anders A., Jönsen, Andreas, Pucholt, Pascal, Wu, Yee Ling, Lundström, Emeli, Eloranta, Maija-Leena, Gunnarsson, Iva, Baecklund, Eva, Jonsson, Roland, Hammenfors, Daniel, Forsblad‐d'Elia, Helena, Eriksson, Per, Mandl, Thomas, Bucher, Sara, Norheim, Katrine B., Auglaend Johnsen, Svein Joar, Omdal, Roald, Kvarnström, Marika, Wahren‐Herlenius, Marie, Truedsson, Lennart, Nilsson, Bo, Kozyrev, Sergey V., Bianchi, Matteo, Lindblad‐Toh, Kerstin, Yu, Chack‐Yung, Nordmark, Gunnel, Sandling, Johanna K., Svenungsson, Elisabet, Leonard, Dag, Rönnblom, Lars, Lundtoft, Christian, Sjöwall, Christopher, Rantapää‐Dahlqvist, Solbritt, Bengtsson, Anders A., Jönsen, Andreas, Pucholt, Pascal, Wu, Yee Ling, Lundström, Emeli, Eloranta, Maija-Leena, Gunnarsson, Iva, Baecklund, Eva, Jonsson, Roland, Hammenfors, Daniel, Forsblad‐d'Elia, Helena, Eriksson, Per, Mandl, Thomas, Bucher, Sara, Norheim, Katrine B., Auglaend Johnsen, Svein Joar, Omdal, Roald, Kvarnström, Marika, Wahren‐Herlenius, Marie, Truedsson, Lennart, Nilsson, Bo, Kozyrev, Sergey V., Bianchi, Matteo, Lindblad‐Toh, Kerstin, Yu, Chack‐Yung, Nordmark, Gunnel, Sandling, Johanna K., Svenungsson, Elisabet, Leonard, Dag, and Rönnblom, Lars

Abstract

Objective: Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjögren's syndrome (SS) has not been studied systematically. This study was undertaken to investigate potential associations of heterozygous C2 deficiency and C4 copy number variation with clinical manifestations in patients with SLE and patients with primary SS. Methods: The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients who had received a diagnosis of SLE (n = 958) or primary SS (n = 911) and in 2,262 healthy controls through the use of DNA sequencing. The concentration of complement proteins in plasma and classical complement function were analyzed in a subgroup of SLE patients. Results: Heterozygous C2 deficiency—when present in combination with a low C4A copy number—substantially increased the risk of SLE (odds ratio [OR] 10.2 [95% confidence interval (95% CI) 3.5–37.0]) and the risk of primary SS (OR 13.0 [95% CI 4.5–48.4]) when compared to individuals with 2 C4A copies and normal C2. For patients heterozygous for rs9332736 with 1 C4A copy, the median age at diagnosis was 7 years earlier in patients with SLE and 12 years earlier in patients with primary SS when compared to patients with normal C2. Reduced C2 levels in plasma (P = 2 × 10−9) and impaired function of the classical complement pathway (P = 0.03) were detected in SLE patients with heterozygous C2 deficiency. Finally, in a primary SS patient homozygous for C2 deficiency, we observed low levels of anti–Scl-70, which suggests a risk of developing systemic sclerosis or potential overlap between primary SS and other systemic autoimmune diseases. Coclusions: We demonstrate that a genetic pattern involving partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and for primary

Published
2022
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32. Vatten- och avloppsinstallationer : en kunskapssammanställning

Author

Johansson, Bengt, Jonsson, Roland, Kling, Rolf, Persson, Mats, Johansson, Bengt, Jonsson, Roland, Kling, Rolf, and Persson, Mats

Abstract

Denna kunskapssammanställning om vatten- och avloppsinstallationer i Sverige kan ge en bred och korrekt förståelse om branschens aktörer, vilka regler som tillämpas, var det finns kunskap och vilka utvecklingsbehov som behöver stödjas. Några viktiga punkter är: Legionella – finns i tappvattensystem och orsakar ohälsa. Begränsning av risker behöver utredas vidare inte mot bakgrund av risker med förväntade högre temperaturer och önskemål om att ta fram system för med lägre energiförbrukning för varmvatten. Risk för legionella i kallvatten finns också. Utformning och placering av rörkopplingar – har stor betydelse för beständighet hos installationer och möjlighet att upptäcka och hantera läckage. Regler och vägledningar som utvecklats över tid har möjliggjort den goda standarden på vatten- och avloppsinstallationer vi har idag. Dimensionering av system – komponenter och flöden samverkar i samma system. Därför finns risker om en komponent eller ett delsystem optimeras av något skäl utan att konsekvenserna för hela förstås. Spillvattensystem är t.ex. beroende av flöden för tappdricksvatten. Det är viktigt att ta med sig förvärvade kunskaper och lärdomar för att undvika problem som tidigare visats sig vara kostsamma. Det gäller i synnerhet för system som installeras dolt, och som förväntas ha en livslängd på flera decennier. Ett regelverk som tar hänsyn till de problem som har lösts genom åren, och som ger goda förutsättningar att förebygga framtida problem, kommer att gynna den som bor eller vistas i byggnaden, den som äger byggnaden, den som bygger eller installerar, den som levererar byggprodukterna och den som försäkrar byggnaden. Det är även bra ur ett hållbarhetsperspektiv, eftersom lång problemfri livslängd oftast minskar miljöbelastningen.

Published
2022

33. Author Correction: Genome-wide association study identifies Sjogrens risk loci with functional implications in immune and glandular cells (vol 13, 4287, 2022)

Author

Khatri, Bhuwan, Tessneer, Kandice L., Rasmussen, Astrid, Aghakhanian, Farhang, Reksten, Tove Ragna, Adler, Adam, Alevizos, Ilias, Anaya, Juan-Manuel, Aqrawi, Lara A., Baecklund, Eva, Brun, Johan G., Bucher, Sara Magnusson, Eloranta, Maija-Leena, Engelke, Fiona, Forsblad-dElia, Helena, Glenn, Stuart B., Hammenfors, Daniel, Imgenberg-Kreuz, Juliana, Jensen, Janicke Liaaen, Johnsen, Svein Joar Auglaend, Jonsson, Malin V., Kvarnstrom, Marika, Kelly, Jennifer A., Li, He, Mandl, Thomas, Martin, Javier, Nocturne, Gaetane, Norheim, Katrine Braekke, Palm, Oyvind, Skarstein, Kathrine, Stolarczyk, Anna M., Taylor, Kimberly E., Teruel, Maria, Theander, Elke, Venuturupalli, Swamy, Wallace, Daniel J., Grundahl, Kiely M., Hefner, Kimberly S., Radfar, Lida, Lewis, David M., Stone, Donald U., Kaufman, C. Erick, Brennan, Michael T., Guthridge, Joel M., James, Judith A., Scofield, R. Hal, Gaffney, Patrick M., Criswell, Lindsey A., Jonsson, Roland, Eriksson, Per, Bowman, Simon J., Omdal, Roald, Ronnblom, Lars, Warner, Blake, Rischmueller, Maureen, Witte, Torsten, Farris, A. Darise, Mariette, Xavier, Alarcon-Riquelme, Marta E., Shiboski, Caroline H., Wahren-Herlenius, Marie, Ng, Wan-Fai, Sivils, Kathy L., Adrianto, Indra, Nordmark, Gunnel, Lessard, Christopher J., Khatri, Bhuwan, Tessneer, Kandice L., Rasmussen, Astrid, Aghakhanian, Farhang, Reksten, Tove Ragna, Adler, Adam, Alevizos, Ilias, Anaya, Juan-Manuel, Aqrawi, Lara A., Baecklund, Eva, Brun, Johan G., Bucher, Sara Magnusson, Eloranta, Maija-Leena, Engelke, Fiona, Forsblad-dElia, Helena, Glenn, Stuart B., Hammenfors, Daniel, Imgenberg-Kreuz, Juliana, Jensen, Janicke Liaaen, Johnsen, Svein Joar Auglaend, Jonsson, Malin V., Kvarnstrom, Marika, Kelly, Jennifer A., Li, He, Mandl, Thomas, Martin, Javier, Nocturne, Gaetane, Norheim, Katrine Braekke, Palm, Oyvind, Skarstein, Kathrine, Stolarczyk, Anna M., Taylor, Kimberly E., Teruel, Maria, Theander, Elke, Venuturupalli, Swamy, Wallace, Daniel J., Grundahl, Kiely M., Hefner, Kimberly S., Radfar, Lida, Lewis, David M., Stone, Donald U., Kaufman, C. Erick, Brennan, Michael T., Guthridge, Joel M., James, Judith A., Scofield, R. Hal, Gaffney, Patrick M., Criswell, Lindsey A., Jonsson, Roland, Eriksson, Per, Bowman, Simon J., Omdal, Roald, Ronnblom, Lars, Warner, Blake, Rischmueller, Maureen, Witte, Torsten, Farris, A. Darise, Mariette, Xavier, Alarcon-Riquelme, Marta E., Shiboski, Caroline H., Wahren-Herlenius, Marie, Ng, Wan-Fai, Sivils, Kathy L., Adrianto, Indra, Nordmark, Gunnel, and Lessard, Christopher J.

Published
2022
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37. Additional file 1 of Impaired activation of STAT5 upon IL-2 stimulation in Tregs and elevated sIL-2R in Sjögren’s syndrome

Author

Keindl, Magdalena, Davies, Richard, Bergum, Brith, Brun, Johan G., Hammenfors, Daniel, Jonsson, Roland, Lyssenko, Valeriya, and Appel, Silke

Abstract

Additional file 1: Table S1. Fluorescently labelled antibodies and amine dyes used for phospho-flow cytometry. Figure S1. Representative gating strategy used in the analysis of phosphorylation of STAT5 in PBMCs. Lymphocytes were gated based on their forward scatter area (FSC-A) and side scatter area (SSC-A) properties, followed by singlet gating based on SSC-A and side scatter height (SSC-H). Subsequently, CD3+ CD4+ T cells were gated. The different samples were then identified through the intensities of their Alexa Fluor 488, Pacific Blue and Pacific Orange staining (barcoding). One representative sample is shown to display further gating steps. Tregs and Tconv were identified based on their surface antigen presentation (Tregs: CD25+ CD127- , Tconv: CD25- ). Finally, cells with phosphorylated STAT5 at position Y964 were gated in Tregs and Tconv. Figure S2. (A) In the non-severe Sjögren’s syndrome (SS) group seropositive patients had significantly higher sIL-2R compared with seronegative patients. (B) A histogram of the saliva weight (ml/5 min) produced by patients with Sjögren’s syndrome after paraffin stimulation. The vertical dashed line shows the cut-off at 3.5 ml/5 min which we used to split between patients with severe and non-severe phenotype. (Mann-Whitney U test was used in the comparison between the different groups. *p≤0.05, **p≤0.01, ***p≤0.001, and ***p≤ 0.0001.). Figure S3. The selected 51 individuals for the phospho-flow cytometry analysis are representative of the whole cohort and display significantly higher sIL-2R in patients with Sjögren’s syndrome (SS) (A), particularly those with low saliva production (B). (Mann-Whitney U test was used in the comparison between the different groups. *p ≤0.05, **p≤0.01, ***p≤0.001, and ***p≤0.0001). Figure S4. Percentage of pSTAT5+ Tregs and their association with serology. (A) Seropositive patients with Sjögren’s syndrome had a significantly higher frequency of pSTAT5+ Tregs at baseline compared with seronegative patients (right panel), whereas no difference was observed in IL-2 stimulated Tregs (left panel). (B) The difference in pSTAT5+ Tregs between baseline and IL-2 stimulation was slightly lower in seropositive patients with Sjögren’s syndrome. (Mann-Whitney U test was used in the comparison between the different groups. *p≤ 0.05, **p≤0.01, ***p≤0.001, and ***p≤0.0001.). Figure S5. Frequency of pSTAT5+ Tregs and their association with plasma sIL-2R. (A) Higher plasma sIL-2R levels significantly associated with higher frequency of pSTAT5+ Tregs at baseline (right panel), whereas no correlation was observed in IL-2 stimulated Tregs (left panel). (B) The difference in pSTAT5+ Tregs between baseline and IL-2 stimulation did not correlate with sIL-2R (To evaluate the association between two variables we applied the Pearson correlation formula.).

Published
2022
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39. X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögrenʼs Syndrome

Author

Liu, Ke, Kurien, Biji T., Zimmerman, Sarah L., Kaufman, Kenneth M., Taft, Diana H., Kottyan, Leah C., Lazaro, Sara, Weaver, Carrie A., Ice, John A., Adler, Adam J., Chodosh, James, Radfar, Lida, Rasmussen, Astrid, Stone, Donald U., Lewis, David M., Li, Shibo, Koelsch, Kristi A., Igoe, Ann, Talsania, Mitali, Kumar, Jay, Maier-Moore, Jacen S., Harris, Valerie M., Gopalakrishnan, Rajaram, Jonsson, Roland, Lessard, James A., Lu, Xianglan, Gottenberg, Jacques-Eric, Anaya, Juan-Manuel, Cunninghame-Graham, Deborah S., Huang, Andrew J. W., Brennan, Michael T., Hughes, Pamela, Illei, Gabor G., Miceli-Richard, Corinne, Keystone, Edward C., Bykerk, Vivian P., Hirschfield, Gideon, Xie, Gang, Ng, Wan-Fai, Nordmark, Gunnel, Eriksson, Per, Omdal, Roald, Rhodus, Nelson L., Rischmueller, Maureen, Rohrer, Michael, Segal, Barbara M., Vyse, Timothy J., Wahren-Herlenius, Marie, Witte, Torsten, Pons-Estel, Bernardo, Alarcón-Riquelme, Marta E., Guthridge, Joel M., James, Judith A., Lessard, Christopher J., Kelly, Jennifer A., Thompson, Susan D., Gaffney, Patrick M., Montgomery, Courtney G., Edberg, Jeffrey C., Kimberly, Robert P., Alarcón, Graciela S., Langefeld, Carl L., Gilkeson, Gary S., Kamen, Diane L., Tsao, Betty P., McCune, Joseph W., Salmon, Jane E., Merrill, Joan T., Weisman, Michael H., Wallace, Daniel J., Utset, Tammy O., Bottinger, Erwin P., Amos, Christopher I., Siminovitch, Katherine A., Mariette, Xavier, Sivils, Kathy L., Harley, John B., and Scofield, Hal R.

Published
2016
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44. Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA

Author

Dahlqvist, Johanna, primary, Ekman, Diana, additional, Sennblad, Bengt, additional, Kozyrev, Sergey V, additional, Nordin, Jessika, additional, Karlsson, Åsa, additional, Meadows, Jennifer R S, additional, Hellbacher, Erik, additional, Rantapää-Dahlqvist, Solbritt, additional, Berglin, Ewa, additional, Stegmayr, Bernd, additional, Baslund, Bo, additional, Palm, Øyvind, additional, Haukeland, Hilde, additional, Gunnarsson, Iva, additional, Bruchfeld, Annette, additional, Segelmark, Mårten, additional, Ohlsson, Sophie, additional, Mohammad, Aladdin J, additional, Svärd, Anna, additional, Pullerits, Rille, additional, Herlitz, Hans, additional, Söderbergh, Annika, additional, Rosengren Pielberg, Gerli, additional, Hultin Rosenberg, Lina, additional, Bianchi, Matteo, additional, Murén, Eva, additional, Omdal, Roald, additional, Jonsson, Roland, additional, Eloranta, Maija-Leena, additional, Rönnblom, Lars, additional, Söderkvist, Peter, additional, Knight, Ann, additional, Eriksson, Per, additional, and Lindblad-Toh, Kerstin, additional

Published
2021
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45. Genetic variants at the RTP4/MASP1 locus are associated with fatigue in Scandinavian patients with primary Sjögren’s syndrome

Author

Norheim, Katrine Brække, primary, Imgenberg-Kreuz, Juliana, additional, Alexsson, Andrei, additional, Johnsen, Svein Joar Auglænd, additional, Bårdsen, Kjetil, additional, Brun, Johan Gorgas, additional, Dehkordi, Rezvan Kiani, additional, Theander, Elke, additional, Mandl, Thomas, additional, Jonsson, Roland, additional, Ng, Wan-Fai, additional, Lessard, Christopher J, additional, Rasmussen, Astrid, additional, Sivilis, Kathy, additional, Ronnblom, Lars, additional, and Omdal, Roald, additional

Published
2021
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48. Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome

Author

Thorlacius, Guðný Ella, Hultin-Rosenberg, Lina, Sandling, Johanna K., Bianchi, Matteo, Imgenberg-Kreuz, Juliana, Pucholt, Pascal, Theander, Elke, Kvarnström, Marika, Forsblad-D'elia, Helena, Bucher, Sara Magnusson, Norheim, Katrine B., Johnsen, Svein Joar Auglænd, Hammenfors, Daniel, Skarstein, Kathrine, Jonsson, Malin V., Baecklund, Eva, Aqrawi, Lara A., Jensen, Janicke Liaaen, Palm, Øyvind, Morris, Andrew P., Alexsson, Andrei, Backlin, Carin, Rönnblom, Lars, Vasaitis, Lilian, Eloranta, Maija Leena, Syvänen, Ann Christine, Mathioudaki, Argyri, Farias, Fabiana H.G., Meadows, Jennifer, Nordin, Jessika, Lindblad-Toh, Kerstin, Björk, Albin, Lundberg, Ingrid E., Sepúlveda, Jorge I.Ramírez, Wahren-Herlenius, Marie, Eriksson, Daniel, Eriksson, Per, Sjöwall, Christopher, Mandl, Thomas, Rantapaä¨-Dahlqvist, Solbritt, Brokstad, Karl A., Jonsson, Roland, Appel, Silke, Brun, Johan G., Norheim, Katrine Brække, Omdal, Roald, Aqrawi, Lara Adnan, Pielberg, Gerli Rosengren, Murén, Eva, Karlsson, Åsa, Andersson, Göran, Ahlgren, Kerstin M., Lobell, Anna, Söderkvist, Peter, Kämpe, Olle, Landegren, Nils, Meadows, Jennifer R.S., Lind, Lars, and Nordmark, Gunnel

Subjects
musculoskeletal diseases, stomatognathic diseases, stomatognathic system, gene polymorphism, autoantibodies, autoimmunity, Sjögren's syndrome, eye diseases
Abstract

Objectives: Clinical presentation of primary Sjögren's syndrome (pSS) varies considerably. A shortage of evidence-based objective markers hinders efficient drug development and most clinical trials have failed to reach primary endpoints. Methods: We performed a multicentre study to identify patient subgroups based on clinical, immunological and genetic features. Targeted DNA sequencing of 1853 autoimmune-related loci was performed. After quality control, 918 patients with pSS, 1264 controls and 107 045 single nucleotide variants remained for analysis. Replication was performed in 177 patients with pSS and 7672 controls. Results: We found strong signals of association with pSS in the HLA region. Principal component analysis of clinical data distinguished two patient subgroups defined by the presence of SSA/SSB antibodies. We observed an unprecedented high risk of pSS for an association in the HLA-DQA1 locus of odds ratio 6.10 (95% CI: 4.93, 7.54, P=2.2×10-62) in the SSA/SSB-positive subgroup, while absent in the antibody negative group. Three independent signals within the MHC were observed. The two most significant variants in MHC class I and II respectively, identified patients with a higher risk of hypergammaglobulinaemia, leukopenia, anaemia, purpura, major salivary gland swelling and lymphadenopathy. Replication confirmed the association with both MHC class I and II signals confined to SSA/SSB antibody positive pSS. Conclusion: Two subgroups of patients with pSS with distinct clinical manifestations can be defined by the presence or absence of SSA/SSB antibodies and genetic markers in the HLA locus. These subgroups should be considered in clinical follow-up, drug development and trial outcomes, for the benefit of both subgroups.

Published
2021
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