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  • 1.
    Boman, Antonia
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Berglin, Ewa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) and Sclerostin Are Related to Joint Destruction in Early Rheumatoid Arthritis Unrelated to Polymorphisms of the Genes2015In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, no 10, article id 3101Article in journal (Other academic)
  • 2.
    Boman, Antonia
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Berglin, Ewa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Receptor activator of nuclear factor kappa-B ligand (RANKL) but not sclerostin or gene polymorphisms is related to joint destruction in early rheumatoid arthritis2017In: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 35, no 5, p. 1005-1012Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to analyze relationships between receptor activator of nuclear factor kappa-B (RANKL), sclerostin and their gene polymorphisms with radiological progression in patients with early rheumatoid arthritis (RA). Patients with early RA (n = 407, symptomatic <1 year) (ARA criteria) examined radiologically at inclusion and after 24 months were consecutively included. Disease activity score and C-reactive protein were regularly recorded. Sclerostin, RANKL, and anti-CCP2 antibodies were analyzed in plasma at baseline using ELISAs. Data on gene polymorphism for sclerostin and RANKL were extracted from Immunochip analysis. Sex- and age-matched controls (n = 71) were identified from the Medical Biobank of Northern Sweden. The concentration of RANKL was significantly higher in patients compared with controls, median (IQR) 0.56 (0.9) nmol/L and 0.20 (0.25) nmol/L (p < 0.001), and in anti-CCP2-positive patients compared with sero-negative individuals. Sclerostin was significantly increased in female patients 0.59 (0.47-0.65) ng/mL compared with female controls 0.49 (0.4-0.65) ng/mL (p < 0.02). RANKL concentration was related to the Larsen score at baseline (p < 0.01), after 24 months (p < 0.001), and to radiological progression at 24 months (p < 0.001). Positivity of RANKL and anti-CCP2 yielded significant risk for progression with negativity for both as reference. No single nucleotide polymorphism encoding TNFSF11 or SOST was associated with increased concentrations of the factors. The concentration of RANKL was related to the Larsen score at baseline, at 24 months, and radiological progression at 24 months particularly in anti-CCP2-positive patients, while the concentration of sclerostin was unrelated to radiological findings.

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  • 3.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Johansson, Linda
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Nygren, E.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Vitamin D in individuals before onset of rheumatoid arthritis: relation to vitamin D binding protein and its associated genetic variants2018In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, p. 23-24Article in journal (Other academic)
  • 4.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    B-Regulatory-, CD19(+)CD20(+) CD24(high)CD38(high) -Cells Are Functionally Impaired In Patients With Rheumatoid Arthritis and Healthy First Degree Relatives Compared With Controls2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Special issue, Supplement 10, p. S393-S394, Meeting Abstract: 917Article in journal (Other academic)
  • 5.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    B Regulatory Cells are Functionally Impaired in Patients with Rheumatoid Arthritis and in Their First-Degree Relatives Compared with Controls2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 450-450Article in journal (Other academic)
  • 6.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    B-regulatory cells are functionally impaired in patients with rheumatoid arthritis and in their first degree relativesManuscript (preprint) (Other academic)
  • 7. Cobb, Joanna E.
    et al.
    Plant, Darren
    Flynn, Edward
    Tadjeddine, Meriem
    Dieude, Philippe
    Cornelis, Francois
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Goulielmos, George
    Boumpas, Dimitrios T.
    Sidiropoulos, Prodromos
    Krintel, Sophine B.
    Ornbjerg, Lykke M.
    Hetland, Merete L.
    Klareskog, Lars
    Haeupl, Thomas
    Filer, Andrew
    Buckley, Christopher D.
    Raza, Karim
    Witte, Torsten
    Schmidt, Reinhold E.
    FitzGerald, Oliver
    Veale, Douglas
    Eyre, Stephen
    Worthington, Jane
    Identification of the Tyrosine-Protein Phosphatase Non-Receptor Type 2 as a Rheumatoid Arthritis Susceptibility Locus in Europeans2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 6, p. e66456-Article in journal (Refereed)
    Abstract [en]

    Objectives: Genome-wide association studies have facilitated the identification of over 30 susceptibility loci for rheumatoid arthritis (RA). However, evidence for a number of potential susceptibility genes have not so far reached genome-wide significance in studies of Caucasian RA.

    Methods: A cohort of 4286 RA patients from across Europe and 5642 population matched controls were genotyped for 25 SNPs, then combined in a meta-analysis with previously published data.

    Results: Significant evidence of association was detected for nine SNPs within the European samples. When meta-analysed with previously published data, 21 SNPs were associated with RA susceptibility. Although SNPs in the PTPN2 gene were previously reported to be associated with RA in both Japanese and European populations, we show genome-wide evidence for a different SNP within this gene associated with RA susceptibility in an independent European population (rs7234029, P = 4.4x10(-9)).

    Conclusions: This study provides further genome-wide evidence for the association of the PTPN2 locus (encoding the T cell protein tyrosine phosphastase) with Caucasian RA susceptibility. This finding adds to the growing evidence for PTPN2 being a pan-autoimmune susceptibility gene.

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  • 8. Eyre, Steve
    et al.
    Bowes, John
    Diogo, Dorothee
    Lee, Annette
    Barton, Anne
    Martin, Paul
    Zhernakova, Alexandra
    Stahl, Eli
    Viatte, Sebastien
    McAllister, Kate
    Amos, Christopher I.
    Padyukov, Leonid
    Toes, Rene E. M.
    Huizinga, Tom W. J.
    Wijmenga, Cisca
    Trynka, Gosia
    Franke, Lude
    Westra, Harm-Jan
    Alfredsson, Lars
    Hu, Xinli
    Sandor, Cynthia
    de Bakker, Paul I. W.
    Davila, Sonia
    Khor, Chiea Chuen
    Heng, Khai Koon
    Andrews, Robert
    Edkins, Sarah
    Hunt, Sarah E.
    Langford, Cordelia
    Symmons, Deborah
    Concannon, Pat
    Onengut-Gumuscu, Suna
    Rich, Stephen S.
    Deloukas, Panos
    Gonzalez-Gay, Miguel A.
    Rodriguez-Rodriguez, Luis
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Martin, Javier
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Plenge, Robert M.
    Raychaudhuri, Soumya
    Klareskog, Lars
    Gregersen, Peter K.
    Worthington, Jane
    High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis2012In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, no 12, p. 1336-1340Article in journal (Refereed)
    Abstract [en]

    Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.

  • 9. Franke, Lude
    et al.
    el Bannoudi, Hanane
    Jansen, Diahann T. S. L.
    Kok, Klaas
    Trynka, Gosia
    Diogo, Dorothee
    Swertz, Morris
    Fransen, Karin
    Knevel, Rachel
    Gutierrez-Achury, Javier
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Greenberg, Jeffrey D.
    Kremer, Joel
    Pappas, Dimitrios A.
    Kanterakis, Alexandros
    Weersma, Rinse K.
    van der Helm-van Mil, Annette H. M.
    Guryev, Viktor
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Gregersen, Peter K.
    Plenge, Robert M.
    Wijmenga, Cisca
    Huizinga, Tom W-J
    Ioan-Facsinay, Andreea
    Toes, Rene E. M.
    Zhernakova, Alexandra
    Association analysis of copy numbers of FC-gamma receptor genes for rheumatoid arthritis and other immune-mediated phenotypes2016In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 24, no 2, p. 263-270Article in journal (Refereed)
    Abstract [en]

    Segmental duplications (SDs) comprise about 5% of the human genome and are enriched for immune genes. SD loci often show copy numbers variations (CNV), which are difficult to tag with genotyping methods. CNV in the Fc gamma receptor region (FCGR) has been suggested to be associated with rheumatic diseases. The objective of this study was to delineate association of FCGR-CNV with rheumatoid arthritis (RA), coeliac disease and Inflammatory bowel disease incidence. We developed a method to accurately quantify CNV in SD loci based on the intensity values from the Immunochip platform and applied it to the FCGR locus. We determined the method's validity using three independent assays: segregation analysis in families, arrayCGH, and whole genome sequencing. Our data showed the presence of two separate CNVs in the FCGR locus. The first region encodes FCGR2A, FCGR3A and part of FCGR2C gene, the second encodes another part of FCGR2C, FCGR3B and FCGR2B. Analysis of CNV status in 4578 individuals with RA and 5457 controls indicated association of duplications in the FCGR3B gene in antibody-negative RA (P = 0.002, OR = 1.43). Deletion in FCGR3B was associated with increased risk of antibody-positive RA, consistently with previous reports (P = 0.023, OR = 1.23). A clear genotype-phenotype relationship was observed: CNV polymorphisms of the FCGR3A gene correlated to CD16A expression (encoded by FCGR3A) on CD8 T-cells. In conclusion, our method allows determining the CNV status of the FCGR locus, we identified association of CNV in FCGR3B to RA and showed a functional relationship between CNV in the FCGR3A gene and CD16A expression.

  • 10. Jiang, X
    et al.
    Kallberg, H
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Klareskog, L
    Alfredsson, L
    Padyukov, L
    A dense mapping of HLA region for study of interaction with smoking in the development of rheumatoid arthritis2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no Suppl. 3, p. 67-67Article in journal (Refereed)
  • 11. Jiang, Xia
    et al.
    Kallberg, Henrik
    Chen, Zuomei
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Davila, Sonia
    Klareskog, Lars
    Padyukov, Leonid
    Alfredsson, Lars
    An Immunochip-based interaction study of contrasting interaction effects with smoking in ACPA-positive versus ACPA-negative rheumatoid arthritis2016In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 55, no 1, p. 149-155Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the gene–environment interaction between smoking and single nucleotide polymorphisms (SNPs), using Immunochip material, on the risk of developing either of two serologically defined subsets of RA.

    Methods: Interaction between smoking and 133 648 genetic markers from the Immunochip was examined for two RA subsets, defined by the presence or absence of ACPA. A total of 1590 ACPA-positive and 891 ACPA-negative cases were compared with 1856 controls in the Swedish Epidemiological Investigation of RA (EIRA) case–control study. Logistic regression models were used to determine the presence of interaction. The proportion attributable to interaction was calculated for each smoking–SNP pair. Replication was carried out in an independent dataset from northern Sweden. To further validate and extend the results, interaction analysis was also performed using genome-wide association studies data on EIRA individuals.

    Results: In ACPA-positive RA, 102 SNPs interacted significantly with smoking, after Bonferroni correction. All 102 SNPs were located in the HLA region, mainly within the HLA class II region, 51 of which were replicated. No additional loci outside chromosome 6 were identified in the genome-wide association studies validation. After adjusting for HLA-DRB1 shared epitope, 15 smoking–SNP pairs remained significant for ACPA-positive RA, with 8 of these replicated (loci: BTNL2HLA-DRAHLA-DRB5HLA-DQA1HLA-DOB and TAP2). For ACPA-negative RA, no smoking–SNP pairs passed the threshold for significance.

    Conclusion: Our study presents extended gene variation patterns involved in gene–smoking interaction in ACPA-positive, but not ACPA-negative, RA. Notably, variants in HLA-DRB1 and those in additional genes within the MHC class II region, but not in any other gene regions, showed interaction with smoking.

  • 12. Jiang, Xia
    et al.
    Kallberg, Henrik
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Klareskog, Lars
    Padyukov, Leonid
    Alfredsson, Lars
    A Dense Mapping Of Human Leukocyte Antigen Region For Study Of Interaction With Smoking In The Development Of Rheumatoid Arthritis2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Special issue, Supplement 10, p. S799-S799, Meeting Abstract: 1875Article in journal (Other academic)
  • 13.
    Johansson, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Pratesi, Federico
    Brink, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    D'Amato, Claudia
    Bartaloni, Debora
    Migliorini, Paola
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Antibodies directed against endogenous and exogenous citrullinated antigens pre-date the onset of rheumatoid arthritis2016In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, article id 127Article in journal (Refereed)
    Abstract [en]

    Background: Anti-citrullinated-peptide antibodies (ACPA) have been detected in individuals with developing rheumatoid arthritis (RA) before the onset of symptom, with an initially limited spectrum of reactivities that gradually broadens. The aim was to analyze the evolution of ACPA response pre-dating symptom onset, using four selected citrullinated exogenous and endogenous antigens. Methods: A cohort of 521 individuals sampled before symptoms of RA appeared and 272 population controls were identified from the Biobank of Northern Sweden; 241 samples from patients with early RA were also collected. ACPA were detected by ELISA on viral citrullinated peptides (VCP) derived from Epstein-Barr-virus nuclear antigen (EBNA) 1 and EBNA2 (VCP1 and VCP2) and histone-4-derived citrullinated peptides (HCP1 and HCP2). Results: In pre-symptomatic individuals vs. patients with early RA, anti-VCP1 antibodies were detected in 10.4 % vs. 36.1 %, anti-VCP2 in 17.1 % vs. 52.3 %, anti-HCP1 in 10.2 % vs. 37.3 %, and anti-HCP2 in 16.3 % vs. 48.5 %, respectively. Anti-VCP and anti-HCP concentrations were significantly increased in pre-symptomatic individuals vs. controls (p < 0.001) and were increased approaching symptom onset. Anti-VCP and anti-HCP appeared simultaneously (median (IQR) 5.3 (6) years before symptom onset) and in combination yielded a high-risk ratio for disease development (OR = 8.0-18.9). Anti-VCP2 and anti-HCP2 antibodies were associated with HLA-DRB1*0401 in pre-symptomatic individuals. Three peptidylarginine deiminase (PAD)I3/PADI4 single nucleotide polymorphisms (SNPs) were significantly associated with anti-HCP1. Conclusions: Anti-VCP and anti-HCP antibodies pre-date symptom onset and predict disease development, but no hierarchy of citrullinated epitopes can be identified. These results suggest that no inciting citrullinated antigen so far described is common to all patients with RA. The association between PADI3/PADI4 polymorphism and anti-HCP1 antibodies suggests a novel link between deimination and production of ACPA.

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  • 14.
    Johansson, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Brink, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    An increased concentration of receptor activator of nuclear factor kappa-B ligand pre-dates the onset of rheumatoid arthritis2017In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 56, no 12, p. 2190-2196Article in journal (Refereed)
    Abstract [en]

    Objectives: RANK ligand (RANKL) is involved in destruction and osteoporosis in RA. In this study, the relationships between RANKL and ACPA, anti-carbamylated protein antibodies (anti-CarP), cytokines and chemokines were analysed in individuals before the onset of RA symptoms, and their associations with radiological findings at disease onset were assessed.

    Methods: This was a case-control study performed within the Medical Biobank of Northern Sweden that included 470 pre-symptomatic individuals [334 women and 136 men; mean (S.D.) age 52.3 (9.4) years] using blood samples donated before symptom onset (pre-dating time; 5.0 years) and 96 controls (60 women and 36 men). Plasma was analysed for RANKL (BioVendor, Karasek, Brno, Czech Republic), anti-CCP2 antibodies (Eurodiagnostics, Malmo, Sweden), anti-CarP antibodies (in-house ELISA), ACPA specificities (ISAC-platform, Phadia AB, Uppsala, Sweden) and cytokines/chemokines (Meso Scale Discovery methods, Rockville, MD, USA). Radiographs of hands and feet were graded using the Larsen score.

    Results: The concentration of RANKL was higher in the pre-symptomatic individuals compared with controls; mean (S.E.M.): 0.50 (0.03) vs 0.22 (0.02) nmol/l (P < 0.001). The concentration increased gradually over time until symptom onset but appeared later than ACPA/RF/anti-CarP antibodies. Positivity for these antibodies yielded higher levels of RANKL compared with seronegativity (P < 0.001). RANKL concentrations were significantly associated with IL-6 and IL-10 concentrations. The combination of positivity for RANKL and anti-CarP antibodies resulted in a higher Larsen score at diagnosis beta = 6.18 (95% CI: 0.93, 11.43; P = 0.022).

    Conclusion: RANKL concentrations were increased several years before symptom onset for RA, particularly in ACPA/RF/anti-CarP-positive individuals, all detectable earlier than RANKL. Positivity for RANKL and anti-CarP antibodies yielded the highest Larsen score at disease onset.

  • 15.
    Johansson, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. Reumatologi.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. Reumatologi.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. Reumatologi.
    PTPN22 polymorphism and anti-cyclic citrullinated peptide antibodies in combination strongly predicts future onset of rheumatoid arthritis and has a specificity of 100% for the disease2006In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 8, no 1, p. R19-Article in journal (Refereed)
  • 16.
    Johansson, Martin
    et al.
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
    Möller, B
    Smedby, T
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
    Oestrogen receptor α gene polymorphisms in systemic lupus erythematosus2005In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 64, no 11, p. 1611-1617Article in journal (Refereed)
  • 17.
    Johansson, Martin
    et al.
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Reumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Reumatology.
    Möller, Bozena
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Reumatology.
    Association of a PDCD1 polymorphism with renal manifestations in systemic lupus erythematosus2005In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 52, no 6, p. 1665-1669Article in journal (Refereed)
  • 18.
    Jönsson, Elias
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ljung, Lotta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Norrman, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Freyhult, Eva
    Department of Medical Sciences, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Sweden.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Dahlqvist, Johanna
    Department of Medical Biochemistry and Microbiology, Medical Sciences, University, Uppsala, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Pulmonary fibrosis in relation to genetic loci in an inception cohort of patients with early rheumatoid arthritis from northern Sweden2022In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 61, no 3, p. 943-952Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Pulmonary manifestations in RA are common comorbidities. Interstitial lung disease (ILD), both idiopathic and in RA, has been associated with several genetic variants. We assessed pulmonary fibrosis (PF) in an inception cohort of RA patients in relation to genetic variants and disease-related factors.

    METHODS: A total of 1466 early RA patients were consecutively included and followed prospectively from the index date until death or 31 December 2016. Clinical and laboratory data and treatment were continuously registered according to the Swedish Rheumatology Quality Register. DNA was available from 1184 patients and 571 151 genome-wide single-nucleotide polymorphisms (SNPs) were analysed. Thirteen identified genetic variants were extracted. At follow-up, the patients answered a questionnaire regarding disease progression and lung involvement that was validated by reviewing medical records and analysing radiological examinations.

    RESULTS: The prevalence of PF was 5.6% and the annualized incidence rate was 5.0/1000 (95% CI 3.80, 6.54). Four SNPs were associated with PF in RA: rs35705950 [MUC5B; OR 2.5 (95% CI 1.5, 4.0), adjusted P-value = 0.00016, q-value = 0.0021]; rs111521887 [TOLLIP; OR 1.9 (95% CI 1.3, 2.8), adjusted P-value = 0.0014, q-value = 0.0092]; rs2609255 [FAM13A; OR 1.7 (95% CI 1.1, 2.5), adjusted P-value = 0.013, q-value = 0.055] and rs2736100 [TERT; OR 1.5 (95% CI 1.0, 2.2), adjusted P-value = 0.046, q-value = 0.15]. Older age and RF positivity were associated with increased risk, while MTX treatment was associated with a lower risk of PF.

    CONCLUSIONS: Development of PF in an inception cohort of RA patients was associated with 4 of 12 ILD risk genes. RA-related factors except for age at diagnosis and RF positivity were of limited importance in PF development.

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  • 19. Kastbom, Alf
    et al.
    Coster, Lars
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Chatzidionysiou, Aikaterini
    van Vollenhoven, Ronald F.
    Padyukov, Leonid
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Saevarsdottir, Saedis
    Influence of FCGR3A genotype on the therapeutic response to rituximab in rheumatoid arthritis: an observational cohort study2012In: BMJ Open, E-ISSN 2044-6055, Vol. 2, no 5, p. e001524-Article in journal (Refereed)
    Abstract [en]

    Objectives: To determine whether a polymorphism in the Fc gamma receptor type IIIA (FCGR3A-F158V), influencing immunoglobulin G binding affinity, relates to the therapeutic efficacy of rituximab in rheumatoid arthritis (RA) patients. Design: Observational cohort study. Setting: Three university hospital rheumatology units in Sweden. Participants: Patients with established RA (n=177; 145 females and 32 males) who started rituximab (Mabthera) as part of routine care. Primary outcome measures: Response to rituximab therapy in relation to FCGR3A genotype, including stratification for sex. Results: The frequency of responders differed significantly across FCGR3A genotypes (p=0.017 in a 3x2 contingency table). Heterozygous patients showed the highest response rate at 83%, as compared with patients carrying 158FF (68%) or 158VV (56%) (p=0.028 and 0.016, respectively). Among 158VV patients, response rates differed between male and female patients (p=0.036), but not among 158FF or 158VF patients (p=0.72 and 0.46, respectively). Conclusions: Therapeutic efficacy of rituximab in RA patients is influenced by FCGR3A genotype, with the highest response rates found among heterozygous patients. This may suggest that different rituximab mechanisms of action in RA are optimally balanced in FCGR3A-158VF patients. Similar to the previously described associations with RA susceptibility and disease course, the impact of 158VV on rituximab response may be influenced by sex.

  • 20. Kastbom, Alf
    et al.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Genetic Variants of the NLRP3 Inflammasome Are Associated with Stroke in Patients with Rheumatoid Arthritis2015In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 42, no 10, p. 1740-1745Article in journal (Refereed)
    Abstract [en]

    Objective. Inflammasomes are intracellular protein complexes important for the production of proinflammatory cytokines. Studies have suggested that the NLRP3 inflammasome influences both the severity of rheumatoid arthritis (RA) and development of atherosclerosis. Therefore, we investigated whether functional genetic variants related to the NLRP3 inflammasome influence the risk of cardiovascular (CV) disease (CVD) in patients with RA. Methods. The incidence of CVD was assessed in 522 patients with established RA by a retrospective survey of medical records in combination with a 6-year prospective followup. NLRP3-Q705K and CARD8-C10X genotypes were analyzed in relation to CVD by logistic regression, adjusting for traditional risk factors, antirheumatic treatment, and age at the onset of RA. Results. Carriage of the NLRP3-Q705K minor allele was associated with an increased risk of stroke/transient ischemic attack (TIA; OR 2.01, 95% CI 1.0-4.1, p = 0.05), while CARD8-C10X was not associated with any type of CV event. Patients with >= 1 variant allele in both polymorphisms had an increased risk of CVD when compared with patients without variant alleles present in both polymorphisms (adjusted OR 3.05, 95% CI 1.42-6.54, p = 0.004). Stratification showed that this risk was confined to stroke/TIA (adjusted OR 5.09, 95% CI 2.27-11.44, p < 0.0001) and not to myocardial infarction (MI)/angina pectoris (adjusted OR 1.58, 95% CI 0.67-3.73). Risk estimates were consistently higher among female patients. Conclusion. Genetic variants of the NLRP3 inflammasome influence the risk of stroke/TIA, but not of MI/angina pectoris in Swedish patients with established RA.

  • 21. Kim, Kwangwoo
    et al.
    Bang, So-Young
    Lee, Hye-Soon
    Cho, Soo-Kyung
    Choi, Chan-Bum
    Sung, Yoon-Kyoung
    Kim, Tae-Hwan
    Jun, Jae-Bum
    Yoo, Dae Hyun
    Kang, Young Mo
    Kim, Seong-Kyu
    Suh, Chang-Hee
    Shim, Seung-Cheol
    Lee, Shin-Seok
    Lee, Jisoo
    Chung, Won Tae
    Choe, Jung-Yoon
    Shin, Hyoung Doo
    Lee, Jong-Young
    Han, Bok-Ghee
    Nath, Swapan K.
    Eyre, Steve
    Bowes, John
    Pappas, Dimitrios A.
    Kremer, Joel M.
    Gonzalez-Gay, Miguel A.
    Rodriguez-Rodriguez, Luis
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Okada, Yukinori
    Diogo, Dorothee
    Liao, Katherine P.
    Karlson, Elizabeth W.
    Raychaudhuri, Soumya
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Martin, Javier
    Klareskog, Lars
    Padyukov, Leonid
    Gregersen, Peter K.
    Worthington, Jane
    Greenberg, Jeffrey D.
    Plenge, Robert M.
    Bae, Sang-Cheol
    High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci2015In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 74, no 3, article id e13Article in journal (Refereed)
    Abstract [en]

    Objective A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. Methods We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45 790 European case-control samples. Results We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5x10(-8)), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. Conclusions This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.

  • 22.
    Kling, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Seddighzadeh, M
    Arlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Alfredsson, L
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Padyukov, L
    Genetic variations in the serotonin 5-HT2A receptor gene (HTR2A) are associated with rheumatoid arthritis2008In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 67, no 8, p. 1111-1115Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To analyse the association between the genetic polymorphisms within the HTR2A gene for the serotonin receptor and rheumatoid arthritis (RA).

    METHODS: HTR2A gene polymorphisms were analysed in patients with RA and controls from two study populations using PCR based restriction endonuclease mapping or TaqMan allelic discrimination with more than 4000 individuals included in the current study.

    RESULTS: At the discovery stage we detected significant differences in frequency of rs6313 (T102C polymorphism) between the patients with RA and controls (p = 0.006). Following validation with an extended set of single nucleotide polymorphisms (SNPs) and number of DNA samples, a trend in associations in allelic model for SNPs rs6314, rs1328674, rs6313 and rs6311 (p = 0.006, 0.002, 0.006, 0.009) was seen, although it was lost after correction for multi-comparison for all but rs1328674 (empirical p value = 0.021). However, haplotype frequency analysis based on these four SNPs showed significantly low representation of TCTT combination in patients with RA in comparison with controls (3.6% and 5.6%, p<0.001 on chi(2) test, empirical p = 0.004 after 100 000 permutations) and a significantly higher frequency of CTCC combination in patients with RA in comparison with controls (3.6% and 2.2%, p = 0.002 on chi(2) test, empirical p = 0.022 after 100 000 permutations).

    CONCLUSIONS: In our study, genetic polymorphisms at the HTR2A gene are associated with susceptibility for RA, suggesting possible links between the serotonergic system and development of the disease.

  • 23. Leonard, Dag
    et al.
    Svenungsson, Elisabet
    Dahlqvist, Johanna
    Alexsson, Andrei
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Taylor, Kimberly E.
    Sandling, Johanna K.
    Bengtsson, Christine
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Frodlund, Martina
    Jonsen, Andreas
    Eketjäll, Susanna
    Jensen-Urstad, Kerstin
    Gunnarsson, Iva
    Sjöwall, Christopher
    Bengtsson, Anders A.
    Eloranta, Maija-Leena
    Syvänen, Ann-Christine
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Criswell, Lindsey A.
    Rönnblom, Lars
    Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 7, p. 1063-1069Article in journal (Refereed)
    Abstract [en]

    Objectives Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA.

    Methods Patients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs).

    Results We identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5x10(-5)) and RA (OR 2.8 (1.4 to 5.6), P=3.8x10(-3)), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5x10(-7)), but not in population controls. The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5x10(-5)) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes.

    Conclusions The IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.

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  • 24.
    Ljung, Lotta
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology. Karolinska Institutet, Clinical Epidemiology Section, Department of Medicine, Stockholm, Sweden.
    Wiberg, Kristina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Low-energy fractures in rheumatoid arthritis - associations with genes and clinical characteristics2019In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, p. 344-345Article in journal (Other academic)
    Abstract [en]

    Background: Patients with rheumatoid arthritis (RA) have increased risk of osteoporosis and low-energy fractures. Several genes associated with bone mineralization, osteoporosis or risk of fracture in the general population have been identified.

    Objectives: To analyse the association between nine selected SNPs and the risk of low-energy fracture, taking clinical patient characteristics into account.

    Methods: We identified a cohort of patients (n=896, 70% women, age at inclusion 60.0±14.8 years) with RA according to ACR criteria from the catchment area of the register of Umeå injury database, Umeå, Sweden, which enabled identification of low-energy fractures (n=254). The follow-up (mean 8.8±6.1 years, total 7928 person-years) started two years after RA diagnosis but not earlier than January 1, 1993 and ended at the first of December 31, 2011, death or the first low-energy fracture. Nine SNPs were analysed in all patients with available DNA-samples (n=667) using KASPTM genotyping assays (LGC genomics Ltd, Hoddesdon, UK): rs3801387 (WNT16), rs6666455 (SOAT), rs3736228 (LRP5), rs4796995 (FAM210A), rs4792909 (SOST), rs2062377 (TNFRSF11B/OPG), rs884205 (TNFRSF11A/RANK), rs9533090 (TNFSF11/RANKL), and rs1373004 (DKK1). Anti-CCP was analysed and clinical patient characteristics (duration of RA, ever smoking, disease activity the first two years after RA diagnosis, and joint erosions) were extracted from patient files. Associations between the risk of fracture and risk alleles in the cohort were evaluated using Kaplan-Meier curves (K-M) and Cox proportional hazards models: crude, adjusted for age and sex, and for clinical patient characteristics.

    Results: The SNPs: rs1373004, rs4792909, and rs2062377 were associated with the risk of fracture in K-M analyses (Figure 1). For the other genes no significant associations were observed. Patients carrying the risk allele of rs1373004 (22.6% of the patients), or who were homozygous for the risk allele of SNP rs4792909 (38.6%), had a >50% higher risk of low-energy fracture compare to other patients, irrespectively of disease characteristics (Table 1). The association between rs2062377 and the risk of fracture was not independent of clinical patient characteristics (Table 1).

  • 25. Okada, Yukinori
    et al.
    Wu, Di
    Trynka, Gosia
    Raj, Towfique
    Terao, Chikashi
    Ikari, Katsunori
    Kochi, Yuta
    Ohmura, Koichiro
    Suzuki, Akari
    Yoshida, Shinji
    Graham, Robert R
    Manoharan, Arun
    Ortmann, Ward
    Bhangale, Tushar
    Denny, Joshua C
    Carroll, Robert J
    Eyler, Anne E
    Greenberg, Jeffrey D
    Kremer, Joel M
    Pappas, Dimitrios A
    Jiang, Lei
    Yin, Jian
    Ye, Lingying
    Su, Ding-Feng
    Yang, Jian
    Xie, Gang
    Keystone, Ed
    Westra, Harm-Jan
    Esko, Tonu
    Metspalu, Andres
    Zhou, Xuezhong
    Gupta, Namrata
    Mirel, Daniel
    Stahl, Eli A
    Diogo, Dorothee
    Cui, Jing
    Liao, Katherine
    Guo, Michael H
    Myouzen, Keiko
    Kawaguchi, Takahisa
    Coenen, Marieke JH
    van Riel, Piet LCM
    van de laar, Mart AFJ
    Guchelaar, Henk-Jan
    Huizinga, Tom WJ
    Dieude, Philippe
    Mariette, Xavier
    Bridges, S Louis, Jr.
    Zhernakova, Alexandra
    Toes, Rene EM
    Tak, Paul P
    Miceli-Richard, Corinne
    Bang, So-Young
    Lee, Hye-Soon
    Martin, Javier
    Gonzalez-Gay, Miguel A
    Rodriguez-Rodriguez, Luis
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Choi, Hyon K
    Kamatani, Yoichiro
    Galan, Pilar
    Lathrop, Mark
    Eyre, Steve
    Bowes, John
    Barton, Anne
    de Vries, Niek
    Moreland, Larry W
    Criswell, Lindsey A
    Karlson, Elizabeth W
    Taniguchi, Atsuo
    Yamada, Ryo
    Kubo, Michiaki
    Liu, Jun S
    Bae, Sang-Cheol
    Worthington, Jane
    Padyukov, Leonid
    Klareskog, Lars
    Gregersen, Peter K
    Raychaudhuri, Soumya
    Stranger, Barbara E
    De Jager, Philip L
    Franke, Lude
    Visscher, Peter M
    Brown, Matthew A
    Yamanaka, Hisashi
    Mimori, Tsuneyo
    Takahashi, Atsushi
    Xu, Huji
    Behrens, Timothy W
    Siminovitch, Katherine A
    Momohara, Shigeki
    Matsuda, Fumihiko
    Yamamoto, Kazuhiko
    Plenge, Robert M
    Genetics of rheumatoid arthritis contributes to biology and drug discovery2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 506, no 7488, p. 376-381Article in journal (Refereed)
    Abstract [en]

    A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

  • 26. Plant, Darren
    et al.
    Flynn, Edward
    Mbarek, Hamdi
    Dieude, Philippe
    Cornelis, Francois
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Dahlqvist, Solbritt Rantapää
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Goulielmos, George
    Boumpas, Dimitrios T
    Sidiropoulos, Prodromos
    Johansen, Julia S
    Ornbjerg, Lykke M
    Hetland, Merete Lund
    Klareskog, Lars
    Filer, Andrew
    Buckley, Christopher D
    Raza, Karim
    Witte, Torsten
    Schmidt, Reinhold E
    Worthington, Jane
    Investigation of potential non-HLA rheumatoid arthritis susceptibility loci in a European cohort increases the evidence for nine markers2010In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 69, no 8, p. 1548-1553Article in journal (Refereed)
    Abstract [en]

    Background Genetic factors have a substantial role in determining development of rheumatoid arthritis (RA), and are likely to account for 50-60% of disease susceptibility. Genome-wide association studies have identified non-human leucocyte antigen RA susceptibility loci which associate with RA with low-to-moderate risk.

    Objectives To investigate recently identified RA susceptibility markers using cohorts from six European countries, and perform a meta-analysis including previously published results.

    Methods 3311 DNA samples were collected from patients from six countries (UK, Germany, France, Greece, Sweden and Denmark). Genotype data or DNA samples for 3709 controls were collected from four countries (not Sweden or Denmark). Eighteen single nucleotide polymorphisms (SNPs) were genotyped using Sequenom MassArray technology. Samples with a >95% success rate and only those SNPs with a genotype success rate of >95% were included in the analysis. Scandinavian patient data were pooled and previously published Swedish control data were accessed as a comparison group. Meta-analysis was used to combine results from this study with all previously published data.

    Results After quality control, 3209 patients and 3692 controls were included in the study. Eight markers (ie, rs1160542 (AFF3), rs1678542 (KIF5A), rs2476601 (PTPN22), rs3087243 (CTLA4), rs4810485 (CD40), rs5029937 (6q23), rs10760130 (TRAF1/C5) and rs7574865 (STAT4)) were significantly associated with RA by meta-analysis. All 18 markers were associated with RA when previously published studies were incorporated in the analysis. Data from this study increased the significance for association with RA and nine markers.

    Conclusions In a large European RA cohort further evidence for the association of 18 markers with RA development has been obtained.

  • 27.
    Rantapää-Dahlqvist, Solbritt
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Brink, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rönnelid, J
    Klareskog, L
    Clusters of single nucleotide polymorphisms within the HLA-DRB1 gene in relation to antibodies against citrullinated peptides in individuals prior to the development of rheumatoid arthritis2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no Suppl. 3, p. 112-113Article in journal (Refereed)
  • 28.
    Renman, Emma
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Brink, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Dysregulated microRNA expression in rheumatoid arthritis families-a comparison between rheumatoid arthritis patients, their first-degree relatives, and healthy controls2021In: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 40, no 6, p. 2387-2394Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Recent studies have demonstrated an altered expression of certain microRNAs in patients with rheumatoid arthritis (RA) as well as their first-degree relatives (FDRs) compared to healthy controls (HCs), suggesting a role of microRNA in the progression of the disease. To corroborate this, a set of well-characterized RA families originating from northern Sweden were analyzed for differential expression of a selected set of microRNAs.

    METHOD: MicroRNA was isolated from frozen peripheral blood cells obtained from 21 different families and included 26 RA patients, 22 FDRs, and 21 HCs. Expression of the selected microRNAs miR-22-3p, miR-26b-5p, miR-34a-3p, miR-103a-3p, miR-142-3p, miR-146a-5p, miR-155, miR-346, and miR-451a was determined by a two-step quantitative real-time polymerase chain reaction (qRT-PCR). Statistical analysis including clinical variables was applied.

    RESULTS: Out of the nine selected microRNAs that previously have been linked to RA, we confirmed four after adjusting for age and gender, i.e., miR-22-3p (p = 0.020), miR-26b-5p (p = 0.018), miR-142-3p (p = 0.005), and miR-155 (p = 0.033). Moreover, a significant trend with an intermediate microRNA expression in FDR was observed for the same four microRNAs. In addition, analysis of the effect of corticosteroid use showed modulation of miR-103a-3p expression.

    CONCLUSIONS: We confirm that microRNAs seem to be involved in the development of RA, and that the expression pattern in FDR is partly overlapping with RA patients. The contribution of single microRNAs in relation to the complex network including all microRNAs and other molecules is still to be revealed. Key Points • Expression levels of miR-22-3p, miR-26b-5p, miR-142-3p, and miR-155 were significantly altered in RA patients compared to those in controls. • In first-degree relatives, a significant trend with an intermediate microRNA expression in FDR was observed for the same four microRNAs.

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  • 29.
    Saevarsdottir, Saedis
    et al.
    DeCODE Genetics/Amgen, Reykjavik, Iceland; Division of Clinical Epidemiology, Department of Medicine, Solna Karolinska Institutet, Stockholm, Sweden; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland; Department of Medicine, Landspitali the National University Hospital of Iceland, Reykjavik, Iceland.
    Stefansdottir, Lilja
    DeCODE Genetics/Amgen, Reykjavik, Iceland.
    Sulem, Patrick
    DeCODE Genetics/Amgen, Reykjavik, Iceland.
    Thorleifsson, Gudmar
    DeCODE Genetics/Amgen, Reykjavik, Iceland.
    Ferkingstad, Egil
    DeCODE Genetics/Amgen, Reykjavik, Iceland.
    Rutsdottir, Gudrun
    DeCODE Genetics/Amgen, Reykjavik, Iceland.
    Glintborg, Bente
    Danish Rheumatologic Biobank and Copenhagen Center for Arthritis Research (COPECARE), Centre for Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Glostrup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Westerlind, Helga
    Division of Clinical Epidemiology, Department of Medicine, Solna Karolinska Institutet, Stockholm, Sweden.
    Grondal, Gerdur
    Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland; Department of Medicine, Landspitali the National University Hospital of Iceland, Reykjavik, Iceland; Center for Rheumatology Research, Landspitali the National University Hospital of Iceland, Reykjavik, Iceland.
    Loft, Isabella C.
    Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark.
    Sorensen, Signe Bek
    Molecular Diagnostics and Clinical Research Unit, IRS-Center Sonderjylland, University Hospital of Southern Denmark, Aabenraa, Denmark.
    Lie, Benedicte A.
    Department of Medical Genetics, University of Oslo, Oslo, Norway; Oslo University Hospital, Oslo, Norway.
    Brink, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Arnthorsson, Asgeir Orn
    DeCODE Genetics/Amgen, Reykjavik, Iceland.
    Baecklund, Eva
    Department of Medical Sciences, Section of Rheumatology, Uppsala University, Uppsala, Sweden.
    Banasik, Karina
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Bank, Steffen
    Molecular Diagnostics and Clinical Research Unit, IRS-Center Sonderjylland, University Hospital of Southern Denmark, Aabenraa, Denmark.
    Bjorkman, Lena I.
    Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden.
    Ellingsen, Torkell
    OPEN Explorative Network, University of Southern Denmark, Odense, Denmark; Rheumatology Research Unit, Odense University Hospital and University of Southern Denmark, Odense, Denmark.
    Erikstrup, Christian
    Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
    Frei, Oleksandr
    NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway.
    Gjertsson, Inger
    Department of Rheumatology and Inflammation Research, Gothenburg University, Gothenburg, Sweden.
    Gudbjartsson, Daniel F.
    DeCODE Genetics/Amgen, Reykjavik, Iceland; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
    Gudjonsson, Sigurjon A.
    DeCODE Genetics/Amgen, Reykjavik, Iceland.
    Halldorsson, Gisli H.
    DeCODE Genetics/Amgen, Reykjavik, Iceland; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
    Hendricks, Oliver
    Danish Hospital for Rheumatic Diseases, University Hospital of Southern Denmark, Sønderborg, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.
    Hillert, Jan
    Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
    Hogdall, Estrid
    Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
    Jacobsen, Søren
    Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Copenhagen Lupus and Vasculitis Clinic, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen, Denmark.
    Jensen, Dorte Vendelbo
    Department of Rheumatology, Center for Rheumatology and Spine Diseases, Gentofte and Herlev Hospital, Rønne, Denmark.
    Jonsson, Helgi
    Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland; Department of Medicine, Landspitali the National University Hospital of Iceland, Reykjavik, Iceland.
    Kastbom, Alf
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Kockum, Ingrid
    Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
    Kristensen, Salome
    Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
    Kristjansdottir, Helga
    Center for Rheumatology Research, Landspitali the National University Hospital of Iceland, Reykjavik, Iceland.
    Larsen, Margit H.
    Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Linauskas, Asta
    Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Department of Rheumatology, North Denmark Regional Hospital, Hjørring, Denmark.
    Hauge, Ellen-Margrethe
    Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
    Loft, Anne G.
    Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
    Ludviksson, Bjorn R.
    Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland; Department of Immunology, Landspitali the National University Hospital of Iceland, Reykjavik, Iceland.
    Lund, Sigrun H.
    DeCODE Genetics/Amgen, Reykjavik, Iceland.
    Markusson, Thorsteinn
    DeCODE Genetics/Amgen, Reykjavik, Iceland; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
    Masson, Gisli
    DeCODE Genetics/Amgen, Reykjavik, Iceland.
    Melsted, Pall
    DeCODE Genetics/Amgen, Reykjavik, Iceland; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
    Moore, Kristjan H.S.
    DeCODE Genetics/Amgen, Reykjavik, Iceland.
    Munk, Heidi
    OPEN Explorative Network, University of Southern Denmark, Odense, Denmark; Rheumatology Research Unit, Odense University Hospital and University of Southern Denmark, Odense, Denmark.
    Nielsen, Kaspar R.
    Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark.
    Norddahl, Gudmundur L.
    DeCODE Genetics/Amgen, Reykjavik, Iceland.
    Oddsson, Asmundur
    DeCODE Genetics/Amgen, Reykjavik, Iceland.
    Olafsdottir, Thorunn A.
    DeCODE Genetics/Amgen, Reykjavik, Iceland; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
    Olason, Pall I.
    DeCODE Genetics/Amgen, Reykjavik, Iceland.
    Olsson, Tomas
    Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
    Ostrowski, Sisse Rye
    Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Hørslev-Petersen, Kim
    Danish Hospital for Rheumatic Diseases, University Hospital of Southern Denmark, Sønderborg, Denmark.
    Rognvaldsson, Solvi
    DeCODE Genetics/Amgen, Reykjavik, Iceland.
    Sanner, Helga
    Section of Rheumatology, Oslo University Hospital, Oslo, Norway; Oslo New University College, Oslo, Norway.
    Silberberg, Gilad N.
    Division of Rheumatology, Department of Medicine, Solna Karolinska Institutet, Stockholm, Sweden.
    Stefansson, Hreinn
    DeCODE Genetics/Amgen, Reykjavik, Iceland.
    Sørensen, Erik
    Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Sørensen, Inge J.
    Copenhagen Lupus and Vasculitis Clinic, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen, Denmark.
    Turesson, Carl
    Rheumatology, Department of Clinical Sciences, Malmö Lund University, Malmö, Sweden.
    Bergman, Thomas
    Division of Clinical Epidemiology, Department of Medicine, Solna Karolinska Institutet, Stockholm, Sweden.
    Alfredsson, Lars
    Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Kvien, Tore K.
    University of Oslo, Oslo, Norway; Diakonhjemmet Hospital, Oslo, Norway.
    Brunak, Søren
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Steinsson, Kristján
    Center for Rheumatology Research, Landspitali the National University Hospital of Iceland, Reykjavik, Iceland.
    Andersen, Vibeke
    Molecular Diagnostics and Clinical Research Unit, IRS-Center Sonderjylland, University Hospital of Southern Denmark, Aabenraa, Denmark; OPEN Explorative Network, University of Southern Denmark, Odense, Denmark; Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
    Andreassen, Ole A.
    NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Hetland, Merete Lund
    Danish Rheumatologic Biobank and Copenhagen Center for Arthritis Research (COPECARE), Centre for Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Glostrup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Klareskog, Lars
    Division of Rheumatology, Department of Medicine, Solna Karolinska Institutet, Stockholm, Sweden.
    Askling, Johan
    Division of Clinical Epidemiology, Department of Medicine, Solna Karolinska Institutet, Stockholm, Sweden.
    Padyukov, Leonid
    Division of Rheumatology, Department of Medicine, Solna Karolinska Institutet, Stockholm, Sweden.
    Pedersen, Ole Bv
    Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark.
    Thorsteinsdottir, Unnur
    DeCODE Genetics/Amgen, Reykjavik, Iceland; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
    Jonsdottir, Ingileif
    DeCODE Genetics/Amgen, Reykjavik, Iceland; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland; Department of Immunology, Landspitali the National University Hospital of Iceland, Reykjavik, Iceland.
    Stefansson, Kari
    DeCODE Genetics/Amgen, Reykjavik, Iceland; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
    Saevarsdottir, Saedis
    DeCODE Genetics/Amgen, Reykjavik, Iceland.
    Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset2022In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 81, no 8, p. 1085-1095Article in journal (Refereed)
    Abstract [en]

    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.

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  • 30.
    Siljehult, Filip
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Eriksson, Catharina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Concentrations of infliximab and anti-drug antibodies in relation to clinical response in patients with rheumatoid arthritis2018In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, no 5, p. 345-350Article in journal (Refereed)
    Abstract [en]

    Objective: The efficacy of anti-tumour necrosis factor-α (anti-TNF-α) treatment with infliximab (IFX) may be reduced by the development of anti-drug antibodies (ADAs). This study evaluated drug concentration and the presence of ADAs, relative to response, in rheumatoid arthritis (RA) patients treated with IFX.

    Method: Ninety-four RA patients were consecutively included and assessed for disease activity at baseline, and after 14, and 30 or 52 weeks. Serum IFX concentration and ADAs were analysed using in-house enzyme-linked immunosorbent assays. ADA analysis was based on binding to TNF-α-coated plates, with the lower detection limit set at mean + 2 sd of controls.

    Results: At 14 and 52 weeks, 74.5% of the patients had moderate to good response. Good responders had significantly higher IFX concentrations than moderate and poor responders at 52 weeks (6.6 ± 1.4 µg/mL vs 3.6 ± 1.3 µg/mL and 2.6 ± 1.6 µg/mL, respectively). An IFX concentration ≥4.66 µg/mL at 14 weeks yielded a moderate to good response at 30/52 weeks, with 91.3% specificity and 39.3% sensitivity. Eleven patients dropped out owing to lack of efficacy and eight owing to side effects; three with IFX concentration ≤ 0.5 µg/mL were ADA positive. At an IFX concentration ≤ 0.5 µg/mL, 43.8% and 30.1% at 14 and 52 weeks, respectively, were ADA positive. None of the good responders had ADAs.

    Conclusion: One-quarter of patients had an IFX concentration ≤ 0.5 µg/mL but only 11.7% had ADAs. High IFX concentration was related to a good response, suggesting that the lack of response could be due to a lack of IFX, rather than to the presence of ADAs.

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  • 31.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Genetic studies in rheumatoid arthritis: familial studies and analysis of relationships to atherothrombotic comorbidity2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background. Rheumatoid arthritis (RA) is an autoimmune disease mainly affecting the joints but has also extra articular manifestations and an increased cardiovascular (CV) co-morbidity. Rheumatoid factor (RF) and antibodies against citrullinated proteins/peptides (ACPA) are diagnostically important and are related to a more severe disease. The aetiology is unknown but RA is considered a complex disease caused by both genetic and environmental factors. The heritability is estimated to be 60% with the main contribution from the HLA region. The relative homogeneity of the population in northern Sweden due to low immigration and founder effects has shown to be suitable for genetic studies.

    Objectives. The aim of this thesis has been to identify genes contributing to the susceptibility of RA and the CV co-morbidity in particular. To achieve this, multi-case families from the four northern most counties of Sweden were collected for linkage studies to identify susceptibility genes. Association studies with genetic polymorphisms in genes, involved in inflammation or being of importance for atherothrombotic manifestations (ATM) in the general population, were performed in RA-patients concerning ATM e.g. myocardial infarction, angina pectoris with intervention, stroke/TIA, deep vein thrombosis/pulmonary embolism (DVT/PE) at follow-up.

    Methods & Results. 47 families with 134 affected and 216 unaffected relatives were included in a genome-wide linkage study (GWL) performed with microsatellite markers at an average of 10cM resolution analysed using ABI PRISM 3730 DNA sequencer and non-parametric multipoint linkage in the Merlin program. Eight linked loci were identified with HLA as the most significant and a novel region on chromosome 14. In a follow-up analysis on a custom Illumina chip, with 13 additional families, yielding a total of 198 affected and 197 unaffected relatives. The majority of the 1536 single nucleotide polymorphisms (SNPs) used in the Illumina follow-up analyses was focused on chromosome 14. Statistical analyses with linkage and transmission disequilibrium test narrowed the region to 4 cM, a region containing multiple plausible RA candidate genes (Paper I). In Paper II  serum samples from 163 affected and 157 first degree relatives were analysed with EliA ACPA assay on ImmunoCAP250 for ACPA (IgA, IgG, IgM) and RF (IgA, IgM) isotypes. Both concentrations and frequencies were increased among the relatives compared with controls but lower compared with RA-patients and with a different relative distribution of the isotypes.

    The genetic contribution to ATM was studied in Paper III and IV using selected SNPs analysed using ABI PRISM 7900HT sequence detector system. In Paper III, RA-patients (n=467) were compared with age and sex matched controls (n=696) with respect to SNPs in tumor necrosis factor receptor II (TNFRII)(M196R), ß-fibrinogen -455 (G-455A), plasminogen activator inhibitor type-1 (PAI-1) (4G/5G) and Factor XIIIA (Val34Leu). Hypertension was predicted by TNFRII R allele and to a higher extent in combination with the A-allele in ß-fibrinogen. The 4G allele in PAI-1 was more frequent in patients with ischemic heart disease (IHD) and the FXIIIA Leu34 variant in patients with DVT/PE. In Paper IV, the minor allele of the polymorphism in growth differentiation factor 15 (GDF15) was found to be associated with RA (n=696) per se but also to ATM, a SNP in the 9p21.3 locus was also associated with ATM. A significant association to stroke was found in female patients homozygote for the minor allele of GDF15. Stoke among male patients was significantly associated with carrying the major allele of two SNPs in the CD40 gene. DVT/PE was associated with the minor allele of GDF15.

    Conclusion. A novel locus on chromosome 14 of importance for RA susceptibility in northern Sweden was found. The minor allele of TNFRII separately and together with the minor allele of ß-fibrinogen -455 was associated with hypertension and the 4G allele in PAI-1 was associated with IHD and  the Leu34 variant was associated with DVT/PE in RA patients. The GDF15 minor allele was associated with RA per se, ATM and DVT/PE in RA patients and a genotype in the SNP on 9p21.3 was associated with ATM. Stroke among females was associated with GDF15 and stroke among males with two SNPs in CD40.

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  • 32.
    Ärlestig, Lisbeth
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Brink, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Hansson, Monika
    Jakobsson, Per Johan
    Holmdahl, Rikard
    Mathsson, Linda
    Ronnelid, Johan
    Klareskog, Lars
    Rantapää-Dahlqvist, Solbritt M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Single Nucleotide Polymorphisms within the HLA-DRB1 Gene in Relation to Antibodies Against Citrullinated Peptides in Individuals Prior to the Development of Rheumatoid Arthritis2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no 10, p. S180-S180Article in journal (Other academic)
  • 33.
    Ärlestig, Lisbeth
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Einarsdottir, Elisabet
    Research Program Unit, Molecular Medicine, University of Helsinki, Finland.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Novel risk locus on chromosome 14 in multi-case families with rheumatoid arthritis from northern SwedenManuscript (preprint) (Other academic)
  • 34.
    Ärlestig, Lisbeth
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Mullazehi, Mohammed
    Department of Immunology, Genetics and Pathology, Uppsala University.
    Kokkonen, Heidi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Rönnelid, Johan
    Department of Immunology, Genetics and Pathology, Uppsala University.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Antibodies against cyclic citrullinated peptides of IgG, IgA and IgM isotype and rheumatoid factor of IgM and IgA isotype are increased in unaffected members of multicase rheumatoid arthritis families from northern Sweden2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no 6, p. 825-829Article in journal (Refereed)
    Abstract [en]

    Background Rheumatoid factors (RFs) and antibodies against cyclic citrullinated peptides (CCPs) of IgG, IgA and IgM isotype have been shown to precede disease onset by years.

    Objective To evaluate serological risk markers in first-degree relatives from multicase families in relation to genetic and environmental risk factors.

    Methods 51 multicase families consisting of 163 individuals with rheumatoid arthritis (RA) (mean±SD age, 60±14 years; disease duration 21 years; 71.8% female) and with 157 first-degree relatives unaffected by RA (54±17 years; 59.9% female) were recruited. Isotypes of antibodies against CCPs (IgG, IgA and IgM) and RFs (IgM and IgA) were determined using automated enzyme immunoassays. Cut-off levels were established using receiver operating characteristic curves based on values for 100 unrelated healthy controls.

    Results The concentrations and frequencies of all anti-CCP and RF isotypes were significantly increased in first-degree relatives and patients with RA compared with unrelated healthy controls. The relative distribution of IgA and IgM isotypes was higher than IgG in the relatives, whereas the IgG isotype dominated in patients with RA. The patients carried human leucocyte antigen-shared epitope (HLA-SE) significantly more often than the relatives (71.4% vs 53.9%, p=0.01), while the frequency of the PTPN22 T variant was similar. HLA-SE, combined with smoking, was significantly related to all combinations of anti-CCP and RF isotypes in patients with RA. No such relationships were found for the first-degree relatives.

    Conclusions All anti-CCP and RF isotypes analysed occurred more commonly in unaffected first-degree relatives from multicase families than in controls, but with different isotype distribution from patients with RA.

  • 35.
    Ärlestig, Lisbeth
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Polymorphisms of the genes encoding CD40 and growth differentiation factor 15 and in the 9p21.3 region in patients with rheumatoid arthritis and cardiovascular diseaseManuscript (preprint) (Other academic)
  • 36.
    Ärlestig, Lisbeth
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Polymorphisms of the Genes Encoding CD40 and Growth Differentiation Factor 15 and in the 9p21.3 Region in Patients with Rheumatoid Arthritis and Cardiovascular Disease2012In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 39, no 5, p. 939-945Article in journal (Refereed)
    Abstract [en]

    Objective. Genes or gene products associated with coronary artery disease in the general population were analyzed in rheumatoid arthritis (RA) patients with atherothrombotic manifestations (ATM). Methods. A cross-sectional study of 681 individuals (498 women; 183 men) with RA (American College of Rheumatology criteria), a mean age of 60.6 +/- 13.2 years, and mean disease duration of 15.5 +/- 12.6 years who were consecutively recruited and followed for 6 years. The prevalence of ATM [i.e., myocardial infarction, angina pectoris with intervention, deep vein thrombosis/pulmonary embolism (DVT/PE), and/or stroke/transient ischemic attack (TIA)] was recorded. Polymorphisms were analyzed in the genes coding for growth differentiation factor 15 (GDF15)/monocyte inhibitory cytokine-1 (MIC-1; rs1058587), CD40 (rs1535045 and rs3765459), and the 9p21.3 locus (rs1333049). Controls were randomly selected (n = 687; matched for age and sex). Results. The distribution of genotypes of GDF15/MIC-1 differed significantly between patients with RA and controls (chi-squared = 6.40, 2 df, p = 0.041). ATM were associated with polymorphism of the GDF15/MIC-1 G allele (OR 2.21, 95% CI 1.17-4.18), and with CC genotype of the 9p21.3 locus (rs1333049; OR 1.92, 95% CI 1.15-3.19). Stroke/TIA in women was associated with GDF15/MIC-1 GG genotype (OR 3.75, 95% CI 1.06-13.33), while stroke/TIA in men was associated with CD40 homozygous major alleles (OR 6.48, 95% CI 1.31-32.0 and OR 2.78,95% CI 0.78-9.91, respectively). DVT/PE was associated with polymorphism in the GDF15/MIC-1 gene (rs1058587) minor allele (OR 3.53, 95% CI 1.30-9.58). Conclusion. The gene polymorphisms analyzed were associated with different ATM in RA. The GDF15/MIC-1 gene polymorphism was also associated with RA per se, suggesting a common etiology for RA and ATM. (First Release April 15 2012; J Rheumatol 2012;39:939-45; doi:10.3899/jrheuin.111336)

  • 37.