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

Saevarsdóttir, Saedís; Stefánsdóttir, Lilja; Sulem, Patrick; Þorleifsson, Guðmar; Ferkingstad, Egil; Rutsdottir, Gudrun; Glintborg, Bente; Westerlind, Helga; Gröndal, Gerður; Loft, Isabella Charlotte; Sørensen, Signe Bek; Lie, Benedicte A.; Brink, Mikael; Ärlestig, Lisbeth; Arnthórsson, Asgeir Ö.; Baecklund, Eva; Banasik, Karina; Bank, Steffen; Björkman, Lena; Ellingsen, Torkell; Erikstrup, Christian; Frei, Oleksandr; Gjertsson, Inger; Guðbjartsson, Daníel F.; Gudjonsson, Sigurjon A.; Halldorsson, Gisli H.; Hendricks, Oliver; Hillert, Jan; Høgdall, Estrid; Jacobsen, Søren; Jensen, Dorte Vendelbo; Jónsson, Helgi; Kastbom, Alf; Kockum, Ingrid; Kristensen, Salome; Kristjánsdóttir, Helga; Larsen, Margit Hørup; Linauskas, Asta; Hauge, Ellen‐Margrethe; Loft, Anne; Lúðvíksson, Björn Rúnar; Lund, Sigrún H.; Markusson, Thorsteinn; Másson, Gísli; Melsted, Páll; Moore, Kristjan H. S.; Munk, Heidi Lausten; Nielsen, Kaspar René; Norddahl, Gudmundur L.; Oddsson, Ásmundur; Olason, Pall I.; Olsson, Tomas; Ostrowski, Sisse Rye; Hørslev‐Petersen, Kim; Rögnvaldsson, Sölvi; Sanner, Helga; Silberberg, Gilad; Stefánsson, Hreinn; Sørensen, Erik; Sørensen, Inge Juul; Turesson, Carl; Bergman, Thomas; Alfredsson, Lars; Kvien, Tore K; Brunak, Søren; Steinsson, Kristján; Andersen, Vibeke; Andreassen, Ole A.; Rantapää-Dahlqvist, Solbritt; Hetland, Merete Lund; Klareskog, Lars; Askling, Johan; Padyukov, Leonid; Pedersen, O B Vesterager; Þorsteinsdóttir, Unnur; Jónsdóttir, Ingileif; Stefánsson, Kāri

doi:10.1136/annrheumdis-2021-221754

Cited by 44 publications

(34 citation statements)

References 51 publications

(90 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Selection of an appropriate b/tsDMARD is also critical for obtaining therapeutic effects at an early treatment course. In recent years, there have been increased reports on predicting optimal b/tsDMARDs using various technological platforms, such as machine learning and multi-omics analyses ( 30 – 33 ). Further studies are needed on the risk factors and treatment strategies for D2T RA, using genomic information and synovial tissue samples, with an in-depth consideration of the pathogenesis of the disease.…”

Section: Discussion: How To Prevent Patients From Becoming Difficult-...mentioning

confidence: 99%

Difficult-to-treat rheumatoid arthritis: Current concept and unsolved problems

Watanabe¹,

Okano²,

Gon³

et al. 2022

Front. Med.

View full text Add to dashboard Cite

Over the past several decades, the treatment of rheumatoid arthritis (RA) has advanced significantly, and clinical, structural, and functional remission are achievable therapeutic goals. However, a substantial number of patients show resistance to multiple drugs. In particular, patients whose disease activity cannot be controlled despite the use of two or more biological disease-modifying antirheumatic drugs (DMARDs) or targeted synthetic DMARDs (tsDMARDs) with different mechanisms of action (MOA) have recently been referred to as having difficult-to-treat RA (D2T RA). D2T RA is a heterogeneous and multifactorial disease state, and the major problems are uncontrolled disease activity and decreased quality of life, as well as the economic burden due to frequent healthcare utilization and multiple admissions. Since the concept of D2T RA is relatively new and publication regarding D2T RA is limited, the mechanism underlying DMARD inefficacy and which factors form a “difficult-to-treat” state in such patients are not yet fully understood. It is also possible that factors contributing to D2T RA may differ by patient, sex, country, and race. The present Mini Review introduces the current concept and unsolved problems of D2T RA, including the definition, prevalence, and factors contributing to D2T RA. We then discuss the management and therapeutic strategies for D2T RA. Finally, we explore a clinical approach to prevent patients from developing D2T RA.

show abstract

Section: Discussion: How To Prevent Patients From Becoming Difficult-...mentioning

confidence: 99%

Difficult-to-treat rheumatoid arthritis: Current concept and unsolved problems

Watanabe¹,

Okano²,

Gon³

et al. 2022

Front. Med.

View full text Add to dashboard Cite

show abstract

“…Genetic association estimates for seropositive and seronegative RA were taken from a published study of RA (21) that reported separate genome-wide association studies (GWAS) of seropositive (18,019 cases and 991,604 controls) and seronegative (8,515 cases and 1,015,471 controls) RA. One hundred and thirty-five autosomal single nucleotide polymorphisms (SNPs) that were associated with RA (either seropositive, seronegative or both) in previous GWAS of European ancestry or multi-ancestry were selected as IVs for RA (22).…”

Section: Methodsmentioning

confidence: 99%

Rheumatoid arthritis and idiopathic pulmonary fibrosis: a bidirectional Mendelian randomisation study

Leavy

Kawano-Dourado

Stewart

et al. 2022

Preprint

View full text Add to dashboard Cite

Introduction: A usual interstitial pneumonia (UIP) pattern of lung injury is a key feature of idiopathic pulmonary fibrosis (IPF) and is also observed in up to 40% of individuals with rheumatoid arthritis (RA) related Interstitial Lung Disease (RA-ILD). The RA-UIP phenotype could result from either a causal relationship of RA on UIP or vice versa, or from a simple co-occurrence of RA and IPF due to shared demographic, genetic or environmental risk factors. Methods: We used two-sample bidirectional Mendelian Randomisation (MR) to investigate the causal effects of RA on UIP and of UIP on RA, using variants from genome-wide association studies of RA (separately for seropositive and seronegative RA) and of IPF as genetic instruments. We conducted inverse-variance-weighted fixed-effect MR as a primary analysis and undertook sensitivity analyses to assess potential violations of the key MR assumption of no (horizontal) pleiotropy. Results: Seropositive RA showed a significant protective effect on IPF (Odds Ratio, OR = 0.93; 95% Confidence Interval, CI: 0.87-0.99; P=0.032), while the MR in the other direction showed a strongly significant causal effect of IPF on seropositive RA (OR = 1.06, 95% CI: 1.04-1.08, P=1.22x10-11). Conclusion: Our findings support the hypothesis that RA-UIP may be due to a cause-effect relationship between IPF and RA, rather than due to a coincidental occurrence of IPF in patients with RA. The causal effect of IPF on seropositive RA suggests that patho-mechanisms involved in the development of UIP may promote RA and would suggest that screening for UIP in asymptomatic RA patients may be warranted and may influence therapy management of patients with RA-UIP.

show abstract

“…The importance of non-HLA susceptibility loci was recently confirmed through analyses performed in large populations of patients with seropositive and seronegative RA. A genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ~1 million controls from Northwestern Europe found 25 sequence variants of the Janus Kinase (JAK)/ signal transducer and activator of transcription proteins (STAT) pathway characterising patients with RA, 33 for seropositive and 2 for seronegative (12). However, both signals in seronegative RA were also found in seropositive RA and pointed to causal genes: a missense variant rs2476601-A in PTPN22 and intronic variant rs7731626-A in ANKRD55.2 Another study, applying mendelian randomisation design on 3 GWASs metanalysis, found differences in cytokine patterns of genetic activity between seronegative and seropositive RA (13).…”

Section: Reviewmentioning

confidence: 99%

Seronegative rheumatoid arthritis: one year in review 2023

Stefano

D’Onofrio

Gandolfo

et al. 2023

Clinical and Experimental Rheumatology

View full text Add to dashboard Cite

In the past 20 years, earlier diagnosis and more intensive management have considerably improved the prognosis of rheumatoid arthritis (RA), with milder disease course achieved in particular in seropositive patients. In contrast, seronegative RA has remained largely neglected, and continues to be surrounded by uncertainties regarding its correct diagnosis, clinical phenotype, optimal treatment strategies and relevant outcomes. The purpose of this review is to summarise new insights about the pathogenic, clinical and prognostic peculiarities of seronegative RA that emerged during 2022, and that make this disease subset at least partially different from its seropositive counterpart.

show abstract

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

Cited by 44 publications

References 51 publications

Difficult-to-treat rheumatoid arthritis: Current concept and unsolved problems

Difficult-to-treat rheumatoid arthritis: Current concept and unsolved problems

Rheumatoid arthritis and idiopathic pulmonary fibrosis: a bidirectional Mendelian randomisation study

Seronegative rheumatoid arthritis: one year in review 2023

Contact Info

Product

Resources

About