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- Acosta-Herrera, M, et al.
(författare)
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Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases
- 2019
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:3, s. 311-319
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Tidskriftsartikel (refereegranskat)abstract
- Immune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies.MethodsWe meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases.ResultsOur analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study.ConclusionsWe have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.
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- Diaz-Gallo, LM, et al.
(författare)
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Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility
- 2013
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 72:7, s. 1233-1238
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Tidskriftsartikel (refereegranskat)abstract
- The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc).Patients and methodsThe case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays.ResultsWe observed evidence of association of the rs6822844 and rs907715 variants with global SSc (pc=6.6E-4 and pc=7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (pc=1.7E-03 and pc=8E-4, respectively).ConclusionsThese results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases.
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- Diaz-Gallo, LM, et al.
(författare)
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Systematic approach demonstrates enrichment of multiple interactions between non-HLA risk variants and HLA-DRB1 risk alleles in rheumatoid arthritis
- 2018
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 77:10, s. 1454-1462
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Tidskriftsartikel (refereegranskat)abstract
- In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), a particular subset of HLA-DRB1 alleles, called shared epitope (SE) alleles, is a highly influential genetic risk factor. Here, we investigated whether non-HLA single nucleotide polymorphisms (SNP), conferring low disease risk on their own, interact with SE alleles more frequently than expected by chance and if such genetic interactions influence the HLA-DRB1 SE effect concerning risk to ACPA-positive RA.MethodsWe computed the attributable proportion (AP) due to additive interaction at genome-wide level for two independent ACPA-positive RA cohorts: the Swedish epidemiological investigation of rheumatoid arthritis (EIRA) and the North American rheumatoid arthritis consortium (NARAC). Then, we tested for differences in the AP p value distributions observed for two groups of SNPs, non-associated and associated with disease. We also evaluated whether the SNPs in interaction with HLA-DRB1 were cis-eQTLs in the SE alleles context in peripheral blood mononuclear cells from patients with ACPA-positive RA (SE-eQTLs).ResultsWe found a strong enrichment of significant interactions (AP p<0.05) between the HLA-DRB1 SE alleles and the group of SNPs associated with ACPA-positive RA in both cohorts (Kolmogorov-Smirnov test D=0.35 for EIRA and D=0.25 for NARAC, p<2.2e-16 for both). Interestingly, 564 out of 1492 SNPs in consistent interaction for both cohorts were significant SE-eQTLs. Finally, we observed that the effect size of HLA-DRB1 SE alleles for disease decreases from 5.2 to 2.5 after removal of the risk alleles of the two top interacting SNPs (rs2476601 and rs10739581).ConclusionOur data demonstrate that there are massive genetic interactions between the HLA-DRB1 SE alleles and non-HLA genetic variants in ACPA-positive RA.
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- Duggal, N, et al.
(författare)
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INVESTIGATING THE ROLE OF ACCELERATED IMMUNESENESCENCE IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 1152-1152
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Advancing age is recognised as a major risk factor for autoimmune inflammatory conditions, such as Rheumatoid Arthritis (RA). Despite strong associations with older age we understand little of the role ageing processes play in disease pathogenesis in RA. The immune system undergoes a dramatic remodelling with age, termed immunesenescence, which contributes towards increased risk of autoimmunity1. Previous research in patients with established RA has shown certain features of immunesenescence, such as thymic atrophy and telomere shortening in T cells, at a younger age2,3.ObjectivesIn this study we aimed to determine if immunesenescence is seen in the very earliest stages of RA and therefore might be a contributor to RA pathogenesis rather than a result of the disease.MethodsWe have assessed aspects of the aged immune phenotype by immunostaining and flow cytometry4 in adults with arthralgia (n=25), undifferentiated arthritis (UA; n=41), confirmed RA of less than 3 months (n=25) and more than 3 months duration (n=78) and compared these to age and sex matched healthy controls (n=38). Nanostring methodology was used to determine gene expression changes associated with the development of RA.ResultsWe observed increased features of T and B cell immunesenescence in DMARD-naïve recently diagnosed RA patients driven by reduced naïve T cells (p<0.01) and B cells (p<0.01), increased senescent (CD28-ve, CD57+ve, KLRG1+ve) T cells (p<0.01), an increased Th17/Treg ratio (p<0.01) and increased frequency of age-associated B cells (p<0.01). With the exception of naïve T cell frequency, which was reduced in UA patients (p<0.05), these changes were not seen in the very early stages of RA, namely patients with arthralgia and UA. These data suggest that immunesenescence only occurs once disease is established. Furthermore, using nanostring we have identified several biological ageing processes (DNA damage, autophagy) associated with this state of immunesenescence in RA.ConclusionAccelerated immune ageing is an early feature of RA and biological ageing processes represent novel targets to modulate disease progression.References[1]Duggal NA, Upton JA, Phillips AC, Sapey E, Lord JM (2013) An age-related numerical and functional deficit in CD19+CD24hiCD38hi B cells is associated with an increase in systemic autoimmunity. Aging Cell 12:873-881.[2]Goronzy, J.J. and Weyand CM (2001). Thymic function and peripheral T-cell homeostasis in rheumatoid arthritis. Trends Immunol. 22(5):251-5.[3]Steer SE, Williams FMK, Kato B, Gardner JP, Norman PJ, Hall MA, Kimra M, Vaughan R, Aviv A, Spector T (2007) Reduced telomere length in rheumatoid arthritis in independent of disease activity and duration. Ann Rheum Dis 66:476-480.[4]Duggal NA, Pollock RD, Lazarus NR, Harridge S, Lord JM (2018). Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood. Aging Cell 17:e12750Disclosure of InterestsNone declared
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