Despite the success of genome-wide association studies (GWAS) in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA) susceptibility, the lack of information on ...the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples), Exomechip genotyping (n = 18,409 case/control samples) and targeted exon-sequencing (n = 2,236 case/controls samples) to demonstrate that three protein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3 x 10(-21)), A928V (rs35018800, OR = 0.53, P = 1.2 x 10(-9)), and I684S (rs12720356, OR = 0.86, P = 4.6 x 10(-7)). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6 x 10(-18)), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; P(omnibus) = 0.005). Finally, in a phenome-wide association study (PheWAS) assessing >500 phenotypes using electronic medical records (EMR) in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, ...complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.
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.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Treatment strategies blocking tumour necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA). However, a significant subset of patients does not respond for ...unknown reasons. Currently, there are no means of identifying these patients before treatment. This study was aimed at identifying genetic factors predicting anti-TNF treatment outcome in patients with RA using a genome-wide association approach.
We conducted a multistage, genome-wide association study with a primary analysis of 2 557 253 single-nucleotide polymorphisms (SNPs) in 882 patients with RA receiving anti-TNF therapy included through the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry and the database of Apotheekzorg. Linear regression analysis of changes in the Disease Activity Score in 28 joints after 14 weeks of treatment was performed using an additive model. Markers with p<10(-3) were selected for replication in 1821 patients from three independent cohorts. Pathway analysis including all SNPs with p<10(-3) was performed using Ingenuity.
772 markers showed evidence of association with treatment outcome in the initial stage. Eight genetic loci showed improved p value in the overall meta-analysis compared with the first stage, three of which (rs1568885, rs1813443 and rs4411591) showed directional consistency over all four cohorts studied. We were unable to replicate markers previously reported to be associated with anti-TNF outcome. Network analysis indicated strong involvement of biological processes underlying inflammatory response and cell morphology.
Using a multistage strategy, we have identified eight genetic loci associated with response to anti-TNF treatment. Further studies are required to validate these findings in additional patient collections.
Abstract
Background/Aims
Early diagnosis and intervention improves outcomes of immune mediated rheumatic and musculoskeletal diseases (RMDs) but may be hampered by diagnostic uncertainty. The extent ...to which rationally selected molecular parameters add value to clinical characteristics for diagnostic prediction in undifferentiated disease states warrants investigation. B lymphocytes play an increasingly recognised role in rheumatoid arthritis (RA) pathogenesis, and cell-specific methylation patterns link environmental exposures to genetic risk. We derived and tested the practical utility of a B lymphocyte-derived DNA methylation signature for predicting RA in an early arthritis clinic cohort.
Methods
CD19+ B cell and peripheral blood mononuclear cell (PBMC) whole genome DNA methylation array data were available, respectively, from 109 inflammatory arthritis patients naïve to immunomodulatory drugs (Newcastle, UK; 38% confirmed to have a diagnosis of RA within 1 year) and 50 untreated undifferentiated arthritis (UA) patients (Leiden, The Netherlands; 68% classifiable RA within 1 year by 1987 ACR criteria versus alternate diagnoses). A bespoke machine learning pipeline employed a sequential model-based optimisation (SMBO) procedure for selecting, tuning and applying methods amongst ten feature-selection, six data-sampling and two classification algorithms in the Newcastle “training cohort.” The predictive performance of the resultant optimised molecular classifier was assessed in the independent Leiden “test cohort” alongside a previously described clinical prediction rule, using comparative area under receiver operating characteristic (AUROC) curves. A modification to the clinical prediction rule that incorporated a single parameter to reflect molecular classification was also assessed. The pipeline was implemented using the R machine learning package mlr.
Results
Using the SMBO approach, 27 CpGs maximally discriminatory for RA were selected from B lymphocyte DNA methylome training data, and a molecular classifier was derived using the random forest algorithm. Applied to the independent PBMC methylome in UA patients, the classifier and the validated Leiden prediction rule performed similarly in predicting RA (AUROC 95% CI = 0.8 0.66-0.94 versus 0.78 0.64-0.92). Interestingly, incorporating a molecular risk score based on the 27-CpG signature into the validated Leiden clinical prediction rule significantly improved its performance (AUROC 95% CI = 0.89 0.79-0.98 versus 0.78 0.64-0.92; p = 0.048). When applied to the sub-cohort of 25 patients in the Leiden cohort who were negative for anti-citrullinated peptide autoantibodies (ACPA), enhanced performance of the modified over the un-modified clinical prediction rule was maintained (AUROC 95% CI = 0.82 0.65-1 versus 0.70 0.45-0.95, respectively), although the difference did not reach statistical significance in this smaller cohort.
Conclusion
We provide a proof of principle for the application of a B lymphocyte-derived epigenetic signature to enhance prediction of RA in UA patients using stored PBMCs. Further refinement of our pipeline represents a plausible means to expedite the diagnosis in undifferentiated RMDs and could offer pathophysiological insight.
Disclosure
N. Naamane: None. E. Niemantsverdriet: None. N. Thalayasingam: None. N. Nair: None. A.D. Clark: None. K. Murray: None. B. Hargreaves: None. L.N. Reynard: None. S. Eyre: None. A. Barton: None. A.H.M. van der Helm-van Mil: None. A.G. Pratt: None.
Abstract
Background
Black North American communities have been disproportionately affected by COVID-19. These data have been largely based on case counts, hospitalizations and mortality data. ...Serologic testing enables a more complete determination of infection burden by documenting infection in persons with symptomatic as well as asymptomatic infection. We used serologic testing to determine the extent to which SARS-CoV-2 had penetrated into the Black community. We examined risk factors associated with seropositivity, including the presence of medical comorbidities and the social determinants of health.
Methods
We conducted a cross-sectional survey in a COVID-19 high-prevalence zone in Ontario along with 2 areas that have lower rates of COVID-19 cases. SARS-CoV-2 IgG antibodies were determined using the EUROIMMUN assay. The study samples were collected between August 15, 2020, and December 15, 2020 prior to the deployment of COVID-19 vaccines. Proportions were compared using Fishers Exact test or chi-square; potential risk factors were examined using a multiple logistic regression approach.
Results
Among 387 evaluable subjects, the majority, 274 (70.8%) were enrolled from northwest Greater Toronto Area (GTA) and adjoining suburban areas of Peel, Ontario with a high proportion of Black residents. The seropositivity rates for the lower prevalence areas (Oakville and London, Ontario) were comparable (3.3% (2/60; 95% CI 0.4-11.5) and 3.9% (2/51; 95% CI 0.5-13.5), respectively). The seropositivity rate for the northwest GTA was 12.6% (26/206); RR 3.5, 95% CI 1.3-9.8). Persons under the age of 19 years had the highest seropositivity rate (10/50; 20.0%, 95% CI 10.3-33.7%). Front-line workers were greater than 3 times more likely to be seropositive compared with non-frontline workers (13.0 vs 3.2%; p=.01; RR 3.3 (95% CI 1.3 – 8.3). There was an interaction effect between race and location of residence as this relates to the relative risk of seropositivity.
Conclusion
During the pre-vaccine phase of the COVID-19 pandemic, the seropositivity rate for SARS-CoV-2 within a COVID-19 high-prevalence area was 3-fold greater than lower prevalence areas of Ontario, Canada. The data help to define the burden of COVID-19 within a community with a high proportion of Black residents compared with other communities.
Disclosures
All Authors: No reported disclosures
Aspergillus endocarditis is very difficult to cure, even with aggressive surgical debridement and antifungal therapy. Patients with embolic involvement of the central nervous system have an extremely ...poor prognosis. We describe a patient with prosthetic valve endocarditis due to Aspergillus fumigatus who developed emboli in the brain, eye, and lower extremities. With aggressive surgical debridement of involved sites, aortic valve and root replacement, and long-term therapy with oral voriconazole, he remains without any evidence of infection 2 years later.
Racialized communities, including Black Canadians, have disproportionately higher COVID-19 cases. We examined the extent to which SARS-CoV-2 infection has affected the Black Canadian community and ...the factors associated with the infection.
We conducted a cross-sectional survey in an area of Ontario (northwest Toronto/Peel Region) with a high proportion of Black residents along with 2 areas that have lower proportions of Black residents (Oakville and London, Ontario). SARS-CoV-2 IgG antibodies were determined using the EUROIMMUN assay. The study was conducted between August 15, 2020, and December 15, 2020.
Among 387 evaluable subjects, the majority, 273 (70.5%), were enrolled from northwest Toronto and adjoining suburban areas of Peel, Ontario. The seropositivity values for Oakville and London were comparable (3.3% (2/60; 95% CI 0.4-11.5) and 3.9% (2/51; 95% CI 0.5-13.5), respectively). Relative to these areas, the seropositivity was higher for the northwest Toronto/Peel area at 12.1% (33/273), relative risk (RR) 3.35 (1.22-9.25). Persons 19 years of age or less had the highest seropositivity (10/50; 20.0%, 95% CI 10.3-33.7%), RR 2.27 (1.23-3.59). There was a trend for an interaction effect between race and location of residence as this relates to the relative risk of seropositivity.
During the early phases of the pandemic, the seropositivity within a COVID-19 high-prevalence zone was threefold greater than lower prevalence areas of Ontario. Black individuals were among those with the highest seroprevalence of SARS-CoV-2.
Age is a leading predictor of poor outcomes after brain injuries like stroke. The extent to which age is associated with preexisting burdens of brain changes, visible on neuroimaging but rarely ...considered in acute decision-making or trials, is unknown.
To explore the mediation of age on functional outcome by neuroimaging markers of frailty (hereinafter neuroimaging frailty) in patients with acute ischemic stroke receiving endovascular thrombectomy (EVT).
This cohort study was a post hoc analysis of the Safety and Efficacy of Nerinetide (NA-1) in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) randomized clinical trial, which investigated intravenous (IV) nerinetide in patients who underwent EVT within a 12-hour treatment window. Patients from 48 acute care hospitals in 8 countries (Canada, US, Germany, Korea, Australia, Ireland, UK, and Sweden) were enrolled between March 1, 2017, and August 12, 2019. Markers of brain frailty (brain atrophy subcortical or cortical, white matter disease periventricular or deep, and the number of lacunes and chronic infarctions) were retrospectively assessed while reviewers were blinded to other imaging (eg, computed tomography angiography, computed tomography perfusion) or outcome variables. All analyses were done between December 1, 2022, and January 31, 2023.
All patients received EVT and were randomized to IV nerinetide (2.6 mg/kg of body weight) and alteplase (if indicated) treatment vs best medical management.
The primary outcome was the proportion of the total effect of age on 90-day outcome, mediated by neuroimaging frailty. A combined mediation was also examined by clinical features associated with frailty and neuroimaging markers (total frailty). Structural equation modeling was used to create latent variables as potential mediators, adjusting for baseline, early ischemic changes; stroke severity; onset-to-puncture time; nerinetide treatment; and alteplase treatment.
Among a total of 1105 patients enrolled in the study, 1102 (median age, 71 years IQR, 61-80 years; 554 50.3% male) had interpretable imaging at baseline. Of these participants, 549 (49.8%) were treated with IV nerinetide. The indirect effect of age on 90-day outcome, mediated by neuroimaging frailty, was associated with 85.1% of the total effect (β coefficient, 0.04 per year 95% CI, 0.02-0.06 per year; P < .001). When including both frailty constructs, the indirect pathway was associated with essentially 100% of the total effect (β coefficient, 0.07 per year 95% CI, 0.03-0.10 per year; P = .001).
In this cohort study, a secondary analysis of the ESCAPE-NA1 trial, most of the association between age and 90-day outcome was mediated by neuroimaging frailty, underscoring the importance of features like brain atrophy and small vessel disease, as opposed to chronological age alone, in predicting poststroke outcomes. Future trials could include such frailty features to stratify randomization or improve adjustment in outcome analyses.
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