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- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 2. |
- Giustozzi, M., et al.
(författare)
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Safety of Anticoagulation in Patients Treated with Urgent Reperfusion for Ischemic Stroke Related to Atrial Fibrillation
- 2020
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Ingår i: Stroke. - 0039-2499. ; 51:8, s. 2347-2354
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: The optimal timing for starting oral anticoagulant after an ischemic stroke related to atrial fibrillation remains a challenge, mainly in patients treated with systemic thrombolysis or mechanical thrombectomy. We aimed at assessing the incidence of early recurrence and major bleeding in patients with acute ischemic stroke and atrial fibrillation treated with thrombolytic therapy and/or thrombectomy, who then received oral anticoagulants for secondary prevention. Methods: We combined the dataset of the RAF and the RAF-NOACs (Early Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Treated With Non-Vitamin K Oral Anticoagulants) studies, which were prospective observational studies carried out from January 2012 to March 2014 and April 2014 to June 2016, respectively. We included consecutive patients with acute ischemic stroke and atrial fibrillation treated with either vitamin K antagonists or nonvitamin K oral anticoagulants. Primary outcome was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding within 90 days from the inclusion. Treated-patients were propensity matched to untreated-patients in a 1:1 ratio after stratification by baseline clinical features. Results: A total of 2159 patients were included, 564 (26%) patients received acute reperfusion therapies. After the index event, 505 (90%) patients treated with acute reperfusion therapies and 1287 of 1595 (81%) patients untreated started oral anticoagulation. Timing of starting oral anticoagulant was similar in reperfusion-treated and untreated patients (median 7.5 versus 7.0 days, respectively). At 90 days, the primary study outcome occurred in 37 (7%) patients treated with reperfusion and in 146 (9%) untreated patients (odds ratio, 0.74 [95% CI, 0.50-1.07]). After propensity score matching, risk of primary outcome was comparable between the 2 groups (odds ratio, 1.06 [95% CI, 0.53-2.02]). Conclusions: Acute reperfusion treatment did not influence the risk of early recurrence and major bleeding in patients with atrial fibrillation-related acute ischemic stroke, who started on oral anticoagulant. © 2020 Georg Thieme Verlag. All rights reserved.
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| 4. |
- Werth, V, et al.
(författare)
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BIIB059, A HUMANIZED MONOCLONAL ANTIBODY TARGETING BDCA2 ON PLASMACYTOID DENDRITIC CELLS (PDC), SHOWS DOSE-RELATED EFFICACY IN THE PHASE 2 LILAC STUDY IN PATIENTS (PTS) WITH ACTIVE CUTANEOUS LUPUS ERYTHEMATOSUS (CLE)
- 2020
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 120-121
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- CLE represents an unmet medical need with no approved therapy. BIIB059, a humanized monoclonal antibody, binds to BDCA2 and inhibits pro-inflammatory mediators production, including type I interferons. BIIB059 was evaluated in Phase 1 studiesNCT02106897andNCT03224793. LILAC is a 2-part Phase 2 study: Part A enrolled SLE pts; Part B enrolled pts with active CLE (NCT02847598).Objectives:Evaluate efficacy and safety of BIIB059 in pts enrolled in Part B at Week 16, end of treatment (EOT) period.Methods:Pts with active CLE, SCLE and/or CCLE and adjudicated Cutaneous Lupus Disease Area and Severity Index – Activity (CLASI-A) ≥8 were enrolled and randomized to receive either BIIB059 (50, 150 or 450 mg) or placebo (PBO) s.c. Q4W. Primary endpoint was dose response defined by % change in CLASI-A score from baseline (BL) to Week 16. Secondary endpoints included CLASI-50 response rate and ≥ 7-point reduction in CLASI-A score from baseline to EOT. Adverse events and serious adverse events were recorded throughout the study.Results:132 pts with active CLE were randomized. The study met its primary endpoint, demonstrating a dose response (p= 0.0005) and a statistically significant difference in % change from BL in CLASI-A score in BIIB059-treated pts vs PBO. Table 1 and Table 2 summarize efficacy and safety results, respectively.Table 1.Efficacy EndpointsBIIB059PBO50 mg150 mg450 mgLS Mean (SE)LS Mean (SE)LSMD*from PBO (95% CI)P val.LS Mean(SE)LSMD*from PBO (95% CI)P val.LS Mean(SE)LSMD*from PBO (95% CI)P val.Primary EndpointCLASI-A % change from BL-14.5 (6.4)-40.8 (7.5)-26.3 (-45.7; -7.0)0.008-47.9 (7.4)-33.5 (-52.7; -14.3)0.001-43.5 (5.5)-28.0 (-44.5; -11.5)0.001Secondary Endpointsn(%)n(%)LSMD*from PBO (95% CI)P val.n(%)LSMD*from PBO (95% CI)P val.n(%)LSMD*from PBO (95% CI)P val.Prop. of participants achieving CLASI 507/32 (21.9%)10/26 (38.5%)15.8% (-7; 39)0.13311/25 (44.0%)21 (-2.8; 45)0.05920/43 (46.5%)23 (3; 44)0.024Prop. of participants achieving a ≥7-point CLASI-A reduction from BL7/32 (21.9%)9/26 (34.6%)12.3 (-11.3; 35.8)0.22812/25 (48.0%)22.2 (-2.0; 46.3)0.05518/43 (41.8%)16.8 (-6.7; 40.4)0.048*LSMD=LS Mean DifferencePBOBIIB059OVERALLN=3350 mgN=26150 mgN=25450 mgN=48PooledN=99N=132Any Event, n(%)18 (54.5)17 (65.4)12 (48)33 (68.8)62 (62.6)80 (60.6)SeverityMild11 (33.3)11 (42.3)8 (32.0)19 (39.6)38 (38.4)49 (37.1)Moderate4 (12.1)6 (23.1)3 (12.0)12 (25.0)21 (21.2)25 (18.9)Severe3 (9.1)01 (4.0)2 (4.2)3 (3.0)6 (4.5)Related events6 (18.2)9 (34.6)4 (16.0)16 (33.3)29 (29.3)35 (26.5)Serious events2 (6.1)03 (12.0)2 (4.2)5 (5.1)7 (5.3)Related serious events1 (3.0)01 (4.0)1 (2.1)2 (2.0)3 (2.3)Events leading to drug withdrawal01 (3.8)1 (4.0)1 (2.1)3 (3.0)3 (2.3)Events leading to study withdrawal0001 (2.1)1 (1.0)1 (0.8)Fatal events000000Conclusion:BIIB059 administration to pts with active CLE resulted in statistically significant dose-related improvement in disease activity vs PBO with no untoward safety signals. Further development of BIIB059 in CLE is warranted.Disclosure of Interests:Victoria Werth Grant/research support from: Biogen, Celgene, Gilead, Janssen, Viela, Consultant of: Biogen, Gilead, Janssen, Abbvie, GSK, Resolve, AstraZeneca, Amgen, Eli Lilly, EMD Serono, BMS, Viela, Kyowa Kirin, Richard Furie Grant/research support from: AstraZeneca, Biogen, Consultant of: AstraZeneca, Biogen, Juanita Romero-Diaz Consultant of: Biogen, Sandra Navarra Speakers bureau: Astellas, Novartis, Pfizer, Johnson & Johnson, Abbvie, Kenneth Kalunian Grant/research support from: Pfizer, Lupus Research Alliance, Sanford Consortium, Consultant of: Genentech, Nektar, BMS, Janssen, AstraZeneca, Biogen, Vielabio, Equillium, Eli Lilly, ILTOO, Abbvie, Amgen, Roche, Gilead, Ronald van Vollenhoven Grant/research support from: AbbVie, Arthrogen, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Pfizer, and UCB, Consultant of: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, GSK, Janssen, Lilly, Medac, Merck, Novartis, Pfizer, Roche, and UCB, Filippa Nyberg Consultant of: Biogen, Benjamin Kaffenberger Grant/research support from: Amgen, Biogen, InflaRx, Veloce Biopharmaceuticals, Dermatology Foundation, Saira Sheikh: None declared, Goran Radunovic: None declared, XIAOBI HUANG Shareholder of: Biogen, Employee of: Biogen, HUA CARROLL Shareholder of: Biogen, Employee of: Biogen, Francois Gaudreault Shareholder of: Biogen, Employee of: Biogen, Adam Meyers Shareholder of: Biogen, Employee of: Biogen, Catherine Barbey Shareholder of: Biogen, Employee of: Biogen, Cristina Musselli Shareholder of: Biogen, Employee of: Biogen, NATHALIE FRANCHIMONT Shareholder of: Biogen, Employee of: Biogen
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