Iyas Daghlas

Lipoprotein(a) exhibits in vitro antifibrinolytic properties, though it remains uncertain whether this translates into an effect on thromboembolic disease risk. We applied Mendelian randomization (MR) to evaluate the relationship between genetically predicted lipoprotein(a) levels, venous thromboembolism (VTE), and circulating coagulation protein levels. We instrumented lipoprotein(a) using two genetic variants (rs10455872 and rs3798220) that explain 36% of circulating lipoprotein(a) variance. The primary outcomes were first (81,190 cases) and recurrent VTE (1,775 cases). Comparator outcomes included coronary artery disease (181,522 cases) and calcific aortic stenosis (13,765 cases). We performed MR analyses to estimate the association of a genetically predicted 100 nmol/L increase in lipoprotein(a) with each outcome. In exploratory analyses, we tested associations with levels of 35 coagulation proteins in the UK Biobank (n = 46,218) and deCODE (n = 35,559) cohorts. Genetically predicted lipoprotein(a) was associated with a small reduction in risk of first VTE (odds ratio [OR] 0.98, 95% confidence interval [CI] 0.96–0.99, P = 0.002), though this was not supported by colocalization (posterior=12%), suggesting that the MR association was driven by genetic confounding. There was no association with recurrent VTE (hazard ratio 1.03, 95% CI 0.91–1.16, P = 0.68). In contrast, genetically predicted lipoprotein(a) was strongly associated with increased risk of coronary artery disease (OR 1.31, 95% CI 1.29–1.33) and calcific aortic stenosis (OR 1.35, 95% CI 1.30–1.40). After multiple testing correction, genetically predicted lipoprotein(a) had no significant association with any coagulation proteins. Human genetic evidence does not support a clinically meaningful role for lipoprotein(a) in VTE risk. These findings support targeting of lipoprotein(a)-lowering therapies toward atherosclerotic and valvular diseases rather than thromboembolic indications.

Objective: Immune effector cell-associated neurotoxicity syndrome (ICANS) typically manifests within the first week following chimeric antigen receptor (CAR) T-cell therapy and has rarely been described to develop beyond 1 month after treatment. This report describes the occurrence of markedly delayed ICANS in the setting of non-infectious meningoencephalitis. Methods: We report two cases of markedly delayed ICANS with cerebrospinal fluid (CSF) pleocytosis comprised primarily of CAR T-cells. Results: Two patients, aged 54 and 67 years, developed ICANS at 71 and 46 days, respectively, following administration of ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy. CSF analysis demonstrated elevated total nucleated cell (TNC) counts of 1055 and 605 cells/μL, respectively, with marked lymphocytic predominance (94% and 90%), of which 90.4% and 95.4% were CAR T-cells. Both patients improved with corticosteroids and immunotherapy. Discussion: The identification of CAR T-cells in CSF analysis proved critical for clinical management, enabling early discontinuation of empiric meningeal antimicrobial therapy and implementation of targeted immunosuppressive treatment. This report highlights a rare presentation of markedly delayed ICANS associated with robust infiltration of CAR T-cells into the CSF, expanding our understanding of the temporal spectrum and pathophysiology of ICANS.

Background: Non-monogenic arteriopathies are often classified as distinct entities according to the arterial territory involved, yet they share clinical features and may co-occur in the same individual. This pattern suggests shared susceptibility across anatomically distinct arteriopathies, potentially driven by common biological and genetic mechanisms. Methods: We investigated the shared genetic architecture of five arteriopathies (cervical artery dissection (CeAD), intracranial aneurysm (IA), spontaneous coronary artery dissection (SCAD), aortic aneurysm and dissection (AAD), and fibromuscular dysplasia (FMD)) using LD score regression, Association analysis based on SubSETs (ASSET), pairwise Multi-Trait Analysis of Genome-wide association summary statistics (MTAG), pleiotropy mapping and Mendelian randomization (MR) to identify shared loci and prioritise candidate causal genes. Results: LD score regression identified significant positive genetic correlations between CeAD-SCAD (rg = 0.64), IA-AAD (rg = 0.33), IA-SCAD (rg = 0.37), CeAD-AAD (rg = 0.56) and SCAD-AAD (rg = 0.20). ASSET identified 37 shared independent loci, and in MTAG analyses, one novel locus was identified for CeAD and SCAD (SLC39A8) and one for IA (FGF5). 13 loci showed strong cross-trait colocalization, including PHACTR1, LRP1, and CDKN2B-AS1. Using the Genotype-Phenotype Map, we found that arteriopathy-associated variants colocalized with blood pressure- and migraine-related traits, while many showed effect directions opposite to those observed for coronary artery disease. Proteome-wide MR identified 67 circulating proteins associated with at least one trait, including ECM1 and SHISA5 for CeAD and FGF5 for IA, with 17 supported by colocalization. Transcriptome-wide MR identified 204 colocalized tissue?specific signals, of which, 14 were shared across multiple traits. Enrichment analyses implicated pathways related to vascular development, smooth muscle cell function, extracellular matrix organization, and TGF-? signaling. Conclusions: These findings support shared genetic architecture across anatomically distinct arteriopathies, implicating pathways involved in vascular structure and prioritising therapeutic targets for future mechanistic investigation.

It is uncertain whether the protein targets of direct oral anticoagulants (DOACs) causally influence cerebral venous thrombosis (CVT) risk. We used Mendelian randomization (MR) to examine the association between genetically proxied levels of DOAC protein targets and CVT risk. We identified genetic proxies for the protein targets of established and emerging DOACs: circulating thrombin, activated factor X (FXa), and factor XI (FXI). CVT cases were ascertained from the UK Biobank (n = 337,134) and FinnGen cohorts (n = 454,144). For each drug target, we estimated the association between a genetically proxied one-standard deviation reduction in circulating protein levels and CVT risk using the Wald ratio. Cohort-specific estimates were meta-analyzed using the fixed-effect inverse variance-weighted method. We identified 422 total CVT cases across both cohorts. Genetically proxied lower levels of all 3 DOAC protein targets associated with reduced CVT risk: FXI (odds ratio [OR] 0.38, 95% CI 0.26-0.55), FXa (OR 0.28, 95% CI 0.10-0.78), and thrombin (OR 0.22, 95% CI 0.07-0.74). We found strong genetic evidence linking FXI to CVT pathogenesis and suggestive genetic evidence for FXa and thrombin. Inhibition of these proteins with DOACs may represent an effective therapeutic strategy for CVT.

Background: The ABCD ² score, used to triage patients with transient ischemic attack (TIA), was developed before contemporary use of dual antiplatelet therapy (DAPT) and therefore estimates pretreatment stroke risk. However, posttreatment stroke risk after DAPT may be more relevant for clinical triage. We aimed to quantify residual ischemic stroke risk following DAPT in patients with high‐risk TIA. Methods: We conducted a post hoc analysis of high‐risk patients with TIA enrolled in the POINT (Platelet‐Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial who were treated with DAPT. We calculated Kaplan–Meier estimates of ischemic stroke risk at 2, 7, and 90 days. Risk estimates were further stratified according to ABCD ² category (4–5 versus 6–7) and presence of infarct on index imaging despite symptom resolution. Observed risks were compared with ABCD ² predictions. Results: A total of 1052 POINT participants experienced a TIA and were treated with DAPT. Cumulative ischemic stroke risks were 1.3% (95% CI, 0.6–1.9) at 2 days, 2.0% (95% CI, 1.2–2.9) at 7 days, and 4.1% (95% CI, 2.8–5.3) at 90 days, all below ABCD ² ‐predicted risks of 5.1, 7.4, and 11.9%, respectively. Incident ischemic stroke risk did not differ by ABCD ² category ( P =0.80) but was higher in those with acute infarct on index imaging ( P =0.02). In patients with infarct on imaging despite symptom resolution, 2‐day ischemic stroke risk (3.4% [95% CI, 0.1–6.1]) approximated ABCD ² risk predictions, whereas those without evidence of infarct were at 6‐fold lower 2‐day risk (0.8% [95% CI, 0.0–1.4]). Conclusions: High‐risk patients with TIA treated with DAPT had substantially lower early stroke risk than predicted by ABCD ² , particularly in the absence of acute infarct on neuroimaging. Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT00991029.

Background: Lipoprotein(a) (Lp(a)) is a highly atherogenic lipoprotein and the target of investigational therapies. Using a Mendelian randomization study design, we aimed to clarify associations between genetically predicted Lp(a) levels and cerebrovascular disease outcomes and related phenotypes. Methods: We obtained genetic associations with Lp(a) levels ( n =343 681), ischemic stroke subtypes (≤62 100 cases), intracranial hemorrhage subtypes (≤15 400 cases), and 12 related cerebrovascular phenotypes. Lp(a) was proxied using 2 LPA genetic variants (rs10455872 and rs3798220) that explain 36% of the variance in Lp(a) levels. We performed Mendelian randomization analyses to estimate the association of a genetically predicted 100 nmol/L increase in Lp(a) levels on each outcome. Results: Genetically predicted Lp(a) levels associated with significantly increased risk of all‐cause ischemic stroke (odds ratio [OR], 1.04 [95% CI, 1.02–1.07], P =2.05×10 ⁻⁴ ) and large artery atherosclerotic stroke (OR, 1.23 [95% CI, 1.14–1.33], P =3.54×10 ⁻⁷ ). There was a nominal association with cardioembolic stroke (OR, 1.07 [95% CI, 1.01–1.13], P =0.02), and no evidence for association with small vessel stroke (OR, 0.98 [95% CI, 0.91–1.06], P =0.60). Associations with early‐onset stroke were similar, though with a greater magnitude of association for large artery atherosclerotic stroke (OR, 1.37 [95% CI, 1.15–1.64], P =5.58×10 ⁻⁴ ). Analyses of secondary outcomes paralleled these findings, including significant associations of genetically predicted Lp(a) with carotid plaque and atrial fibrillation, nominal associations with lobar hemorrhage and autopsy‐confirmed microinfarcts, and null associations with cerebral small vessel disease phenotypes. Conclusions: Elevated Lp(a) is primarily associated with ischemic stroke due to large artery atherosclerosis, while showing no link to cerebral small vessel disease. These findings support prioritization of patients with atherosclerotic cerebrovascular disease in Lp(a)‐lowering stroke prevention trials.

Observational studies have linked migraine to a wide range of risk factors and diseases, although the causality of these associations is uncertain. Mendelian randomization (MR) is an analytic paradigm that exploits germline genetic variants as natural experiments, providing a framework for causal inference from observational data. In this narrative review, we summarize the core principles and assumptions of MR and highlight methodological considerations unique to its application to migraine research. We review key MR findings across several domains of migraine research, noting areas of consistent evidence, as well as conflicting results. We then discuss limitations of MR in the context of migraine research, emphasizing that MR is not a panacea for causal inference. We conclude by underscoring the need for interdisciplinary collaboration between methodologists and domain experts to prioritize patient-relevant questions, refine analytic approaches and translate genetic insights into more effective therapies.

Background: Although genetic evidence supports IL‐6 (interleukin‐6) signaling inhibition as protective against atherosclerotic disease, its potential effects on thromboembolic outcomes are not well established. We conducted a Mendelian randomization analysis to investigate the association of genetically proxied IL‐6 signaling inhibition with venous thromboembolism, cardioembolic stroke, and coagulation cascade protein levels. Methods: IL‐6 signaling inhibition was proxied using the rs2228145 IL6R missense variant, which impairs classical IL‐6 signaling and lowers CRP (C‐reactive protein) levels. Genetic associations with thromboembolic disease outcomes were obtained from genome‐wide association studies of venous thromboembolism (81 190 cases) and cardioembolic stroke (10 804 cases). As atherosclerotic comparator traits, we included coronary artery disease (181 522 cases) and large‐artery atherosclerotic stroke (6399 cases). Genetic associations with 35 coagulation cascade protein levels were obtained from the UK Biobank (n=6218) and deCODE cohorts (n=35 559). Mendelian randomization estimates were derived using the Wald ratio method, scaled per 1‐unit decrease in natural log‐transformed CRP levels. Results: Genetically proxied IL‐6 signaling inhibition was associated with increased risk of venous thromboembolism (odds ratio [OR], 1.31 [95% CI, 1.16–1.47], P =6.5×10 ⁻⁶ ) but not with cardioembolic stroke (OR, 1.25 [95% CI, 0.73–2.14], P =0.42). Conversely, protective associations were observed for both coronary artery disease and large‐artery atherosclerotic stroke. Proteomic analyses demonstrated significant reductions in levels of 5 procoagulant and 7 anticoagulant or antifibrinolytic proteins. Conclusions: These findings suggest that IL‐6 signaling inhibition dysregulates coagulation homeostasis and increases venous thromboembolism risk. Further experimental, translational, and epidemiologic studies are warranted to delineate underlying mechanisms and to evaluate thromboembolic safety in pharmacologic IL‐6 signaling inhibition.