Novel Drug Targets for Ischemic Stroke Identified Through Mendelian Randomization Analysis of the Blood Proteome

Abstract

Background: Novel, effective, and safe drugs are warranted for treatment of ischemic stroke. Circulating protein biomarkers with causal genetic evidence represent promising drug targets, but no systematic screen of the proteome has been performed. Methods: First, using Mendelian randomization (MR) analyses, we assessed 653 circulating proteins as possible causal mediators for 3 different subtypes of ischemic stroke: large artery atherosclerosis, cardioembolic stroke, and small artery occlusion. Second, we used MR to assess whether identified biomarkers also affect risk for intracranial bleeding, specifically intracerebral and subarachnoid hemorrhages. Third, we expanded this analysis to 679 diseases to test a broad spectrum of side effects associated with hypothetical therapeutic agents for ischemic stroke that target the identified biomarkers. For all MR analyses, summary-level data from genome-wide association studies (GWAS) were used to ascertain genetic effects on circulating biomarker levels versus disease risk. Biomarker effects were derived by meta-analysis of 5 GWAS (N≤20 509). Disease effects were derived from large GWAS analyses, including MEGASTROKE (N≤322 150) and UK Biobank (N≤408 961) studies. Results: Several biomarkers emerged as causal mediators for ischemic stroke. Causal mediators for cardioembolic stroke included histo-blood group ABO system transferase, coagulation factor XI, scavenger receptor class A5 (SCARA5), and tumor necrosis factor–like weak inducer of apoptosis (TNFSF12). Causal mediators for large artery atherosclerosis included ABO, cluster of differentiation 40, apolipoprotein(a), and matrix metalloproteinase-12. SCARA5 (odds ratio [OR]=0.78; 95% CI, 0.70–0.88; P =1.46×10 −5 ) and TNFSF12 (OR=0.86; 95% CI, 0.81–0.91; P =7.69×10 −7 ) represent novel protective mediators of cardioembolic stroke. TNFSF12 also increased the risk of subarachnoid (OR=1.53; 95% CI, 1.31–1.78; P =3.32×10 −8 ) and intracerebral (OR=1.34; 95% CI, 1.14–1.58; P =4.05×10 −4 ) hemorrhages, whereas SCARA5 decreased the risk of subarachnoid hemorrhage (OR=0.61; 95% CI, 0.47–0.81; P =5.20×10 −4 ). Multiple side effects beyond stroke were identified for 6 of 7 biomarkers, most (75%) of which were beneficial. No adverse side effects were found for coagulation factor XI, apolipoprotein(a), and SCARA5. Conclusions: Through a systematic MR screen of the circulating proteome, causal roles for 5 established and 2 novel biomarkers for ischemic stroke were identified. Side-effect profiles were characterized to help inform drug target prioritization. In particular, SCARA5 represents a promising target for treatment of cardioembolic stroke, with no predicted adverse side effects.

Linking protein to phenotype with Mendelian Randomization detects 38 proteins with causal roles in human diseases and traits

“…Previous studies have also leveraged the increased availability of pQTL data for drug target and biomarker discovery [12][13][14][15][16][17][18]. For example, in one of the largest pQTL studies to date, Sun et al [14] applied an aptamer-based approach (rather than an antibody-based assay as here) to perform extensive co-localization analyses and used MR to assess the causal contribution of IL1RL1-IL18R1 locus to atopic dermatitis, and that of MMP12 to coronary heart disease.…”

Coagulation factor XII, XI, and VIII activity levels and secondary events after first ischemic stroke

“…32 In this study, genetically determined FXI levels were identified as one of five causal mediators of ischemic stroke, with the cardioembolic subtype appearing to drive this effect. 32 In both studies, no adverse side effects appeared to be linked to the genetic influences on variation in FXI levels, providing further justification for clinical trials on FXI-related interventions in the context of ischemic stroke. 32 In light of our findings that stroke patients with high FXI:C had a higher risk for secondary events after first stroke, the population of stroke patients with high FXI levels may particularly benefit from such interventions, and FXI:C may be a useful biomarker in identifying individuals who are most likely to benefit from such interventions.…”

IL-6R protective variant rs7529229 reduces interleukin-6 signaling and contributes to decreased ischemic stroke risk

“…In summary, all these ndings show that human genetic variants could be used to repurpose the existing targets for new therapeutic uses [7,16,[20][21]. However, it is largely unknown about the role of rs7529229 in IS, which promotes us to perform a comprehensive analysis.…”