TY - JOUR AB - Background and Purpose—FXI (factor XI) is involved in thrombus propagation and stabilization. It is unknown whether lower FXI levels have a protective effect on risk of ischemic stroke (IS) or myocardial infarction. This study investigated the effect of genetically determined FXI levels on risk of IS, myocardial infarction, and intracerebral hemorrhage.Methods—Two-sample Mendelian randomization analysis was performed. Instruments and genetic association estimates for FXI levels were obtained from a genome-wide association study of 16 169 individuals. Genetic association estimates for IS and its etiological subtypes were obtained from a study of 16 851 cases and 32 473 controls. For myocardial infarction, estimates were obtained from a study of 43 676 cases and 123 504 controls and for intracerebral hemorrhage from a study of 1545 cases and 1481 controls.Results—After applying a Bonferroni correction for multiple testing, the Mendelian randomization analysis supported a causal effect of higher, genetically determined FXI levels on risk of any IS (odds ratio [OR] per 1-unit increase in natural logarithm-transformed FXI levels, 2.54; 95% CI, 1.68–3.84; P=1×10−5) but not myocardial infarction (OR, 1.01; 95% CI, 0.76–1.34; P=0.94) or intracerebral hemorrhage (OR, 1.81; 95% CI, 0.44–7.38; P=0.41). Examining IS subtypes, the main results supported an effect of higher, genetically determined FXI levels on risk of cardioembolism (OR, 4.23; 95% CI, 1.94–9.19; P=3×10−4) and IS of undetermined cause (OR, 3.44; 95% CI, 1.79–6.60; P=2×10−4) but not large artery atherosclerosis (OR, 2.73; 95% CI, 1.15–6.45; P=0.02) or small artery occlusion (OR, 1.19; 95% CI, 0.50–2.82; P=0.69). However, the statistically significant result for IS of undetermined cause was not replicated in all sensitivity analyses.Conclusions—We find Mendelian randomization evidence supporting FXI as a possible t AU - Gill,D AU - Georgakis,MK AU - Laffan,M AU - Sabater-Lleal,M AU - Malik,R AU - Tzoulaki,I AU - Veltkamp,R AU - Dehghan,A DO - 10.1161/STROKEAHA.118.022792 EP - 2763 PY - 2018/// SN - 0039-2499 SP - 2761 TI - Genetically determined FXI (Factor XI) levels and risk of stroke T2 - Stroke UR - http://dx.doi.org/10.1161/STROKEAHA.118.022792 UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000447974800039&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202 UR - http://hdl.handle.net/10044/1/64302 VL - 49 ER -