血液タンパク質を狙った安全な抗凝固薬

タイトル: Mendelian randomization analysis supports Factors II and XI as actionable anticoagulant targets

概要: BackgroundAnticoagulants are routinely used by millions of patients worldwide to prevent blood clots. Yet, problems with anticoagulant therapy remain, including a persistent and cumulative bleeding risk in patients undergoing prolonged anticoagulation. New safer anticoagulant targets are needed. MethodsWe performed two-sample Mendelian randomization (MR) and genetic colocalization to prioritize anticoagulant targets with the strongest efficacy (venous thromboembolism [VTE] prevention) and safety (low bleeding risk) profiles. We leveraged three large-scale plasma protein datasets (deCODE, n=35,559; Fenland n = 10,708; ARIC n= 7,213) and one liver gene expression dataset (n =246) to evaluate evidence for a causal effect of 26 coagulation cascade plasma proteins on VTE from a new genome-wide association meta-analysis of 44,232 VTE cases and 847,152 controls (from the UK Biobank, FinnGen and Estonian Biobank), stroke subtypes (from UK Biobank and International Stroke Genetics consortium 73,652 cases and 1,234,808 controls), bleeding outcomes (FinnGen, n=309,154) and over one million parental lifespans (UK Biobank and LifeGen consortium). ResultsGenetically predicted reductions in F2 blood levels were associated with lower VTE risk (OR [odds ratio] per 1 standard deviation [SD] lower F2=0.44, 95% CI=0.38-0.51, p=2.6E-28) and cardioembolic stroke risk (OR = 0.55, 95% CI=0.39-0.76, p=4.2e-04) but not with bleeding (OR = 1.13, 95% CI=0.93-1.36, p=2.2e-01). Genetically predicted F11 reduction were associated with lower risk of VTE (OR = 0.61, 95% CI=0.58-0.64, p=4.1e-85) and cardioembolic stroke (OR = 0.77, 95% CI=0.69-0.86, p=4.1e-06), but not with bleeding (OR = 1.01, 95% CI=0.95-1.08, p=7.5e-01) (Figure 3). These MR associations were concordant across the three blood protein datasets and the hepatic gene expression dataset as well as three different MR and colocalization analyses. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=41 SRC="FIGDIR/small/23299567v1_fig3.gif" ALT="Figure 3"> View larger version (14K): [email protected]@f47370org.highwire.dtl.DTLVardef@c6c09aorg.highwire.dtl.DTLVardef@8ee5d7_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 3.C_FLOATNO Genetically predicted reductions in blood F2 and F11 levels on safety and efficacy outcomes in a multicis MR analysis. Effect of 1 standard deviation decrease (inhibition) in F2 or F11 blood protein levels measured in deCODE on efficacy and safety outcomes. PPH4 stands for "posterior probability of hypothesis 4" as calculated with the coloc method, the posterior probability that two traits share a common variant. C_FIG ConclusionThese results provide strong genetic evidence that F2 and F11 may represent safe and efficacious therapeutic targets to prevent VTE and cardioembolic strokes without substantially increasing bleeding risk.