Stroke genetics informs drug discovery and risk prediction across ancestries

Daniel Strbian työryhmän jäsenenä Correction; Early Access DOI: 10.1038/s41586-022-05492-5 Early Access: NOV 2022Previous 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.Peer reviewe

Renal Impairment and Prognosis of Patients with Atrial Fibrillation Undergoing Coronary Intervention - The AFCAS Trial.

Renal impairment is a well-known risk factor for cardiovascular complications, but the effect of different stages of renal impairment on thrombotic/thromboembolic and bleeding complications in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) remains largely unknown. We sought to evaluate the incidence and clinical impact of four stages of renal impairment in patients with AF undergoing PCI.We assessed renal function by estimated glomerular filtration rate (eGFR) and outcomes in 781 AF patients undergoing PCI by using the data from a prospective European multicenter registry. End-points included all-cause mortality, major adverse cardiac and cerebrovascular events (MACCE) and bleeding events at 12 months.A total of 195 (25%) patients had normal renal function (eGFR ≥90 mL/min), 290 (37%) mild renal impairment (eGFR 60-89), 263 (34%) moderate renal impairment (eGFR 30-59) and 33 (4%) severe renal impairment (eGFR <30). Degree of renal impairment remained an independent predictor of mortality and MACCE in an adjusted a Cox regression model. Even patients with mild renal impairment had a higher risk of all-cause mortality (HR 2.25, 95%CI 1.02-4.98, p=0.04) and borderline risk for MACCE (HR 1.56, 95%CI 0.98- 2.50, p=0.06) compared to those with normal renal function.Renal impairment is common in patients with AF undergoing PCI and even mild renal impairment has an adverse prognostic effect in these patients requiring multiple antithrombotic medications

Baseline characteristics of the study population.

<p>P-value < 0.05 = *, p value < 0.01 = **, all values are compared with eGFR ≥90 ml/min/1.73 m² group. Data are reported as number and percentage or mean ± SD.; eGFR = estimated glomerular filtration rate; CHA₂ DS₂ VASC = C ongestive heart failure, H ypertension, A ge ≥75 years, D iabetes, prior S troke/transient ischaemic attack/systemic embolism, associated V ascular disease, A ge 65–74 years, and female S ex category; HAS-BLED = Hypertension, Abnormal liver or kidney function, prior Stroke, Bleeding history or predisposition, Labile INR, Elderly, and concomitant Drugs; PCI = percutaneous coronary intervention; CABG = coronary artery bypass graft surgery; TIA = transient ischemic attack.</p><p>Baseline characteristics of the study population.</p

Freedom from MACCE according to eGFR groups at 12-month follow-up.

<p>Freedom from MACCE according to eGFR groups at 12-month follow-up.</p

Freedom from any bleeding event according to eGFR groups at 12-month follow-up.

<p>Freedom from any bleeding event according to eGFR groups at 12-month follow-up.</p

Cardiac and antithrombotic medication at discharge.

<p>P-value < 0.05 = *, p value < 0.01 = **, all values are compared with eGFR ≥90mL/min group. Data are reported as number and percentage or mean ± SD; eGFR estimated glomerular filtration rate; VKA, vitamin K antagonist; INR, international normalized ratio; ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers</p><p>Cardiac and antithrombotic medication at discharge.</p