Frontiers in Cardiovascular Medicine (Jul 2022)

A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype

  • Jara Cárcel-Márquez,
  • Jara Cárcel-Márquez,
  • Elena Muiño,
  • Cristina Gallego-Fabrega,
  • Cristina Gallego-Fabrega,
  • Natalia Cullell,
  • Natalia Cullell,
  • Miquel Lledós,
  • Laia Llucià-Carol,
  • Laia Llucià-Carol,
  • Tomás Sobrino,
  • Francisco Campos,
  • José Castillo,
  • Marimar Freijo,
  • Juan Francisco Arenillas,
  • Victor Obach,
  • José Álvarez-Sabín,
  • Carlos A. Molina,
  • Marc Ribó,
  • Jordi Jiménez-Conde,
  • Jaume Roquer,
  • Lucia Muñoz-Narbona,
  • Elena Lopez-Cancio,
  • Mònica Millán,
  • Rosa Diaz-Navarro,
  • Cristòfol Vives-Bauza,
  • Gemma Serrano-Heras,
  • Tomás Segura,
  • Laura Ibañez,
  • Laura Heitsch,
  • Laura Heitsch,
  • Pilar Delgado,
  • Rajat Dhar,
  • Jerzy Krupinski,
  • Raquel Delgado-Mederos,
  • Luis Prats-Sánchez,
  • Pol Camps-Renom,
  • Natalia Blay,
  • Lauro Sumoy,
  • Rafael de Cid,
  • Joan Montaner,
  • Carlos Cruchaga,
  • Carlos Cruchaga,
  • Jin-Moo Lee,
  • Joan Martí-Fàbregas,
  • Israel Férnandez-Cadenas

DOI
https://doi.org/10.3389/fcvm.2022.940696
Journal volume & issue
Vol. 9

Abstract

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BackgroundOccult atrial fibrillation (AF) is one of the major causes of embolic stroke of undetermined source (ESUS). Knowing the underlying etiology of an ESUS will reduce stroke recurrence and/or unnecessary use of anticoagulants. Understanding cardioembolic strokes (CES), whose main cause is AF, will provide tools to select patients who would benefit from anticoagulants among those with ESUS or AF. We aimed to discover novel loci associated with CES and create a polygenetic risk score (PRS) for a more efficient CES risk stratification.MethodsMultitrait analysis of GWAS (MTAG) was performed with MEGASTROKE-CES cohort (n = 362,661) and AF cohort (n = 1,030,836). We considered significant variants and replicated those variants with MTAG p-value < 5 × 10−8 influencing both traits (GWAS-pairwise) with a p-value < 0.05 in the original GWAS and in an independent cohort (n = 9,105). The PRS was created with PRSice-2 and evaluated in the independent cohort.ResultsWe found and replicated eleven loci associated with CES. Eight were novel loci. Seven of them had been previously associated with AF, namely, CAV1, ESR2, GORAB, IGF1R, NEURL1, WIPF1, and ZEB2. KIAA1755 locus had never been associated with CES/AF, leading its index variant to a missense change (R1045W). The PRS generated has been significantly associated with CES improving discrimination and patient reclassification of a model with age, sex, and hypertension.ConclusionThe loci found significantly associated with CES in the MTAG, together with the creation of a PRS that improves the predictive clinical models of CES, might help guide future clinical trials of anticoagulant therapy in patients with ESUS or AF.

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