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. 2024 Apr;22(4):936-950.
doi: 10.1016/j.jtha.2023.11.027. Epub 2023 Dec 15.

A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment

Cristina Gallego-Fabrega  1 , Gerard Temprano-Sagrera  2 , Jara Cárcel-Márquez  3 , Elena Muiño  3 , Natalia Cullell  4 , Miquel Lledós  3 , Laia Llucià-Carol  3 , Jesús M Martin-Campos  3 , Tomás Sobrino  5 , José Castillo  6 , Mònica Millán  7 , Lucía Muñoz-Narbona  7 , Elena López-Cancio  8 , Marc Ribó  9 , Jose Alvarez-Sabin  10 , Jordi Jiménez-Conde  11 , Jaume Roquer  11 , Silvia Tur  12 , Victor Obach  13 , Juan F Arenillas  14 , Tomas Segura  15 , Gemma Serrano-Heras  16 , Joan Marti-Fabregas  17 , Marimar Freijo-Guerrero  18 , Francisco Moniche  19 , Maria Del Mar Castellanos  20 , Alanna C Morrison  21 , Nicholas L Smith  22 , Paul S de Vries  21 , Israel Fernández-Cadenas  23 , Maria Sabater-Lleal  24 ; Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium; Spanish Stroke Genetic Consortium
Collaborators, Affiliations

A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment

Cristina Gallego-Fabrega et al. J Thromb Haemost. 2024 Apr.

Abstract

Background: Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient's prognosis.

Objectives: To investigate the association between genetically determined natural hemostatic factors' levels and increased risk of HT after r-tPA treatment.

Methods: Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT.

Results: Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10-11. Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10-10; rs1421067 (CHD9), P = 1.81 × 10-14; and rs34780449, near ROBO1 gene, P = 1.64 × 10-8. Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10-14. Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [-0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05).

Conclusion: We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed.

Keywords: fibrinogen; hemorrhagic transformation; hemostatic factors; r-tPA treatment; von Willebrand factor.

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Conflict of interest statement

Declaration of competing interests There are no competing interests to disclose.

Figures

FIGURE 1
FIGURE 1
Graphic representation of the study design. CPC, conditional probability of colocalization; FVII, factor VII; FVIII, factor VIII; FXI, factor XI; GWAS, genome-wide association study; HT, hemorrhagic transformation; IVW, inverse-variance weighted; LDSC, linkage disequilibrium score regression; MR, Mendelian randomization; PAI-1, plasminogen activator inhibitor-1; tPA, tissue plasminogen activator; VWF, von Willebrand factor.
FIGURE 2
FIGURE 2
Multitrait analysis. (A) Manhattan plot for fibrinogen–hemorrhagic transformation (HT) multitrait analysis. (B) Manhattan plot for von Willebrand factor–HT multitrait analysis. In orange: newly identified loci associated with HT; in red: newly identified locus associated with fibrinogen and HT.
FIGURE 3
FIGURE 3
Locus zoom. (A) Colocalization of fibrinogen (FIBR) and recombinant tissue plasminogen activator (tPA) rs34780449 locus. (B) Colocalization of FIBR and recombinant tPA rs56026866 locus. (C) Colocalization of FIBR and recombinant tPA rs1421067 locus. (D) Colocalization of von Willebrand factor and r-tPA rs10942300 locus. Chr, chromosome; GWAS, genome-wide association study.
See this image and copyright information in PMC

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