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

被引：2

作者：

Gallego-Fabrega, Cristina ^{[1
]}

Temprano-Sagrera, Gerard ^{[2
]}

Carcel-Marquez, Jara ^{[1
]}

Muino, Elena ^{[1
]}

Cullell, Natalia ^{[1
,3
]}

Lledos, Miquel ^{[1
]}

Llucia-Carol, Laia ^{[1
]}

Martin-Campos, Jesus M. ^{[1
]}

Sobrino, Tomas ^{[4
]}

Castillo, Jose ^{[5
]}

Millan, Monica ^{[6
]}

Munoz-Narbona, Lucia ^{[6
]}

Lopez-Cancio, Elena ^{[7
]}

Ribo, Marc ^{[8
]}

Alvarez-Sabin, Jose ^{[9
]}

Jimenez-Conde, Jordi ^{[10
]}

Roquer, Jaume ^{[10
]}

Tur, Silvia ^{[11
]}

Obach, Victor ^{[12
]}

Arenillas, Juan F. ^{[13
]}

Segura, Tomas ^{[14
]}

Serrano-Heras, Gemma ^{[15
]}

Marti-Fabregas, Joan ^{[16
]}

Freijo-Guerrero, Marimar ^{[17
]}

Moniche, Francisco ^{[18
]}

Castellanos, Maria del Mar ^{[19
]}

Morrison, Alanna C. ^{[20
]}

Smith, Nicholas L. ^{[21
,22
,23
]}

de Vries, Paul S. ^{[20
]}

Fernandez-Cadenas, Israel ^{[1
]}

Sabater-Lleal, Maria ^{[2
,24
]}

机构：

[1] Inst Recerca St Pau IR St PAU, Stroke Pharmacogen & Genet Grp, Barcelona, Spain

[2] Inst Recerca St Pau IR St PAU, Genom Complex Dis Grp, St Quinti 77-79, Barcelona 08041, Spain

[3] Hosp Univ Mutua Terrassa, Neurol Unit, Terrassa, Spain

[4] Hlth Res Inst Santiago de Compostela IDIS, Clin Neurosci Res Labs, Santiago De Compostela, Spain

[5] Hosp Clin Univ Santiago CHUS, Dept Neurol, Santiago De Compostela, Spain

[6] Hosp Univ Hermanos Trias & Pujol HUGTP, Dept Neurosci, Badalona, Spain

[7] Hosp Univ Cent Asturias HUCA, Neurol Dept, Stroke Unit, Inst Invest Sanitaria Principado Asturias ISPA, Oviedo, Spain

[8] Hosp Univ Valle Hebron HUVH, Stroke Unit, Barcelona, Spain

[9] Univ Autonoma Barcelona UAB, Hosp Univ Valle Hebron HUVH, Dept Neurol, Barcelona, Spain

[10] Inst Invest Prov Barcelona, Dept Neurol, Neurovasc Res Grp, Barcelona, Spain

[11] Hosp Univ Son Espases HUSE, Dept Neurol, Mallorca, Spain

[12] Hosp Clin Barcelona, Dept Neurol, Barcelona, Spain

[13] Univ Valladolid, Hosp Clin Univ, Dept Neurol, Valladolid, Spain

[14] Univ Castilla La Mancha UCLM, Complejo Hosp Univ Albacete CHUA, Dept Neurol, Albacete, Spain

[15] Complejo Hosp Univ Albacete CHUA, Res Unit, Albacete, Spain

[16] Hosp Santa Creu & Sant Pau, IIB St Pau, Dept Neurol, Barcelona, Spain

[17] Biocruces Bizkaia Hlth Res Inst, Neurovasc Unit, Bilbao, Spain

[18] Hosp Univ Virgen Rocio, Inst Biomed Sevilla IBIS, Dept Neurol, Seville, Spain

[19] Hosp Univ A Coruna CHUAC, Biomed Res Inst, Dept Neurol, La Coruna, Spain

[20] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Houston, TX USA

[21] Univ Washington, Dept Epidemiol, Seattle, WA USA

[22] Kaiser Permanente Washington, Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA

[23] Seattle Epidemiol Res & Informat Ctr, Dept Vet Affairs, Off Res & Dev, Seattle, WA USA

[24] Karolinska Inst, Dept Med, Cardiovasc Med Unit, Stockholm, Sweden

来源：

JOURNAL OF THROMBOSIS AND HAEMOSTASIS | 2024年 / 22卷 / 04期

基金：

英国生物技术与生命科学研究理事会;

关键词：

fibrinogen hemorrhagic transformation hemostatic factors r-tPA treatment von Willebrand; factor; TISSUE-PLASMINOGEN ACTIVATOR; ACUTE ISCHEMIC-STROKE; GENOME-WIDE ASSOCIATION; INTRACEREBRAL HEMORRHAGE; THROMBOLYTIC THERAPY; FIBRINOGEN DEPLETION; RISK; METAANALYSIS; ALTEPLASE; ECASS;

D O I：

10.1016/j.jtha.2023.11.027

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 identi fied a genomic region on chromosome 16 with shared covariance: fibrinogen -HT, P = 2.45 x 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 x 10 -10 ; rs1421067 ( CHD9 ), P = 1.81 x 10 -14 ; and rs34780449, near ROBO1 gene, P = 1.64 x 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 x 10 -14 . Mendelian randomization analysis did not find signi ficant 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 identi fied 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.

引用

页码：936 / 950

页数：15

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