Unraveling the Influence of Common von Willebrand factor variants on von Willebrand Disease Phenotype: An Exploratory Study on the Molecular and Clinical Profile of von Willebrand Disease in Spain Cohort
| Autor: | Nira Navarro, Rubén Berrueco, Irene Corrales, José Mateo, Manuela Dobón, Joana Costa Pinto, María Ferreiro, Ángeles Palomo, Almudena Pérez-Rodríguez, Javier García-Frade, Santiago Bonanad, Javier Batlle, Iris Garcia-Martínez, Emilia Fontanes, Shally Marcellini, Reyes Aguinaco, María José Paloma, Maria Cristina Tenório, Carme Altisent, Ana María Rodríguez-Huerta, Carlos Aguilar, Nieves Alonso, Ramón Rodríguez-González, Rosa Vidal, Aurora de Andrés-Jacob, Karmele Arribalzaga, Faustino García-Candel, María del Mar Nieto, Belén Iñigo, Sonia Herrero, Víctor Jiménez-Yuste, Ana Moreto, Rafael Parra, Nerea Castro Quismondo, Pascual Marco, Andrés Moret, Nina Borràs, Ana Rosa Cid, N. Cabrera, Fernando Batlle-López, Nuria Bermejo, Nuria Fernández-Mosteirín, María Paz Martínez, Rosa Campos, María Fernanda López-Fernández, Jorge Cuesta, Francisco Vidal, Inmaculada Soto, Rocío Pérez-Montes, Maria Eva Mingot-Castellano |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Nonsynonymous substitution Adult Male Heterozygote congenital hereditary and neonatal diseases and abnormalities Mutation Missense single nucleotide variants Locus (genetics) Hemorrhage 030204 cardiovascular system & hematology association study Polymorphism Single Nucleotide 03 medical and health sciences Young Adult von willebrand disease 0302 clinical medicine Von Willebrand factor ABO blood group system hemic and lymphatic diseases von Willebrand Factor Von Willebrand disease medicine Humans Computer Simulation Prospective Studies Registries Factor VIII biology Haplotype Homozygote Hematology Middle Aged medicine.disease Phenotype von willebrand factor von Willebrand Diseases 030104 developmental biology Haplotypes Spain Immunology biology.protein Epistasis Regression Analysis Female circulatory and respiratory physiology |
| Zdroj: | THROMBOSIS AND HAEMOSTASIS r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu Fundació Sant Joan de Déu r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau instname r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu r-ISABIAL. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica y Sanitaria de Alicante |
| ISSN: | 0340-6245 |
| Popis: | The clinical diagnosis of von Willebrand disease (VWD), particularly type 1, can be complex because several genetic and environmental factors affect von Willebrand factor (VWF) plasma levels. An estimated 60% of the phenotypic variation is attributable to hereditary factors, with the ABO blood group locus being the most influential. However, recent studies provide strong evidence that nonsynonymous single nucleotide variants (SNVs) contribute to VWF and factor VIII phenotypic variability in healthy individuals. This study aims to investigate the role of common VWF SNVs on VWD phenotype by analyzing data from 219 unrelated patients included in the “Molecular and Clinical Profile of von Willebrand Disease in Spain project.” To that end, generalized linear mixed-effects regression models were fitted, and additive and epistatic analyses, and haplotype studies were performed, considering five VWD-related measures (bleeding score, VWF:Ag, VWF:RCo, factor VIII:C, and VWF:CB). According to these analyses, homozygotes: for p.Thr789Ala(C) would be expected to show 39% higher VWF:Ag levels; p.Thr1381Ala(C), 27% lower VWF:Ag levels; and p.Gln852Arg(C), 52% lower VWF:RCo levels. Homozygotes for both p.Thr789Ala(C) and p.Gln852Arg(T) were predicted to show 185% higher VWF:CB activity, and carriers of two copies of the p.Thr1381Ala(T)/p.Gln852Arg(T) haplotype would present a 100% increase in VWF:RCo activity. These results indicate a substantial effect of common VWF variation on VWD phenotype. Although additional studies are needed to determine the true magnitude of the effects of SNVs on VWF, these findings provide new evidence regarding the contribution of common variants to VWD, which should be taken into account to enhance the accuracy of the diagnosis and classification of this condition. ClinicalTrials.gov identifier: NCT02869074. |
| Databáze: | OpenAIRE |
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