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.
СтатьяМногоцентровое исследованиеНазвание и аннотация: Перевод пока не подготовлен
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Borràs Nina, Garcia-Martínez Iris, Batlle Javier, Pérez-Rodríguez Almudena, Parra Rafael, Altisent Carme, López-Fernández María Fernanda, Costa Pinto Joana, Batlle-López Fernando, Cid Ana Rosa, Bonanad Santiago, Cabrera Noelia, Moret Andrés, Mingot-Castellano María Eva, Navarro Nira, Pérez-Montes Rocío, Marcellini Shally, Moreto Ana, Herrero Sonia, Soto Inmaculada, Fernández-Mosteirín Núria, Jiménez-Yuste Víctor, Alonso Nieves, de Andrés-Jacob Aurora, Fontanes Emilia, Campos Rosa, Paloma María José, Bermejo Nuria, Berrueco Rubén, Mateo José, Arribalzaga Karmele, Marco Pascual, Palomo Ángeles, Castro Quismondo Nerea, Iñigo Belén, Del Mar Nieto María, Vidal Rosa, Martínez María Paz, Aguinaco Reyes, Tenorio Maria, Ferreiro María, García-Frade Javier, Rodríguez-Huerta Ana María, Cuesta Jorge, Rodríguez-González Ramón, García-Candel Faustino, Dobón Manuela, Aguilar Carlos, Corrales Irene, Vidal Francisco
Аннотация
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.