Comparison of genotypes and phenotypes for von Willebrand factor gene variants using Japanese genome database

Blood Vessels, Thrombosis & Hemostasis Pub Date : 2025-04-10 DOI:10.1016/j.bvth.2025.100070

Takafumi Akimoto , Hiroshi Inaba , Soichi Ogishima , Kazuki Kumada , Ayano Mitsuhashi , Ryui Miyashita , Tomoko Yamaguchi , Masato Bingo , Yushi Chikasawa , Keiko Shinozawa , Takeshi Hagiwara , Kagehiro Amano , Eiichi N. Kodama , Ei Kinai

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Abstract

von Willebrand disease (VWD) is a common inherited bleeding disorder. The aim of this study was to determine the predicted disease states associated with various pathogenic von Willebrand factor (VWF) variants and their phenotypes using the largest Japanese whole-genome database. Of the 5857 VWF gene variants registered in the Japanese Multi-Omics Reference Panel (jMorp), variants with the following criteria were extracted: (1) caused protein abnormalities due to genetic alterations; (2) have already been detected and included in a database, including known association with VWD; and (3) highly likely pathogenic by in silico analysis. We measured VWF activity, antigen, propeptide, and collagen binding activity in stored plasma samples obtained from heterozygous carriers of the selected variants. A total of 29 VWF variants (26 single nucleotide and 3 small insertions/deletions) were detected, and 6 of these were found in Leiden Open Mutation Database. We obtained 43 plasma samples from individuals carrying these 29 variants as heterozygous. For the 43 variant carriers, their mean age was 43.0 years, and blood group was type O in 17 (39.5%). Analysis of these plasma samples showed low VWF levels (<50%) in 6 (14.0%). Low VWF levels were found in 2 of 8 of the nonsense (25%) and 4 of 31 of the missense variants (12.9%). Taking into consideration the limitation of using stored plasma samples, analysis of the jMorp indicated that most VWF gene variants with predicted pathogenic potential did not correlate with phenotypic expression. Our results supported incomplete penetrance and variable expressivity of the VWF gene variants.

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利用日本基因组数据库比较血管性血友病因子基因变异的基因型和表型

血管性血友病（VWD）是一种常见的遗传性出血性疾病。本研究的目的是利用日本最大的全基因组数据库确定与各种致病性血管性血友病因子（VWF）变异及其表型相关的预测疾病状态。在日本多组学参考小组（jMorp）中登记的5857个VWF基因变异中，提取了符合以下标准的变异：(1)由于遗传改变导致蛋白质异常；(2)已被发现并已被纳入数据库，包括已知与VWD有关；(3)经计算机分析，极有可能致病。我们测量了VWF活性、抗原、前肽和胶原结合活性，这些血浆样品来自于选择的变异的杂合携带者。共检测到29个VWF变异（26个单核苷酸和3个小插入/缺失），其中6个在Leiden开放突变数据库中发现。我们从携带这29种杂合变异的个体中获得了43份血浆样本。43例变异携带者平均年龄43.0岁，17例（39.5%）为O型血。对这些血浆样本的分析显示，其中6例（14.0%）的VWF水平较低（50%）。8例无义变异中2例（25%）和31例错义变异中4例（12.9%）存在低VWF水平。考虑到使用储存血浆样本的局限性，对jMorp的分析表明，大多数具有预测致病潜力的VWF基因变异与表型表达无关。我们的研究结果支持VWF基因变体的不完全外显性和可变表达性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Blood Vessels, Thrombosis & Hemostasis

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