Novel Insights Into the Genetic Background of Patients With Low Von Willebrand Factor Levels Using Next-generation Sequencing
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 254
- 试验地点
- 2
- 主要终点
- Genetic variants in the VWF gene or other genes associated with low VWF plasma levels
研究概览
简要总结
Von Willebrand disease (VWD) is caused by either quantitative or qualitative von Willebrand (VWF) defects and is the commonest inherited bleeding disorder with an estimated prevalence of about 1% in the general population. According to several guidelines, patients with a mild quantitative reduction in VWF (30-50 IU/dL) should be labeled as "low VWF". Quantitatively VWF defects account for almost 75% of all cases with VWD and among them, low VWF seems to be the most common form. Studies on patients with VWD reported only around 50% VWF mutations in low VWF cases indicating that some possible genes outside of the VWF gene may be responsible for the low VWF levels. To date, using genome-wide association study (GWAS) more than 19 non-VWF loci (such as ABO blood group system, Stabilin 2, Scavenger Receptor Class A Member 5, C-Type Lectin Domain Family 4 Member M, etc.) were identified to be associated with VWF levels. The identified genes are related to different mechanisms of the VWF life-cycle such as synthesis, secretion, glycosylation, or clearance. Despite the importance of the genetic background of low VWF levels for understanding its etiology, this issue is not well investigated yet. Thus the Low VWF Milan Cohort (LOVMIC) Study is designed to address some unanswered questions in patients with low VWF.
详细描述
Despite the absence of mutation in the VWF gene in a significant number of individuals with reduced VWF levels and also the lack of knowledge for the responsible mechanisms, this study sought to determine the following goals:
- Evaluation of the genetic background of low VWF level dilemma and identifying the gene (s) outside of the VWF gene that is associated with decreased VWF levels.
- Evaluating the correlation between candidate variants and patients' bleeding manifestations.
Study design:
Non-pharmacological Interventional National Monocentric Study. Promoter: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Coordinating center and patient recruitment unit: Department of General Medicine - Hemostasis and Thrombosis - Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
Setting: outpatients' clinic
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •for patients:
- •Adult patients who were diagnosed with "low VWF" and have VWF:Ag and/or VWF:RCo between 30-50 IU/dL with a ratio of VWF:RCo/VWF:Ag > 0.
- •Subjects who have given informed consent to participate in the study according to the Declaration of Helsinki
- •Inclusion Criteria for healthy controls:
- •Healthy subjects with no known bleeding disorders and with negative thrombophilia screening results
- •Subjects who have given informed consent to participate in the study according to the Declaration of Helsinki
排除标准
- •Pregnant women
- •Patients with acquired von Willebrand disease syndrome
研究组 & 干预措施
low VWF
In patients with low VWF levels, whole-exome sequencing will be performed to identity possible variants in the VWF gene or other genes that are associated with reduced VWF plasma levels. Furthermore, a correlation study between variants identified and the bleeding symptoms of patients will be performed.
干预措施: Whole-exome sequencing (Diagnostic Test)
Healthy controls
In healthy controls, the investigators will analyze the whole-exome sequencing to include the variants that are either not present in healthy controls or are present but with a significantly lower frequency than the patients.
干预措施: Whole-exome sequencing (Diagnostic Test)
结局指标
主要结局
Genetic variants in the VWF gene or other genes associated with low VWF plasma levels
时间窗: 8 months after starting the project
More than 19 different genes have been identified by genome-wide association studies that affect the plasma VWF levels. These genes (in addition to VWF) are including STXBP5, SCARA5, ABO, STAB2, STX2, TCN2, CLEC4M, PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA. Some studies showed an association between specific variants with a minor allele frequency (MAF) \> 10% and the reduction of VWF levels or severe clinical symptoms in patients with VWD. As a primary outcome, whole-exome sequencing will be carried out in 300 subjects (150 patients and 150 healthy controls) to identify variants either in the VWF gene or the aforementioned genes or some new genes that are associated with reduced VWF levels in plasma.
次要结局
- Correlation between the bleeding presentation and identified variants in patients with low VWF(12 months after starting the project)