von Willebrand factor antigen levels are associated with burden of rare nonsynonymous variants in the VWF gene.
von Willebrand factor antigen levels are associated with burden of rare nonsynonymous variants in the VWF gene.
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DOI：
10.1182/blood.2020009999
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发表时间：
2021-06-10
期刊：
影响因子：
20.3
通讯作者：
Di Paola J
中科院分区：
文献类型：
--
作者：
Sadler B;Christopherson PA;Haller G;Montgomery RR;Di Paola J
Von Willebrand病(VWD)是一种表型异质性疾病，35%的1型VWD患者没有已知的致病von Willebrand因子(VWF)基因变异。Sadler等人对737名患有1型VWD或低VWF水平的患者的整个基因组VWF基因进行了测序。他们报告说，致病和非致病的罕见非同义变异的积累导致了VWF的水平，并解释了VWF抗原水平的31%的差异。罕见的非同义VWF变异体的数量与VWF：Ag水平显著相关，与VWD类型无关。在大多数VWF：Ag水平较高的患者中，仅有VWF序列不能揭示VWD的病因。大约35%的1型von Willebrand病(VWD)患者在von Willebrand因子(VWF)基因中没有已知的致病变异。为了了解VWF编码变异对VWD风险和VWF抗原(VWF：Ag)水平的影响，我们研究了527例低VWF和VWD患者和210名健康对照。进行VWF测序，检测VWF：Ag水平。联合注解依赖耗竭(CADD)评分>；20被用作预测致病性的量度。罕见的非同义vWF变异数显著预测vWF：Ag水平(P=1.6 2×10−2 1)。与健康受试者比较，VWD 1型(P=2.4×10−13)和低vWF(P=1.6×10−2 7)的稀有非同义变异体的平均数之间存在相关性：1型患者的稀有变异体的平均数是低VWF者的2倍，是健康者的8倍。罕见的非同义变异的数量显著预测vWF：Ag水平，即使在控制了具有CADD20分的变异或vWF中已知的致病变异的存在后(P=2.7x10−14)。VWF中罕见的非同义变异体的数量以及CADD>；20变异体的存在都与VWF水平显著相关。即使在控制已知的致病变异时，与罕见的非同义变异的关联仍然存在，这表明在VWF或其他地方的其他变异与VWF：Ag水平有关。VWF：Ag水平较高、罕见的非同义VWF基因变异较少的患者可以从下一代测序中受益，以找到他们出血的原因。
von Willebrand disease (VWD) is phenotypically heterogeneous, and 35% of patients with type 1 VWD have no known pathogenic von Willebrand factor (VWF) gene variant. Sadler et al sequenced the entire genomic VWF locus of 737 patients with type 1 VWD or low VWF levels. They report that an accumulation of rare nonsynonymous variants, both pathogenic and nonpathogenic, contributes to the level of VWF and accounts for 31% of the variance in VWF antigen levels. The number of rare nonsynonymous VWF variants is significantly associated with VWF:Ag levels, regardless of VWD type. VWF sequence alone will not reveal the cause of VWD in a majority of patients with higher VWF:Ag levels. Approximately 35% of patients with type 1 von Willebrand disease (VWD) do not have a known pathogenic variant in the von Willebrand factor (VWF) gene. We aimed to understand the impact of VWF coding variants on VWD risk and VWF antigen (VWF:Ag) levels, studying 527 patients with low VWF and VWD and 210 healthy controls. VWF sequencing was performed and VWF:Ag levels assayed. A combined annotation-dependent depletion (CADD) score >20 was used as a predicted pathogenicity measure. The number of rare nonsynonymous VWF variants significantly predicted VWF:Ag levels (P = 1.62 × 10−21). There was an association between average number of rare nonsynonymous VWF variants with VWD type 1 (P = 2.4 × 10−13) and low VWF (P = 1.6 × 10−27) compared with healthy subjects: type 1 subjects possessed on average >2 times as many rare variants as those with low VWF and 8 times as many as healthy subjects. The number of rare nonsynonymous variants significantly predicts VWF:Ag levels even after controlling for presence of a variant with a CADD score >20 or a known pathogenic variant in VWF (P = 2.7 × 10−14). The number of rare nonsynonymous variants in VWF as well as the presence of a variant with CADD >20 are both significantly associated with VWF levels. The association with rare nonsynonymous variants holds even when controlling for known pathogenic variants, suggesting that additional variants, in VWF or elsewhere, are associated with VWF:Ag levels. Patients with higher VWF:Ag levels with fewer rare nonsynonymous VWF gene variants could benefit from next-generation sequencing to find the cause of their bleeding.
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DOI：
10.1126/science.1219240
发表时间：
2012-07-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Tennessen JA;Bigham AW;O'Connor TD;Fu W;Kenny EE;Gravel S;McGee S;Do R;Liu X;Jun G;Kang HM;Jordan D;Leal SM;Gabriel S;Rieder MJ;Abecasis G;Altshuler D;Nickerson DA;Boerwinkle E;Sunyaev S;Bustamante CD;Bamshad MJ;Akey JM;Broad GO;Seattle GO;NHLBI Exome Sequencing Project
通讯作者：
NHLBI Exome Sequencing Project
影响因子：
6.5
作者：
Laffan MA;Lester W;O'Donnell JS;Will A;Tait RC;Goodeve A;Millar CM;Keeling DM
通讯作者：
Keeling DM
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
37.8
作者：
Smith NL;Chen MH;Dehghan A;Strachan DP;Basu S;Soranzo N;Hayward C;Rudan I;Sabater-Lleal M;Bis JC;de Maat MP;Rumley A;Kong X;Yang Q;Williams FM;Vitart V;Campbell H;Mälarstig A;Wiggins KL;Van Duijn CM;McArdle WL;Pankow JS;Johnson AD;Silveira A;McKnight B;Uitterlinden AG;Wellcome Trust Case Control Consortium;;Aleksic N;Meigs JB;Peters A;Koenig W;Cushman M;Kathiresan S;Rotter JI;Bovill EG;Hofman A;Boerwinkle E;Tofler GH;Peden JF;Psaty BM;Leebeek F;Folsom AR;Larson MG;Spector TD;Wright AF;Wilson JF;Hamsten A;Lumley T;Witteman JC;Tang W;O'Donnell CJ
通讯作者：
O'Donnell CJ
影响因子：
4.2
作者：
Pang, Shirley Yin-Yu;Hsu, Jacob Shujui;Ho, Shu-Leong
通讯作者：
Ho, Shu-Leong