Manderstedt Eric, Halldén Christer, Lind-Halldén Christina, Elf Johan, Svensson Peter J, Engström Gunnar, Melander Olle, Baras Aris, Lotta Luca A, Zöller Bengt
Department of Environmental Science and Bioscience, Kristianstad University, Kristianstad, Sweden.
Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden.
J Thromb Haemost. 2022 Apr;20(4):929-935. doi: 10.1111/jth.15630. Epub 2022 Jan 12.
The protein C anticoagulant system plays a key role in maintaining the hemostatic balance. Although several studies have identified thrombomodulin gene (THBD) variants among venous thromboembolism (VTE) patients, the role of THBD in relation to VTE in humans remains to be clarified.
This study aimed to determine the thrombotic risk of rare and common THBD variants in a large population-based cohort of middle-aged and older adults.
PATIENTS/METHODS: The exome sequence of THBD was analyzed for qualifying variants in 28,794 subjects (born 1923-1950, 60% women), who participated in the Malmö Diet and Cancer study (1991-1996). Patients were followed from baseline until the first event of VTE, death, or 2018. Qualifying variants were defined as loss-of-function or non-benign (PolyPhen-2) missense variants with minor allele frequency <0.1%.
The single common coding variant rs1042579 was not associated with incident VTE. Sixteen rare variants were classified as qualifying and included in collapsing analysis. Seven individuals with VTE compared to 24 individuals without VTE carried one qualifying variant. Cox multivariate regression analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking and alcohol consumption, rs6025, rs1799963, and the top two eigenvectors from a principal components analysis showed a hazard ratio of 3.0 (95% confidence interval 1.4-6.3) for the rare qualifying variants. The distributions of qualifying variants in THBD showed a difference for individuals with and without incident VTE indicating a possible position effect.
Rare qualifying THBD variants were associated with VTE, suggesting that rare variants in THBD contribute to development of VTE.
蛋白C抗凝系统在维持止血平衡中起关键作用。尽管多项研究已在静脉血栓栓塞症（VTE）患者中鉴定出血栓调节蛋白基因（THBD）变体，但THBD在人类VTE中的作用仍有待阐明。
本研究旨在确定在一个以人群为基础的中老年队列中，罕见和常见THBD变体的血栓形成风险。
患者/方法：对参与马尔默饮食与癌症研究（1991 - 1996年）的28794名受试者（出生于1923 - 1950年，60%为女性）的THBD外显子序列进行分析，以寻找合格变体。从基线开始对患者进行随访，直至首次发生VTE、死亡或至2018年。合格变体定义为功能丧失或非良性（PolyPhen - 2）错义变体，次要等位基因频率<0.1%。
单一常见编码变体rs1042579与VTE发病无关。16个罕见变体被分类为合格变体并纳入合并分析。7名VTE患者与24名无VTE患者携带一个合格变体。在对年龄、性别、体重指数、收缩压、吸烟和饮酒、rs6025、rs1799963以及主成分分析的前两个特征向量进行校正的Cox多变量回归分析中，罕见合格变体的风险比为3.0（95%置信区间1.4 - 6.3）。THBD中合格变体的分布在有和无VTE发病的个体中存在差异，表明可能存在位置效应。
罕见的合格THBD变体与VTE相关，提示THBD中的罕见变体促成了VTE的发生。
