Venous thrombosis is a major medical disorder caused by both genetic and environmental factors. Little is known about the genetic background of venous thrombosis in the Chinese population. A total of 1,304 individuals diagnosed with a first venous thrombosis and 1,334 age- and sex-matched healthy participants were enrolled in this study. Resequencing of THBD (encoding thrombomodulin) in 60 individuals with venous thrombosis and 60 controls and a functional assay showed that a common variant, c.-151G>T (rs16984852), in the 5' UTR significantly reduced the gene expression and could cause a predisposition to venous thrombosis. Therefore, this variant was genotyped in a case-control study, and results indicated that heterozygotes had a 2.80-fold (95% confidence interval = 1.88-4.29) increased risk of venous thrombosis. The THBD c.-151G>T variant was further investigated in a family analysis involving 176 first-degree relatives from 38 index families. First-degree relatives with this variant had a 3.42-fold increased risk of venous thrombosis, and their probability of remaining thrombosis-free was significantly lower than that of relatives without the variant. In addition, five rare mutations that might be deleterious were also identified in thrombophilic individuals by sequencing. This study is the largest genetic investigation of venous thrombosis in the Chinese population. Further study on genetics of thrombosis should focus on resequencing of THBD and other hemostasis genes in different populations.

Protein S (ProS) is a physiological inhibitor of coagulation with an important function in the downregulation of thrombin generation. ProS deficiency is a major risk factor for venous thrombosis. This study enrolled 40 ProS-deficient probands to investigate the molecular basis of hereditary ProS deficiency in Chinese patients. A mutation analysis was performed by resequencing the PROS1 gene. Large deletions were identified by multiplex ligation-dependent probe amplification (MLPA) analysis. A total of 20 different mutations, including 15 novel mutations, were identified in 21 of the 40 index probands. Small mutations were detected in 18 (45.0%) probands, and large deletions were found in 3 (7.5%) probands, leaving 19 (47.5%) patients without causative variants. To evaluate the functional consequences of 2 novel missense variants, ex vivo thrombin-generation assays, bioinformatics tools, and in vitro expression studies were employed. The p.Asn365Lys ProS variant was found to have moderately impaired secretion and reduced activated protein C cofactor activity. In contrast, the p.Pro410His mutant appeared to have severely impaired secretion but full anticoagulant activity. This study is the largest investigation of ProS deficiency in China and the first investigation of the influence of Type I ProS missense mutations on the global level of coagulation function. The p.K196E mutation, which is common in the neighboring Japanese population, was not found in our Chinese population, and null mutations were common in our Chinese population but not common in Japan. Further genetic analysis is warranted to understand the causes of ProS deficiency in patients without a genetic explanation. Am. J.

Summary Background Venous thrombosis (VT) is a worldwide medical problem. In order to identify individuals at high risk early, it is necessary to find more genetic risk factors. Nowadays, the studies on genetic factors of thrombosis are mainly focused on coagulation and anticoagulation factors. The exploration of other proteins involved in thrombosis and hemostasis may lead to a breakthrough. Objectives We used APOH as a candidate gene to investigate the existence of genetic variation that could increase the risk of thrombosis. Methods/Results In the current study, with a resequencing method followed by a case–control study, four polymorphisms (c.−32C>A, c.422T>C, c.461G>A, and c.1004G>C) in APOH (encoding β2‐glycoprotein I) were found to be in high linkage disequilibrium, which could result in three haplotypes. The H2 heterozygotes and H3 homozygotes had approximately 1.5‐fold and seven‐fold increased risks for VT, respectively. The minor allele frequency in the general population was ~ 10%. In addition, H3 individuals showed a significantly decreased level of β2‐glycoprotein I, but an increased level of thrombin generation. Functional tests indicated that the mutant β2‐glycoprotein I had a significantly lower capacity to extend thrombin clotting time and increase thrombin generation potential. Conclusions This study revealed APOH as a new candidate gene associated with thrombosis, and further genetic research on this gene in patients in whom the cause of thrombophilia is unknown is therefore warranted.

Protein C (PC) is a well-characterized anticoagulant enzyme. However, the association between PC and ischemic stroke (IS) remains controversial. The aim of the present study was to investigate whether any genetic variant in the human protein C gene (PROC) was associated with susceptibility to IS in the Chinese Han population. All exons and the 5'- and 3'-untranslated regions of PROC were initially sequenced to identify informative variants. Potential abnormal variants were analyzed in a population of 788 IS patients and 1,200 healthy controls. The analysis was stratified by stroke etiology, and the results were replicated in 262 IS patients and 288 healthy controls. Finally, functional studies were performed to evaluate the effects of the variant. A three-nucleotide duplication/deletion variant (c.574_576del) was identified and found to be significantly associated with IS (OR 2.56, 95 % CI 1.45-4.52, P = 0.001). Stratification by stroke etiology after adjustment for IS risk factors showed that this association persisted in the lacunar and cardioembolic subtypes (P < 0.001 and P = 0.008, respectively) but not in the atherothrombotic and undetermined subtypes (P = 0.070 and P = 0.998, respectively). The functional studies showed a significant difference in the anticoagulant activity of PC in c.574_576del carriers and non-carriers (P < 0.001). Our results suggested that the novel PROC c.574_576del variant is a possible genetic determinant of an increased risk of IS and diminished anticoagulant activity of PC.

Antithrombin (AT) deficiency increases the risk of thrombosis. Current evidence shows that some SERPINC1 mutations responsible for antithrombin deficiency often present a slightly decreased or normal activity and therefore could not be detected by functional tests. This study was designed to compare activity assays and direct genetic analyses in identifying hereditary antithrombin deficiency. In total, 400 consecutive patients with venous thrombosis were enrolled. Functional assays showed that 16 of the 400 individuals had decreased antithrombin activity, and 14 of them were confirmed by genetic analysis. Of the remaining 384 patients, 95 individuals without a known risk factor and 95 individuals with predisposing factors were also selected for gene sequencing. Eight additional causative mutations were identified in nine individuals and they should also be considered as antithrombin deficiency. In addition, a recurrent mutation, p.Arg356_Phe361del, was characterised. The mutant appeared to have a partially impaired secretion and a reduction in functional activity by 50 %. This study indicated that including genetic analysis in screening tests for identifying antithrombin deficiency was essential. Specifically, a genetic analysis of SERPINC1 is strongly recommended when individuals experience unprovoked thrombotic diseases, even if the AT activities are normal.

Venous thromboembolism (VTE) is the third most prevalent cardiovascular complication. Increasing studies have demonstrated that some microRNAs (miRNAs) are aberrantly expressed in VTE and play crucial roles in mediating the development of VTE. Therefore, our study intends to explore the detailed function and molecular mechanism of miR-200c-3p in VTE progression. In our research, VTE rat models were first established via inferior vena cava (IVC) ligation and the time-dependent effects of IVC ligation on thrombus formation were discovered. The results of reverse transcription quantitative polymerase-chain reaction (RT-qPCR) and western blotting showed that serpin family C member 1 (SERPINC1) was downregulated in VTE rat models and showed an inverse correlation with thrombus load. MiRNA target prediction tools and luciferase reporter assay confirmed SERPINC1 as a target for miR-200c-3p. VTE rats were injected with miR-200c-3p inhibitor for 24 h to investigate whether miR-200c-3p knockdown influences thrombus formation in vivo . Histological examination through hematoxylin-eosin staining revealed that miR-200c-3p downregulation markedly inhibited the formation of thrombus in IVC of rats. Additionally, miR-200c-3p was upregulated while SERPINC1 was downregulated in serum and inferior vena cava of VTE rats as well as in plasma of patients with VTE. Linear regression analysis demonstrated that miR-200c-3p expression was negatively correlated to SERPINC1 expression in VTE rats and patients with VTE. Our study determines the previously unelucidated function of miR-200c-3p in VTE, which might provide a potential novel insight for the treatment of VTE.

This article uses the NMNL (nested multinominal logit) model to analyze the impact of different policies on the cost of owning a vehicle by a consumer and discusses the changes in the share of various fuel-driven types of passenger vehicles that may be brought by different policy portfolios. This article also considers the differences in the development of various technical routes, conducts the nested classification calculation of different models, divides the differences in product preferences and obtains the market share results that are more in line with the market development status, providing a basis for the formulation of policies related to new energy vehicles. The study found that the popularization of NEVs requires more cost-reducing measures. As policies that consumers can perceive, consumers are more sensitive to fiscal and taxation policies than other types of policies. Based on the calculation of policy effects, this article recommends a policy plan to gradually impose vehicle purchase tax on NEVs after 2024, increase the fuel tax rate in stages after 2025, and impose an excise tax on BEVs and FCEVs after 2030. The plan can guarantee the stability of support for NEVs and the gradual reduction of financial investment.

This paper describes our system used in the SemEval-2022 Task 11 Multilingual Complex Named Entity Recognition, achieving 3rd for track 1 on the leaderboard. We propose Dictionary-fused BERT, a flexible approach for entity dictionaries integration. The main ideas of our systems are: 1) integrating external knowledge (an entity dictionary) into pretrained models to obtain contextualized word and entity representations 2) designing a robust loss function leveraging a logit matrix 3) adding an auxiliary task, which is an on-top binary classification to decide whether the token is a mention word or not, makes the main task easier to learn. It is worth noting that our system achieves an F1 of 0.914 in the postevaluation stage by updating the entity dictionary to the one of Meng et al. (2021), which is higher than the score of 1st on the leaderboard of the evaluation stage.