CropMetabolome: a comprehensive metabolome database for major crops cross eight categories.

Chemical compositions of crops are of great agronomical importance, as crops serve as resources for nutrition, energy, and medicines for human and livestock. For crop metabolomics research, the lack of crop reference metabolome and high-quality reference compound mass spectra, as well as utilities for metabolic profiling, has hindered the discovery and functional study of phytochemicals in crops. To meet these challenging needs, we have developed the Crop Metabolome database (abbreviated as CropMetabolome) that is dedicated to the construction of crop reference metabolome, repository, and dissemination of crop metabolomic data, and profiling and analytic tools for metabolomics research. CropMetabolome contains a metabolomics database for more than 50 crops (belonging to eight categories) that integrated self-generated raw mass spectral data and public-source datasets. The reference metabolome for 59 crop species was constructed, which have functions that parallel those of reference genome in genomic studies. CropMetabolome also contains 'Standard compound mass spectral library', 'Flavonoids library', 'Pesticide library', and a set of related analytical tools that enable metabolic profiling based on a reference metabolome (CropRefMetaBlast), annotation and identification of new metabolites (CompoundLibBlast), deducing the structure of novel flavonoid derivatives (FlavoDiscover), and detecting possible residual pesticides in crop samples (PesticiDiscover). In addition, CropMetabolome is a repository to share and disseminate metabolomics data and a platform to promote collaborations to develop reference metabolome for more crop species. CropMetabolome is a comprehensive platform that offers important functions in crop metabolomics research and contributes to improve crop breeding, nutrition, and safety. CropMetabolome is freely available at https://www.cropmetabolome.com/.

RefMetaPlant: a reference metabolome database for plants across five major phyla.

Plants are unique with tremendous chemical diversity and metabolic complexity, which is highlighted by estimates that green plants collectively produce metabolites numbering in the millions. Plant metabolites play crucial roles in all aspects of plant biology, like growth, development, stress responses, etc. However, the lack of a reference metabolome for plants, and paucity of high-quality standard compound spectral libraries and related analytical tools, have hindered the discovery and functional study of phytochemicals in plants. Here, by leveraging an advanced LC-MS platform, we generated untargeted mass spectral data from >150 plant species collected across the five major phyla. Using a self-developed computation protocol, we constructed reference metabolome for 153 plant species. A 'Reference Metabolome Database for Plants' (RefMetaPlant) was built to encompass the reference metabolome, integrated standard compound mass spectral libraries for annotation, and related query and analytical tools like 'LC-MS/MS Query', 'RefMetaBlast' and 'CompoundLibBlast' for searches and profiling of plant metabolome and metabolite identification. Analogous to a reference genome in genomic research, RefMetaPlant provides a powerful platform to support plant genome-scale metabolite analysis to promote knowledge/data sharing and collaboration in the field of metabolomics. RefMetaPlant is freely available at https://www.biosino.org/RefMetaDB/.

Pijx confers broad-spectrum seedling and panicle blast resistance by promoting the degradation of ATP ß subunit and OsRbohC-mediated ROS burst in rice.

Rice blast, caused by the fungal pathogen Magnaporthe oryzae, is one of the most important diseases of rice. Utilization of blast-resistance genes is the most economical, effective, and environmentally friendly way to control the disease. However, genetic resources with broad-spectrum resistance (BSR) that is effective throughout the rice growth period are rare. In this work, using a genome-wide association study, we identify a new blast-resistance gene, Pijx, which encodes a typical CC-NBS-LRR protein. Pijx is derived from a wild rice species and confers BSR to M. oryzae at both the seedling and panicle stages. The functions of the resistant haplotypes of Pijx are confirmed by gene knockout and overexpression experiments. Mechanistically, the LRR domain in Pijx interacts with and promotes the degradation of the ATP synthase ß subunit (ATPb) via the 26S proteasome pathway. ATPb acts as a negative regulator of Pijx-mediated panicle blast resistance, and interacts with OsRbohC to promote its degradation. Consistently, loss of ATPb function causes an increase in NAPDH content and ROS burst. Remarkably, when Pijx is introgressed into two japonica rice varieties, the introgression lines show BSR and increased yields that are approximately 51.59% and 79.31% higher compared with those of their parents in a natural blast disease nursery. In addition, we generate PPLPijx Pigm and PPLPijx Piz-t pyramided lines and these lines also have higher BSR to panicle blast compared with Pigm- or Piz-t-containing rice plants. Collectively, this study demonstrates that Pijx not only confers BSR to M. oryzae but also maintains high and stable rice yield, providing new genetic resources and molecular targets for breeding rice varieties with broad-spectrum blast resistance.

A de novo evolved gene contributes to rice grain shape difference between indica and japonica.

The role of de novo evolved genes from non-coding sequences in regulating morphological differentiation between species/subspecies remains largely unknown. Here, we show that a rice de novo gene GSE9 contributes to grain shape difference between indica/xian and japonica/geng varieties. GSE9 evolves from a previous non-coding region of wild rice Oryza rufipogon through the acquisition of start codon. This gene is inherited by most japonica varieties, while the original sequence (absence of start codon, gse9) is present in majority of indica varieties. Knockout of GSE9 in japonica varieties leads to slender grains, whereas introgression to indica background results in round grains. Population evolutionary analyses reveal that gse9 and GSE9 are derived from wild rice Or-I and Or-III groups, respectively. Our findings uncover that the de novo GSE9 gene contributes to the genetic and morphological divergence between indica and japonica subspecies, and provide a target for precise manipulation of rice grain shape.

Incorporation and solidification mechanism of manganese doped cement clinker.

Using municipal and industrial solid waste as a substitute raw material and fuel in cement rotary kiln co-processing is considered an economic and environmentally friendly alternative to the use of traditional fuels. However, the presence of heavy metals in solid waste is a growing concern in the cement rotary kiln co-processing technique. The solidification mechanism of heavy metals in cement clinker is directly related to their stabilization. Cement clinkers doped with manganese oxide (MnO2: 0.0%-5.0% wt%) were prepared in a laboratory to investigate the impacts of extrinsic Mn on cement clinker calcination. The insignificant changes in X-ray diffractometer patterns indicated that the fixed Mn had little influence on the mineral lattice structure. Raman spectra and X-ray photoelectron spectroscopy revealed the transformation of the silicate phase when the Mn dose was increased. Moreover, the satisfactory solidification ratio confirmed the incorporation of Mn in the cement clinker. These results provided evidence of the influence rule of Mn in the cement clinker calcination process. Furthermore, Raman spectroscopy showed great potential for the qualitative and semi-quantitative analysis of the cementitious materials derived from cement rotary kiln co-processing. These results will be important for the further development of green cement manufacturing technology.

CRISPR-Cas9-mediated editing of the OsHPPD 3' UTR confers enhanced resistance to HPPD-inhibiting herbicides in rice.

This study reports the creation of herbicide-resistant rice lines via CRISPR-Cas9-mediated editing of the 3' UTR of OsHPPD. Resistance index calculations revealed that two resistant lines, TS8-2#-10 and TS8-8#-6, exhibited 4.8-fold and 3.7-fold greater resistance to HPPD-inhibiting herbicides compared with the wild type, YG3012.

Thrombin increases the expression of cholesterol 25-hydroxylase in rat astrocytes after spinal cord injury.

Astrocytes are important cellular centers of cholesterol synthesis and metabolism that help maintain normal physiological function at the organism level. Spinal cord injury results in aberrant cholesterol metabolism by astrocytes and excessive production of oxysterols, which have profound effects on neuropathology. 25-Hydroxycholesterol (25-HC), the main product of the membrane-associated enzyme cholesterol-25-hydroxylase (CH25H), plays important roles in mediating neuroinflammation. However, whether the abnormal astrocyte cholesterol metabolism induced by spinal cord injury contributes to the production of 25-HC, as well as the resulting pathological effects, remain unclear. In the present study, spinal cord injury-induced activation of thrombin was found to increase astrocyte CH25H expression. A protease-activated receptor 1 inhibitor was able to attenuate this effect in vitro and in vivo. In cultured primary astrocytes, thrombin interacted with protease-activated receptor 1, mainly through activation of the mitogen-activated protein kinase/nuclear factor-kappa B signaling pathway. Conditioned culture medium from astrocytes in which ch25h expression had been knocked down by siRNA reduced macrophage migration. Finally, injection of the protease activated receptor 1 inhibitor SCH79797 into rat neural sheaths following spinal cord injury reduced migration of microglia/macrophages to the injured site and largely restored motor function. Our results demonstrate a novel regulatory mechanism for thrombin-regulated cholesterol metabolism in astrocytes that could be used to develop anti-inflammatory drugs to treat patients with spinal cord injury.

Effects of chronic realgar exposure on liver lipidome in mice and identification sensitive lipid biomarker model for realgar-induced liver damage.

Chronic or excessive use of realgar induced liver damage. The biomarkers and exact mechanism have not been fully investigated. We performed an untargeted lipidomics study to investigate the effects of realgar on liver lipidome in mice and explore the sensitive biomarker model of realgar induced liver damage. It was found that realgar exposure induced arsenic accumulation in the liver, increased ROS generation, elevated MDA levels, decreased antioxidant enzymes levels, induced cell apoptosis, changed hepatocyte ultrastructure and morphology, and altered ALT, AST levels. Lipidomics study detected 30 classes and 1457 molecules in mice liver. The numbers of 49 and 103 lipid molecules were significantly altered (FDR<0.05) in the livers of 0.45 g/kg and 1.35 g/kg realgar-exposed mice. The glycerophospholipid and sphingomyelin were the most affected lipid class. We focused on the effect of chronic realgar exposure on the mutual transformation of lipid subclasses and the fatty acid chain composition of lipids in mouse liver, and found that realgar affected the mutual transformation of PE-PC, PC-LPC and SM-Cer. Notably, we found that realgar exposure increased PUFAs linked phospholipids in mouse liver tissues. We identified two sensitive lipid molecules [PE (44:2p) and PE (16:0/22:5)] in combination can accurately distinguish and predict realgar induced liver damage, they are associated with oxidative damage and mitochondrial respiration in liver tissue. Our study provides an experimental basis for the mechanism research and early detection of realgar-induced liver damage.

Concentrations, congener patterns, and correlations of unintentional persistent organic pollutants in cement kilns co-processing hazardous waste.

Emissions from two typical cement kilns co-processing different kind of hazardous waste were analyzed for 143 congeners of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls, polychlorinated naphthalenes, polybrominated dibenzo-p-dioxins and dibenzofurans, and polybrominated diphenyl ethers. The congener distributions in different process stages were investigated. One of the plants co-processed waste chemical reagents from laboratories. The emission factor (TEQ basis) for the plant was 2.09 ng WHO2005 TEQ/t, with the kiln head and the kiln back end contributing 1.18, 0.91 ng WHO2005 TEQ/t, respectively. The other plant co-processed municipal waste incineration fly ash. The emission factor for the plant was 0.12 ng WHO2005 TEQ/t, with the kiln head and the kiln back end contributing 0.022, and 0.10 ng WHO2005 TEQ/t. These results indicate that co-processing of waste containing reagents from laboratories may lead to higher emission levels than co-processing of other types of waste. The congener patterns of persistent organic pollutants (POPs) in ash samples from the humidifier tower were similar to those in samples from the bag filter at the kiln back end. The correlation coefficients of five pollutants between the humidifier and bag filters samples were generally high, which indicated that conditions in those two stages similarly favored the formation of these POPs. Comparison of the concentrations for different process stages suggested that the main stage for formation of unintentional POPs was the humidifier tower. These results improve our understanding of emission characteristics and could be used for simultaneous control of multiple POPs.

Insight into the regulation of NLRP3 inflammasome activation by mitochondria in liver injury and the protective role of natural products.

Due to high mortality rates and poor prognosis, liver injury remains one of the leading causes of mortality worldwide. Amounting evidence suggested that the activation of the nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome, which promotes pro-interleukin-1ß (pro-IL-1ß) and pro-interleukin-18 (pro-IL-18) cleavage and maturation play a vital role in the occurrence and development of liver injury and liver disease. Mitochondrial dysfunction is a common co-occurring event in liver injury. Abnormal mitochondrial function has also been shown to be closely related to NLRP3 inflammasome activation. Currently, natural products have attracted the attention of researchers as potential therapeutic agents for liver injury and liver disease due to their less toxicity and multi-targeting advantages. A number of natural products have been discovered to prevent and treat liver injury by modulating the activation of NLRP3 inflammasome. In this review, we highlight the mechanisms involved in the regulation of NLRP3 inflammasome activation by mitochondria during liver injury and natural products that target mitochondrial function processes to prevent or treat liver injury. Our paper may shed insight into novel viewpoint and target for prevention and treatment of liver injury based on NLRP3 inflammasome.

Realgar Alleviated Neuroinflammation Induced by High Protein and High Calorie Diet in Rats via the Microbiota-Gut-Brain Axis.

PURPOSE: Gastrointestinal heat retention syndrome (GHRS) often occurs in adolescents, resulting into nervous system injury. Realgar, an arsenic mineral with neuroprotective effect, has been widely used to treat GHRS. However, its mechanism of action remains unknown. METHODS: A GHRS rat model was established using a high protein and high calorie diet. We performed macroscopic characterization by assessing bowel sounds, hot/cold preference, anal temperature, and fecal features. Atomic fluorescence spectroscopy was employed to evaluate brain arsenic level while hippocampal ultrastructural changes were analyzed using transmission electron microscopy. In addition, inflammatory cytokines and BBB breakdown were analyzed by western blotting, immunofluorescence assays, and immunohistochemistry staining. We also evaluated hippocampal metabolites by LC-MS while fecal microorganisms were assessed by 16S rDNA sequencing. RESULTS: Our data showed that the high protein and high calorie diet induced GHRS. The rat model depicted decreased bowel sounds, increased fecal characteristics score, preference for low temperature zone, and increased anal temperature. In addition, there was increase in inflammatory factors IL-6, Iba-1, and NF-κB p65 as well as reduced BBB structural protein Claudin-5 and Occludin. The data also showed appearance of hippocampus metabolites disorder and fecal microbial imbalance. Realgar treatment conferred a neuroprotective effect by inhibiting GHRS-specific characteristics, neuroinflammatory response, BBB impairment, metabolites disorder, and microbial imbalance in the GHRS rat model. CONCLUSION: Taken together, our analysis demonstrated that realgar confers a neuroprotective effect in GHRS rats through modulation of the microbiota-gut-brain axis.

Degradation of COD in antibiotic wastewater by a combination process of electrochemistry, hydroxyl-functionalized ball-milled zero-valent iron/Fe3O4 and Oxone.

In this study, the significant iron-based material, hydroxyl-functionalized ball-milled zero-valent iron/Fe3O4 (HFB-ZVI/Fe3O4) was employed for the experiments. The performance of the Electro + HFB-ZVI/Fe3O4 + Oxone system for the degradation of chemical oxygen demand (COD) in antibiotic wastewater was investigated. A direct current was applied between a graphite plate anode and two iron plate cathodes, and a series of operational parameters, such as applied electric current, the dosage of HFB-ZVI/Fe3O4 composite, the dosage of Oxone, and initial solution pH, were explored to evaluate the oxidation process. The application of electric current enhanced the gradual degradation of COD and the increase of current intensity accelerated COD degradation. The neutral condition was favourable for the rapid degradation of COD in a short reaction time by the Electro + HFB-ZVI/Fe3O4 + Oxone process and promoted the degradation efficiency of COD. An increase of electric current gradually decreased the reaction solution pH, the larger the electric current applied in the reaction process, the lower the final pH of the reaction solution. Under the optimal experimental conditions (1 g/L HFB-ZVI/Fe3O4 composite, 0.3 g/L Oxone, current intensity = 500 mA, initial solution pH = 7.85), Electro + HFB-ZVI/Fe3O4 + Oxone achieved 99% COD degradation in antibiotic wastewater. Radicals quenching experiments indicated the contribution to COD degradation by hydroxyl radicals (HO•), sulphate radicals (SO4•-) and other oxidants were 66.03%, 24.014% and 9.756%, respectively. The possible mechanism of COD degradation in the Electro + HFB-ZVI/Fe3O4 + Oxone system was also discussed in this study. The findings in this work provided useful information for the treatment of wastewater.

Development of Rice Variety With Durable and Broad-Spectrum Resistance to Blast Disease Through Marker-Assisted Introduction of Pigm Gene.

Rice blast, caused by Magnaporthe oryzae (M. oryzae), is one of the most destructive diseases threatening rice production worldwide. Development of resistant cultivars using broad-spectrum resistance (R) genes with high breeding value is the most effective and economical approach to control this disease. In this study, the breeding potential of Pigm gene in geng/japonica rice breeding practice in Jiangsu province was comprehensively evaluated. Through backcross and marker-assisted selection (MAS), Pigm was introduced into two geng rice cultivars (Wuyungeng 32/WYG32 and Huageng 8/HG8). In each genetic background, five advanced backcross lines with Pigm (ABLs) and the same genotypes as the respective recurrent parent in the other 13 known R gene loci were developed. Compared with the corresponding recurrent parent, all these ABLs exhibited stronger resistance in seedling inoculation assay using 184 isolates collected from rice growing regions of the lower region of the Yangtze River. With respect to panicle blast resistance, all ABLs reached a high resistance level to blast disease in tests conducted in three consecutive years with the inoculation of seven mixed conidial suspensions collected from different regions of Jiangsu province. In natural field nursery assays, the ABLs showed significantly higher resistance than the recurrent parents. No common change on importantly morphological traits and yield-associated components was found among the ABLs, demonstrating the introduction of Pigm had no tightly linked undesirable effect on rice economically important traits and its associated grain weight reduction effect could be probably offset by others grain weight genes or at least in the background of the aforementioned two varieties. Notably, one rice line with Pigm, designated as Yangnonggeng 3091, had been authorized as a new variety in Jiangsu province in 2021, showing excellent performance on both grain yield and quality, as well as the blast resistance. Together, these results suggest that the Pigm gene has a high breeding value in developing rice varieties with durable and broad-spectrum resistance to blast disease.

Research Advances on Anti-Cancer Natural Products.

Malignant tumors seriously threaten people's health and life worldwide. Natural products, with definite pharmacological effects and known chemical structures, present dual advantages of Chinese herbs and chemotherapeutic drug. Some of them exhibit favorable anti-cancer activity. Natural products were categorized into eight classes according to their chemical structures, including alkaloids, terpenoids and volatile oils, inorganic salts, phenylpropanoids, flavonoids and isoflavones, quinone, saponins and polysaccharides. The review focused on the latest advances in anti-cancer activity of representative natural products for every class. Additionally, anti-cancer molecular mechanism and derivatization of natural products were summarized in detail, which would provide new core structures and new insights for anti-cancer new drug development.

New paeonol derivative C302 reduces hypertension in spontaneously hypertensive rats through endothelium-dependent and endothelium-independent vasodilation.

Hypertension is a major risk factor for cardiovascular disease and Chinese herb monomers could provide new structural skeletons for anti-hypertension new drug development. Paeonol is a Chinese herbal monomer extracted from Cortex moutan, exhibited some anti-hypertensive activity. The study focused on the structural optimization of paeonol to provide promising lead compounds for anti-hypertension new drug development. Herein, twelve new paeonol derivatives (PD) were designed and synthesized and their vasodilation activity was evaluated by in vitro vasodilation drug screening platform based on Myograph. Its anti-hypertension activity, PD-C302 (2-hydroxy-4-methoxyvalerophenone) as a representative with the optimal vasodilation activity, was determined by its response to blood pressure in spontaneously hypertensive rats (SHR) in vivo. Moreover, its molecular mechanism was probed by the vasodilation activity of rat superior mesenteric artery rings with or without endothelium pre-contracted by potassium chloride (KCl) or phenylephrine hydrochloride (PE). It was indicated that PD-C302 significantly reduced the blood pressure in SHR, which would involve in PD-C302-induced vasodilation. Furthermore, endothelium-dependent pathways and endothelium-independent pathways both contributed importantly to PD-C302-induced vasodilation at low concentration of PD-C302. Endothelium-independent pathways (vascular smooth muscle cell-mediated vasodilation), were mainly responsible for the PD-C302-induced vasodilation at high concentration of PD-C302, which involved in opening multiple K+ channels to restrain Ca2+ channels, and then triggered vasodilation to reduce blood pressure. PD-C302 has a simple structure and favorable anti-hypertensive activity in vivo, which could be a promising lead compound for anti-hypertension new drug development.

Research Advances on Matrine.

Matrine is an alkaloid extracted from traditional Chinese herbs including Sophora flavescentis, Sophora alopecuroides, Sophora root, etc. It has the dual advantages of traditional Chinese herbs and chemotherapy drugs. It exhibits distinct benefits in preventing and improving chronic diseases such as cardiovascular disease and tumors. The review introduced recent research progresses on extraction, synthesis and derivatization of Matrine. The summary focused on the latest research advances of Matrine on anti-atherosclerosis, anti-hypertension, anti-ischemia reperfusion injury, anti-arrhythmia, anti-diabetic cardiovascular complications, anti-tumor, anti-inflammatory, anti-bacterium, anti-virus, which would provide new core structures and new insights for new drug development in related fields.

Analysis of the heavy metals (As, Pb, Cu, Zn) by leaching and sequential extraction procedure from a municipal solid waste incinerator fly ash co-processing cement kiln plant.

The municipal solid waste incineration (MSWI) fly ash has been a major problem with the rapid development of the cities in China. And the cement rotary kiln co-processing technique is accepted as an effective method to dispose detrimental heavy metals in MSWI fly ash. This study focused on presented the total leaching content and the morphological distribution of the heavy metals in cement solid samples doped with MSWI fly ash. These samples were collected from a MSWI fly ash co-processing cement rotary kiln plant. The leaching test and the sequential extraction procedure were adopted to measure the migration characteristic of As, Pb, Cu, and Zn. In addition, the leachability of clinker samples under different simulated environmental conditions was also detected to analyze the security of the cement product doped with MSWI fly ash. This work demonstrates the feasibility of the cement rotary kiln MSWI fly ash co-processing technique and provides a scientific guidance to related plant.

Substandard starch grain4 may function in amyloplast development by influencing starch and lipid metabolism in rice endosperm.

The amyloplast is a specialized plastid in rice endosperm cells where starch is synthesized and stored as starch granules (SGs). However, little is known about the molecular mechanism underlying amyloplast and SG development. In this study, a novel mutant (c134) demonstrating a floury endosperm with enlarged SGs and amyloplasts was identified. The floury endosperm was caused by rounder, loosely packed SG. Grain-quality profile and expression analysis showed reduced contents of total starch and amylose in the c134 mutant, as well as reduced expression of a number of genes involved in starch biosynthesis. Galactosyldiacylglycerol (GDG) content and fatty acid synthesis play important roles in plastid development, and in the c134 endosperm, an obvious decrease in GDG and various fatty acids was observed, with down-regulated expression of various genes involved in lipid biosynthesis. Furthermore, map-based cloning revealed an amino acid substitution (glycine to aspartic acid) in the substandard starch grain4 (SSG4) protein. The results of this study suggest that SSG4 influences the regulation of starch and lipid metabolism as well as amyloplast development, a finding that is useful for potential genetic improvement of rice grain quality in future starch and lipid breeding and biotechnology.

Whole exome sequencing identifies genetic variants in Chinese Han pregnant women with venous thromboembolism.

OBJECTIVES: Venous thromboembolism (VTE) is a common health problem, causing considerable morbidity and mortality. The incidence of VTE is higher in pregnant women than in those who are not pregnant. However, genetic factors for VTE in pregnant women are largely unknown. METHODS: We performed a large-scale prospective cohort study of 65,138 pregnancies. 24 pregnant patients diagnosed with VTE and 24 matched pregnant women without VTE were enrolled and sequenced by whole exome sequencing. We investigated the occurrence of known VTE risk variants, damaging variants found in thrombophilia genes and rare damaging variants possibly related to VTE in pregnancies. An exome-wide association study was also performed using a case-control design. RESULTS: Our findings suggest that VTE in pregnancies may be mainly related to (i) the presence of known pathogenic variants in affected individual like F2, (ii) possibly damaging variants found in major thrombophilia gene GCKR, and (iii) 1 pathogenic and 13 likely pathogenic rare damaging variants associated with genetic errors. In exome-wide association stage, 42 variants at 34 genes may show suggestive associations with VTE in pregnancies (the lowest P = 3.5 × 10-7). ZFP41 (rs6558339, P = 8.85 × 10-5) in 24 patients were the only exonic missense variant. CONCLUSION: The combined findings suggest that some genes may be involved in the mechanism of basement membranes, sterol accumulation and atherosclerosis, lipid metabolism and coagulation deficiency. These identified risk variants may improve the understanding of VTE pathogenesis in pregnancies and provide potential biomarker for development of clinical diagnosis.