Genetic association of preeclampsia to von Willebrand factor and its size-regulator ADAMTS13

Genetic association of preeclampsia to von Willebrand factor and its size-regulator ADAMTS13 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Genetic association of preeclampsia to von Willebrand factor and its size-regulator ADAMTS13 A. Inkeri Lokki, Michael Triebwasser, Emma Daly, Mitja I. Kurki, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5685318/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Preeclampsia is a common pregnancy-specific vascular disorder that develops during the second half of pregnancy. Preeclampsia shares features with thrombotic microangiopathies. Here we analyzed whether sequence variants in the coagulation system genes predispose to preeclampsia. We performed targeted exomic sequencing of 58 genes in a total of 615 preeclamptic women and 2094 controls. A common missense variant rs1800385 (Val1565Leu) in the gene coding for von Willebrand Factor ( VWF) (OR=1.72, p-value=3.57E-4) and a low-frequency missense variant rs41314453 (Ala732Val) in the gene coding for a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) (OR=1.97, p-value=0.044) were associated with preeclampsia. rs41314453 is known to decrease ADAMTS13 expression and activity. Thus, the reduced enzyme activity could promote the formation of large vWF polymers on endothelial cells and platelets and thereby increase vascular prothrombotic activity in preeclampsia. Our results support a role for an impaired ability of ADAMTS13 to limit VWF polymerization in the pathogenesis of PE. Ultralarge multimers of VWF could mediate platelet accumulation in the turbulent intervillous spaces in preeclamptic placentae, calling upon novel therapeutics to control the VWF-ADAMTS13 axis in severe cases having low ADAMTS13 in the presence of high VWF levels and multimerization. Biological sciences/Genetics Health sciences/Diseases Health sciences/Medical research Health sciences/Molecular medicine Health sciences/Risk factors preeclampsia pregnancy coagulation cascade von willebrand factor ADAMTS13 genetic association Figures Figure 1 Figure 2 Figure 3 Introduction Preeclampsia (PE) is a common pregnancy-specific vascular disorder with diverse clinical characteristics. It affects approximately 3% of pregnancies and accounts for over 50,000 maternal and 900,000 perinatal deaths annually 1 . No specific treatment, other than delivery, is available for PE. For prevention, low-dose aspirin administered from < 16 weeks of gestation has been suggested to reduce the risk of preterm PE (resulting in delivery before 37 wks of gestation) in women at high risk for PE, but its use remains controversial 2 . Despite common signs, proteinuria and hypertension, the etiology of PE could be heterogeneous, especially in a subset of cases. There is a familial predisposition to PE and strong epidemiological evidence suggests that the risk for PE is inherited 3 . However, the individual variant effects of the candidate genes discovered thus far are modest. Finnish population presents an opportunity to study complex diseases, because the allele frequencies observed in the modern Finnish population result from several bottleneck events in the founder population which helps to identify relevant pathways for disease pathogenesis due to the enrichment of associating variants 4 . The coagulation system is activated by changes in the vascular endothelium, and by platelet activation, adhesion, aggregation and interaction among leukocytes. In these processes, platelet interactions with von Willebrand factor (VWF) are an important contributor. Dysregulation of the platelet activity and coagulation system may result in thrombotic microangiopathies, including hemolytic anemia, and thrombocytopenia in women with PE 5 . No firm consensus regarding the role of platelets and coagulation biology in the development of PE has been reached 6 – 8 . Early results linking common variants such as FV Leiden and the prothrombin 3′ UTR variant to PE risk have not been replicated in larger studies 9 . To investigate the role of the genetic burden of coagulation proteins in PE, we designed a targeted exome sequencing study to screen the exons and splicing sites of genes involved in blood coagulation and its regulation. Results In the 58 selected genes we discovered 107 annotated variants and 151 presumably benign variants (data not shown). Key results of this association analysis are shown in Table 2 (significant and borderline significant variants noted). The significantly associated variants in Table 2 are all listed as variant of unknown significance by the American College of Medical Genetics (ACMG) classification 10 . Overall, the most significant associations were available in the hemostasis axis, including VWF and its size-regulating ADAMTS13 enzyme. Also, two protective antithrombin variants were discovered. The gene coding for von Willebrand Factor ( VWF) wasassociated with PE by three likely or probable LoF variants with significant p-values (Figure 1A). Rs1800385 (p.Val1565Leu) in the middle of the VWF gene is a missense variant that increases the risk for PE (OR=1.72, 95% confidence interval (CI) 1.27-2.32, p-value=3.57E-4). The intronic variant rs34444862 located 8 base pairs downstream of exon 35, and the second missense variant rs34230288 (p.Ala2178Ser) increase the risk for PE (OR=2.30, 95%CI=1.19-4.35, p-value=0.01; OR=2.2, CI 1.11-4.17, p-value=0.017, respectively). In ADAMTS13 , the intronic variant rs36218903 increased the risk for PE (OR=3.06, CI 95%=1.42-6.53; p-value=0.002), while the splice region variant rs36219245 decreased risk (OR=0.57, 95% CI 0.40-0.80; p-value=8.62E-4), (Figure 1B). The missense variant rs41314453 (Ala732Val) in ADAMTS13 had a suggested increase in PE risk (OR=1.97, 95% CI=0.99-3.78; p-value=0.044). We also found that in our cohorts rs5878 and rs5877 in SERPINC1 encoding for antithrombin (III), a critical plasma protease inhibitor and a member of the serpin superfamily, decreased the risk for PE (OR= 0.85 (95% CI=0.74 - 0.98), and 0.86 (95% CI=0.74-1), p-value=0.02 and 0.03, respectively). Comparison of the frequency of blood groups between patients carrying VWF and/or ADAMTS13 variants in the Finnish population revealed that women affected by PE blood group A are significantly more prevalent (Χ 2 = 16.227, p<0.0001; Figure 2). In contrast, blood group O was significantly underrepresented in the PE patients (Χ 2 = 21.403, p<0.0001). Discussion Our results suggest that genetic variants in VWF and in its size and functional regulator ADAMTS13 associate with primary hemostasis abnormalities. Variants in genes coding for both proteins may predispose to PE. Women with blood group A are at particular risk of VWF-mediated PE, while mothers with blood group O have a lower incidence of PE. These observations further support the proposed causative role of platelet dysregulation in a specific subgroup of PE. Importantly, we found associations within the VWF and ADAMTS13 axis, that cooperates to promote platelet-vascular wall interactions. A decrease in ADAMTS13 activity and an increase in VWF levels have also been previously associated with PE 11 , although the underlying and causative mechanisms in the VWF pathway have been under debate 12 , 13 . It is possible that VWF abnormalities are particularly associated with PE with severe features 14 . Common genetic variants within other coagulation genes are associated with PE 15 . Two of the discovered common PE-associating variants rs5878 and rs5877 in SERPINC1 that encode antithrombin are related reduced generation of thrombin and formation of fibrin. While we were able to confirm the reported association between Factor V Leiden (rs6025) and PE, the literature provides sparse insight into the potential associations we discovered in other F5 loci or variants discovered in F2 , F7 , and SERPINA5. Overall, the link between common coagulation variants, regulation of the coagulation system and an increased risk of preeclampsia 16 , 17 was strongly corroborated by our data. VWF is a plasma, platelet and endothelial glycoprotein that maintains hemostasis by generating multimers, which induce platelet aggregation and bind several proteins on activated endothelial cells in the vascular wall. Thereby, the multimers can lead to loss of vascular endothelial integrity 18 . This is particularly relevant in the placental vasculature due to its specific hemodynamic conditions. To prevent excessive platelet responses and coagulation, VWF oligomers emerging from endothelial cells or activated platelets are proteolytically cleaved by the ADAMTS13 enzyme 19 , 20 . ADAMTS13 cleaves VWF between tyrosine and methionine at position 842–843. Mutations in the ADAMTS13 gene or, more commonly, autoantibodies against the ADAMTS13 enzyme cause thrombotic thrombocytopenic purpura (TTP). The variant rs34230288 results in the replacement of the alanine at position 2178 with a serine in VWF. This variant has been observed in a patient who was in cis heterozygous for two VWF mutations and suffering from a noncanonical type 2B von Willebrand disease characterized by low VWF activity 21 . Similarly, the variant rs1800385 results in the replacement of valine at position 1565 by leucine resulting in significantly elevated ADAMTS13 activity but available data is insufficient to ascertain it’s functional relevance 22 . Rs41314453 is the main genetic determinant of ADAMTS13 activity. It is important to note that it is in linkage disequilibrium with several intronic variants in ADAMTS13 and variants in the regulatory regions of neighbouring genes 23 . The total effect of rs41314453 is dependent on the sequence context, which may influence the extent and direction of its effect on gene expression 24 . It has been estimated that the variant reduces ADAMTS13 levels by approximately 40% 23,24 . Although this magnitude of a decrease does not reach levels that are considered significant in TTP (< 10%), it may be significant in the context of the strong triggers such as pregnancy. The product of the ADAMTS13 gene with the minor allele T of rs41314453 has up to 29% less VWF cleavage activity than the protein coded by the gene with the major allele 24 . Thereby, rs41314453 may increase the risk for platelet deposition by accumulation of ultralarge VWF multimers (Fig. 3 ). In TTP, the accumulation of platelet-super-adhesive ultralarge VWF multimers on vascular endothelium leads to the spontaneous formation of microthrombi. Pregnancy is also one of the well-known triggers to precipitate attacks of TTP 5 . We recorded the blood groups of the women due to their role in association with VWF levels. Persons with blood group O have 30% lower VWF expression than the other blood groups, and blood group O has implications for platelet physiology 25 . Previously, blood groups A and more convincingly AB have been linked to a modestly increased risk of PE 26 , 27 . In addition, blood group A has been found to predispose to severe COVID-19, while blood group O is protective against infection and microthrombosis 28 . Concurrently, blood group O carries a 30% lower level of VWF, which may be highly elevated in COVID-19 29,30 . COVID-19 infection is also an independent risk factor for PE 33 . Our observed genetic variants of VWF, ADAMTS13 and non-O blood groups, likely contribute to the pathogenesis of PE. Furthermore, these findings may be helpful in the future to risk stratify patients and target novel therapies based on the specific analysis of VWF and ADAMTS13 biomarkers 31 The findings of our study may explain aspects of the pathophysiology of PE and clinical observations related to the preventive use of aspirin. In PE, the placental intervillous blood flow is perturbed due to the lack of vasodilation in the spiral arteries, and local high shear forces prevail, promoting platelet-VWF interactions 32 , 33 . This also increases the risk of local red blood cell lysis and promotes the release of ADP and thromboxane A2, which are known to further activate platelets. ADP increases the expression and release of VWF on platelets 34 . Associated activation of the complement system results in the formation of C5a and of membrane attack complexes, which can further activate platelets and induce release of VWF from endothelial cell Weibel-Palade bodies 35 – 37 . Subsequent reduced ability of ADAMTS13 to cleave VWF multimers would thus promote formation of platelet aggregates, which have been shown to be resistant to ADAMTS13 38 . On the other hand, VWF has been shown to protect the endothelium from complement-mediated injury 39 . Aspirin has been shown to reduce expression of VWF on platelet surfaces 34 . Thereby it may partially compensate for the procoagulant effect of rs41314453 on ADAMTS13 . Reduced platelet activity may improve blood flow in the intervillous space and reduce local ischemia and the severity of PE. TTP is associated with adverse pregnancy outcomes including PE 40 . Previously, a patient suffering from TTP due to a mutation in ADAMTS13 experienced a successful pregnancy under prophylactic treatment by aspirin 41 . More recently, novel drugs to influence the VWF-ADAMTS13 axis have emerged. Drugs like caplacizumab or recombinant ADAMTS13 could thus potentially be used in severe cases that are linked to high level of VWF multimerization and thrombosis 42 . In TMA, activation of the coagulation cascade and complement systems often go hand in hand 43 . Similarly, pregnancy is an inflammatory and procoagulative state. In a blood proteomic study, the most different expression patterns between preeclamptic patients and controls were observed in complement and coagulation pathways and platelet function and VWF were also implicated 44 . Thereby patients with a predisposing complement and/or coagulation pathway variants may present with TMA-like PE 45 . This study was limited by unavailability to study VWF and ADAMTS13 activity or their biomarkers. Furthermore, complete blood cell counts were not measured routinely thereby rendering the analysis of this data inconclusive. The effect of blood group for PE risk in carriers of VWF and ADAMTS13 variants requires further investigation in other well-described case-control cohorts representing varied populations. In summary, our findings demonstrate a link between PE and two important and related hemostatic components VWF and ADAMTS13. Our results support the concept that in some cases, PE with severe features may present as a thrombotic microangiopathy 45 . The fact that PE-associated rs41314453 reduces ADAMTS13 level suggests that the ADAMTS13-VWF axis and regulated VWF size or multimerization are important in preventing PE. Our results may also relate to aspirin, which may show preventive properties against preeclampsia in high-risk individuals. However, in the future based on laboratory assessment of VWF and ADMTS13, novel medications, such as caplacizumab and recombinant ADAMTS13 should be evaluated in PE. Methods Patient cohorts Two independent case-control cohorts, The Finnish Genetics of preeclampsia Consortium ( FINNPEC) cohort and the national FINRISK study cohort were investigated. The study rational is described in detail in the supplementary data. In the final association analyses, we included genotypes of FINNPEC and FINRISK population cohorts, leading to a combined total of 615 cases and 2094 controls. For FINNPEC, all women provided a written informed consent, and the FINNPEC study protocol was approved by the coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa. (FINRISK license 8/2016) 46 . The patients and controls from the FINNPEC cohort are characterized in the Supplementary table S1. The National FINRISK Study description and ethical approvals are available online: https://www.thl.fi/en/web/thlfi-en/research-and-expertwork/population-studies/the-national-finrisk-study. This study was conducted in accordance with the Declaration of Helsinki. Targeted Sequencing and Capture Enrichment Libraries from genomic DNA were prepared in-house (Washington University School of Medicine) 47 . Enzymes were purchased from Enzymatics (Beverly, MA). Briefly, the ends of sheared genomic DNA fragments were repaired by treatment with T4 DNA Polymerase and T4 DNA Polynucleotide Kinase, which phosphorylates the 5' hydroxyl. Next, an adenosine was added to the 3' position at each end of the DNA fragment with Taq Polymerase. Illumina adapters with an overhanging “T” were ligated onto the DNA fragment followed by bead-based size selection to remove adapter-dimers and fragments below the desired size. A barcode consisting of a unique index sequence was added by PCR by targeting the two ligated universal adapters on each fragment end. Sequence capture hybridization and other laboratory methods are described in the Supplementary data. The studied genes and intronic loci of interest are listed in Table 1. Fisher’s exact t-test was used as the primary test of association, and differences in frequencies of variants with p-value < 0.05 were considered significant. Significant and borderline significant variants are listed in Table 2. In addition to the statistical probability test, odds ratios (OR) with 95% confidence intervals (CI95) were calculated for all variants. Comparison of the distribution of P values in benign (synonymous, intronic/intergenic; 151 observed variants) vs. annotated (missense, truncating, essential splice and splice region; 107 observed variants) variants indicate that the expected incidence of two annotated variants with p<0.001 is less than 0.01 in our data, compared with 0 observed variants with p<0.001. The lack of inflated P values indicates that confounders, such as stratification, are not causing false positives. Loss of function (LoF) analyses were done in silico for all genes with associating variants by the Loss of Function – tool of the Variant Effect Predictor (VEP) (https://github.com/ensembl-variation/VEP_plugins/blob/master/LoFtool.pm). In the LoF tool, the following annotations were calculated: LoF score < 0.2 indicates a probably damaging variant, LoF score 0.2-0.7 possibly damaging and LoF score < 0.7 a benign variant. 5/7 of the genes in Table 2 had scores < 0.2, suggesting a probable LoF. Data were analyzed using PlinkSeq, Plink 48 and R. Kaviar 49 . VEP Build 37 was used for additional annotations 50 . Declarations Data-sharing statement The datasets used and/or analysed during the current study available from Professor Hannele Laivuori on reasonable request. Acknowledgements We thank Elisha D.O. Roberson for assistance in data analysis (P30-AR073752). FINNPEC study board consists of Hannele Laivuori (PI), Seppo Heinonen, Eero Kajantie, Juha Kere, Katja Kivinen, and Anneli Pouta. Eija Kortelainen and late Susanna Mehtälä provided technical assistance. We thank all the participants of the FINNPEC study as well as participants of FinMetSeq and FINRISK population cohort studies. Authorship Contribution JPA and HL came up with the study question. SH, EK, JK and HL supervised the collection of the FINNPEC cohort. MP and KA provided the FINRISK data. MT, JES, and JPA designed the targeted exomic sequencing method and MT conducted these laboratory analyses. AIL designed the data analysis with MD. AIL and JPA wrote the manuscript drafts in collaboration with SM and HL. MT, JES and JPA designed the targeted exomic sequencing method and MT conducted these laboratory analyses. ED performed the statistical analysis under the supervision of MK and MD. SM, AJ and RL are the specialists in the complement and coagulation pathways. All authors read and approved the final manuscript. Funding This study was supported by Alfred Kordelin Foundation (AIL), Maud Kuistila Foundation, Jane and Aatos Erkko Foundation (HL), The Academy of Finland (121196 and 278941; HL), Sigrid Jusélius Foundation (HL, SM) and Special State Subsidy for Health Research (TYH2019311, TYH2022315; SM, TYH2020318; RL TYH2021315, TYH2022315; HL). This research reported in this publication was also supported by the National Institutes of Health under Award Numbers F30 HL103072 (MT), U54 HL112303 (JPA), R01 GM099111 (JPA), and P30 AR048335 (JPA). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Finnish Medical Foundation (HL), University of Helsinki Funds (HL), Sakari and Päivikki Sohlberg Foundation (HL), Novo Nordisk Foundation and Signe and Ane Gyllenberg Foundation for Pediatric Research contributed to the FINNPEC sample collection. Data availability statement The datasets generated during and/or analysed during the current study are available from Professor Hannele Laivuori on reasonable request. Conflicts of interest RL is a member of an advisor board and given lectures for Sanofi and Takeda. AJ serves on the scientific advisory boards of Alexion, AstraZeneca Rare Disease, and Novartis International AG, and serves as a consultant for Dianthus Therapeutics and Aurinia Pharmaceuticals. She has been a Principal Investigator for Apellis Pharmaceuticals and is a Principal Investigator for Novartis International AG. She also receives royalty from UptoDate. HL has received honoraria from Orion Corporation. JPA is in the Scientific Advisory Board of Complement Corporation and Kypha, Inc; Scientific Advisory Board. Furthermore, he serves as a consultant in Celldex Therapeutics, formerly Avant Immunotherapeutics, Inc., Biothera and Clinical Pharmacy Services, CDMI. SM has received honoraria from Alexion, AstraZeneca Rare Disease, Biogen, Merck, Pfizer and UCB, and research funding from Alexion. Other authors have no conflicts of interest to report. References Van Lerberghe, W., Manuel, A., Matthews, Z. & Cathy, W. The World Health Report 2005 - Make Every Mother and Child Count . (2005). Rolnik, D. L. et al. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. New England Journal of Medicine (2017) doi:10.1056/nejmoa1704559. Skjaerven, R. et al. Recurrence of pre-eclampsia across generations: exploring fetal and maternal genetic components in a population based cohort. BMJ 331 , 877 (2005). Lim, E. T. et al. Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population. PLoS Genet 10 , e1004494 (2014). McCrae, K. R. Thrombocytopenia in pregnancy. Hematology.American Society of Hematology.Education Program 2010 , 397–402 (2010). Boij, R. et al. Biomarkers of coagulation, inflammation, and angiogenesis are independently associated with preeclampsia. Am J Reprod Immunol 68 , 258–270 (2012). Dehkordi, M. A. e. R., Soleimani, A., Haji-Gholami, A., Vardanjani, A. K. & Dehkordi, S. A. e. R. Association of deficiency of coagulation factors (Prs, Prc, ATIII) and FVL positivity with preeclampsia and/or eclampsia in pregnant women. Int J Hematol Oncol Stem Cell Res (2014). Han, L. et al. Blood coagulation parameters and platelet indices: Changes in normal and preeclamptic pregnancies and predictive values for preeclampsia. PLoS One (2014) doi:10.1371/journal.pone.0114488. Staines-Urias, E. et al. Genetic association studies in pre-eclampsia: systematic meta-analyses and field synopsis. Int J Epidemiol 41 , 1764–1775 (2012). Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. (2015) doi:10.1038/gim.2015.30. Aref, S. & Goda, H. Increased VWF antigen levels and decreased ADAMTS13 activity in preeclampsia. Hematology 18 , 237–241 (2013). Stepanian, A. et al. Von Willebrand factor and ADAMTS13: a candidate couple for preeclampsia pathophysiology. Arterioscler Thromb Vasc Biol 31 , 1703–1709 (2011). Molvarec, A. et al. Increased plasma von Willebrand factor antigen levels but normal von Willebrand factor cleaving protease (ADAMTS13) activity in preeclampsia. Thromb Haemost 101 , 305–311 (2009). Zhang, D. et al. Von Willebrand factor antigen and ADAMTS13 activity assay in pregnant women and severe preeclamptic patients. Journal of Huazhong University of Science and Technology.Medical sciences = Hua zhong ke ji da xue xue bao.Yi xue Ying De wen ban = Huazhong keji daxue xuebao.Yixue Yingdewen ban 30 , 777–780 (2010). Nieves-Colón, M. A. et al. Clotting factor genes are associated with preeclampsia in high-altitude pregnant women in the Peruvian Andes. The American Journal of Human Genetics 109 , 1117–1139 (2022). Wang, J., Ma, H. P., Ti, A. L. T. T. L., Zhang, Y. Q. & Zheng, H. Prothrombotic SERPINC1 Gene Polymorphism may Affect Heparin Sensitivity among Different Ethnicities of Chinese Patients Receiving Heart Surgery. Clinical and Applied Thrombosis/Hemostasis (2015) doi:10.1177/1076029614556744. Gao, C. et al. Heparin promotes platelet responsiveness by potentiating alphaIIbbeta3-mediated outside-in signaling. Blood 117 , 4946–4952 (2011). Sadler, J. E. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem 67 , 395–424 (1998). Dong, J. fei et al. ADAMTS-13 metalloprotease interacts with the endothelial cell-derived ultra-large von Willebrand factor. J Biol Chem 278 , 29633–29639 (2003). Xiang, Y., De Groot, R., Crawley, J. T. B. & Lane, D. A. Mechanism of von Willebrand factor scissile bond cleavage by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). Proc Natl Acad Sci U S A 108 , 11602–11607 (2011). Sacco, M. et al. Noncanonical type 2B von Willebrand disease associated with mutations in the VWF D’D3 and D4 domains. Blood Adv 4 , 3405–3415 (2020). Lasom, S. et al. Protective effect of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 haplotype on coronary artery disease. Blood Coagul Fibrinolysis 28 , 286–294 (2017). De Vries, P. S. et al. Genetic variants in the ADAMTS13 and SUPT3H genes are associated with ADAMTS13 activity. Blood (2015) doi:10.1182/blood-2015-02-629865. Plaimauer, B. et al. Modulation of ADAMTS13 secretion and specific activity by a combination of common amino acid polymorphisms and a missense mutation. Blood 107 , 118–125 (2006). Ward, S. E., O’Sullivan, J. M. & O’Donnell, J. S. The relationship between ABO blood group, von Willebrand factor, and primary hemostasis. Blood 136 , 2864–2874 (2020). Phaloprakarn, C. & Tangjitgamol, S. Maternal ABO blood group and adverse pregnancy outcomes. Journal of Perinatology 33 , 107–111 (2013). Alpoim, P. N. et al. Preeclampsia and ABO blood groups: A systematic review and meta-analysis. Mol Biol Rep (2013) doi:10.1007/s11033-012-2288-2. Liu, N. et al. The impact of ABO blood group on COVID-19 infection risk and mortality: A systematic review and meta-analysis. Blood Rev 48 , (2021). Ladikou, E. E. et al. Von Willebrand factor (vWF): marker of endothelial damage and thrombotic risk in COVID-19? Clinical Medicine 20 , e178 (2020). Gill, J. C., Endres-Brooks, J., Bauer, P. J., Marks, W. J. & Montgomery, R. R. The Effect of ABO Blood Group on the Diagnosis of von Willebrand Disease. Blood 69 , 1691–1695 (1987). Papageorghiou, A. T. et al. Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study. Am J Obstet Gynecol 225 , 289.e1-289.e17 (2021). Brosens, I. A., Robertson, W. B. & Dixon, H. G. The role of the spiral arteries in the pathogenesis of preeclampsia. Obstet Gynecol Annu (1972). Mody, N. A. & King, M. R. Platelet Adhesive Dynamics. Part II: High Shear-Induced Transient Aggregation via GPIbα-vWF-GPIbα Bridging. Biophys J 95 , 2556 (2008). Parker, R. I. & Gralnick, H. R. Effect of aspirin on platelet-von Willebrand factor surface expression on thrombin and ADP-stimulated platelets. Blood 74 , 2016–2021 (1989). Mannes, M. et al. Complement & platelets: Prothrombotic cell activation requires membrane attack complex induced release of danger signals. Blood Adv (2023) doi:10.1182/BLOODADVANCES.2023010817. Aiello, S. et al. C5a and C5aR1 are key drivers of microvascular platelet aggregation in clinical entities spanning from aHUS to COVID-19. Blood Adv 6 , 866–881 (2022). Turner, N. A. & Moake, J. Assembly and Activation of Alternative Complement Components on Endothelial Cell-Anchored Ultra-Large Von Willebrand Factor Links Complement and Hemostasis-Thrombosis. PLoS One 8 , e59372 (2013). Ercig, B. et al. Conformational plasticity of ADAMTS13 in hemostasis and autoimmunity. J Biol Chem 297 , (2021). Noone, D. G. et al. Von Willebrand factor regulates complement on endothelial cells. Kidney Int 90 , 123–134 (2016). Scully, M. How to evaluate and treat the spectrum of TMA syndromes in pregnancy. Hematology Am Soc Hematol Educ Program 2021 , (2021). Moatti-Cohen, M. et al. Unexpected frequency of Upshaw-Schulman syndrome in pregnancy-onset thrombotic thrombocytopenic purpura. Blood 119 , 5888–5897 (2012). Coppo, P. & Joly, B. S. Caplacizumab: A game changer also in pregnancy-associated immune-mediated thrombotic thrombocytopenic purpura? Br J Haematol (2023) doi:10.1111/BJH.18915. Meri, S. Complement activation in diseases presenting with thrombotic microangiopathy. Eur J Intern Med 24 , 496–502 (2013). Youssef, L. et al. Complement and coagulation cascades activation is the main pathophysiological pathway in early-onset severe preeclampsia revealed by maternal proteomics. Sci Rep 11 , 3048 (2021). Lokki, A. I. & Heikkinen-Eloranta, J. Pregnancy induced TMA in severe preeclampsia results from complement-mediated thromboinflammation. Hum Immunol 82 , 371–378 (2021). Borodulin, K. et al. Forty-year trends in cardiovascular risk factors in Finland. Eur J Public Health (2015) doi:10.1093/eurpub/cku174. Triebwasser, M. Excessive Complement Activation Due to Genetic Haploinsufficiency of Regulators in Multiple Human Diseases. Washington University in St.Louis, Arts & Sciences Electronic Theses and Dissertations. (2015). doi:http://dx.doi.org/10.7936/K7V69GR4. Purcell, S. & Sham, P. Genetic Power Calculator. Power 8 , 2005–2008 (2007). Glusman, G., Caballero, J., Mauldin, D. E., Hood, L. & Roach, J. C. Kaviar: an accessible system for testing SNV novelty. Bioinformatics 27 , 3216–3217 (2011). McLaren, W. et al. Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics 26 , 2069–2070 (2010). Tables Table 1. Targeted coagulation-associated genes and intronic loci. Coagulation-associated genes Coagulation loci Gene SNP ABO F7 KLKB1 SERPINA5 F2 rs1799963 ADAMTS13 F8 KNG1 SERPINB2 F5 rs6020 ADRA2A F9 MRVI1 SERPINC1 SERPINE1 rs2227631 CD36 FGA PEAR1 SERPIND1 F10 FGB PIK3CG SERPINE1 F11 FGG PLAT SERPINE2 F12 GP1BA PLAU SHH F13B GP1BB PLG STX2 F2 GP5 PROC STXBP5 F2R GP6 PROCR SVIL F2RL1 GP9 PROS1 TFPI F2RL2 IPCEF1 PROZ TFPI2 F2RL3 ITGA2B SELP VSGI4 F3 ITGB3 SERPINA1 VWF F5 JMJD1C SERPINA10 Table 2. Variants with significant or suggestive associations to preeclampsia within genes coding for coagulation proteins. Loss of function (LoF) is given per gene. All variants in Table 2 had a The American College of Medical Genetics and Genomics classification of variant of uncertain significance due to not enough evidence. RSID number Gene name P-value OR (95% confidence interval) MAF cases MAF controls Consequence (distance from exon, base pairs) LoFtool* rs1800385 VWF 3.57E-4 1.72 (1.27 - 2.32) 0.059 0.035 missense variant, V1565L 0.03 rs34444862 VWF 0.01 2.30 (1.19 - 4.35) 0.015 0.007 intron variant (-8) rs34230288 VWF 0.02 2.18 (1.11 - 4.17) 0.014 0.007 missense variant, A2178S rs36219245 ADAMTS13 8.62E-4 0.57 (0.40 - 0.80) 0.053 0.089 splice region variant (+4) 0.52 rs36218903 ADAMTS13 2.28E-3 3.06 (1.42 - 6.52) 0.012 0.004 intron variant (-33) rs41314453 ADAMTS13 0.04 1.97 (0.99 - 3.78) 0.013 0.007 missense variant, A732V rs5898 F2 0.03 1.31 (1.01 - 1.69) 0.077 0.060 synonymous variant, P395P 0.13 rs2301515 F5 8.06E-3 1.21 (1.05 - 1.39) 0.014 0.007 intron variant (-50) 0.09 rs6023 F5 0.01 1.48 (1.07 - 2.03) 0.050 0.034 splice region variant (+7) rs6025 F5 0.05 1.49 (1.01 – 2.21) 0.030 0.021 missense variant, R534Q rs9332688 F5 0.02 2.10 (1.07 - 3.98) 0.014 0.007 intron variant (-32) rs900258823 F5 0.05 1.49 (1.01 - 2.21) 0.030 0.021 intron variant (-7098) rs6042 F7 0.02 1.32 (1.04 - 1.67) 0.086 0.067 synonymous variant, H176H 0.07 rs6109 SERPINA5 5.70E-3 1.22 (1.06 - 1.41) 0.313 0.272 intron variant (-34) 0.06 rs6115 SERPINA5 0.04 1.15 (1.01 - 1.32) 0.367 0.335 missense variant, S64N rs5878 SERPINC1 0.02 1.17 (1.02 - 1.35) 0.316 0.282 synonymous variant, Q337Q na rs5877 SERPINC1 0.03 1.17 (1.01- 1.34) 0.301 0.269 synonymous variant, V327V na *LoF tool – (loss of function tool); score of LoF susceptibility per gene 0.7 = benign na – not available RSID – Single nucleotide polymorphism identifier, OR – Odds Ratio, MAF - Minor Allele Frequency Additional Declarations Competing interest reported. RL is a member of an advisor board and given lectures for Sanofi and Takeda. AJ serves on the scientific advisory boards of Alexion, AstraZeneca Rare Disease, and Novartis International AG, and serves as a consultant for Dianthus Therapeutics and Aurinia Pharmaceuticals. She has been a Principal Investigator for Apellis Pharmaceuticals and is a Principal Investigator for Novartis International AG. She also receives royalty from UptoDate. HL has received honoraria from Orion Corporation. JPA is in the Scientific Advisory Board of Complement Corporation and Kypha, Inc; Scientific Advisory Board. Furthermore, he serves as a consultant in Celldex Therapeutics, formerly Avant Immunotherapeutics, Inc., Biothera and Clinical Pharmacy Services, CDMI. SM has received honoraria from Alexion, AstraZeneca Rare Disease, Biogen, Merck, Pfizer and UCB, and research funding from Alexion. Other authors have no conflicts of interest to report. Supplementary Files supplementarydataclean.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5685318","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":478836824,"identity":"64460450-452a-41c4-8440-fad399baf8cb","order_by":0,"name":"A. Inkeri Lokki","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIie3PMWrDMBTG8S8Y0uUlWW1q7Cu8oKmQtldRMLhToGNGQUFZGrKmN+noIPDk0isUeoFmayDQvjilQ0H22kF/LULwQ+8BodA/bCgHYKSgIaq9kUskRyOjPkInsnsycjkT5SVoCc4kGp0IhADKC8aXdv6+vAdNqJ676+cZ5auR4zdw6v0jrd20kcGSta3coimJ3bjQGuzfJb6ziRHCrxfGLawjjkhVGscusjr8kiv7RflDS7p+KetBS15ksIGtCI5Uz2BlIYPFlDzWere2hexCijX7Sb4tp3tznGUTKtXHwd5k+aZRyeeSb33kp/jvA/eAUCgUCnX2DaHdR0EoSlbSAAAAAElFTkSuQmCC","orcid":"","institution":"University of Helsinki","correspondingAuthor":true,"prefix":"","firstName":"A.","middleName":"Inkeri","lastName":"Lokki","suffix":""},{"id":478836825,"identity":"e2449079-d2ad-4461-bc4e-5b8c5eae7a62","order_by":1,"name":"Michael Triebwasser","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Triebwasser","suffix":""},{"id":478836826,"identity":"65c7f109-da35-4b98-a2a9-3a19e092298b","order_by":2,"name":"Emma Daly","email":"","orcid":"","institution":"Hospital and Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Emma","middleName":"","lastName":"Daly","suffix":""},{"id":478836827,"identity":"80edef77-9d5a-4e16-962a-3d59e91cb8c0","order_by":3,"name":"Mitja I. Kurki","email":"","orcid":"","institution":"University of Helsinki","correspondingAuthor":false,"prefix":"","firstName":"Mitja","middleName":"I.","lastName":"Kurki","suffix":""},{"id":478836828,"identity":"61044422-a056-4eee-bee3-f760f553866b","order_by":4,"name":"Markus Perola","email":"","orcid":"","institution":"National Institute for Health and Welfare","correspondingAuthor":false,"prefix":"","firstName":"Markus","middleName":"","lastName":"Perola","suffix":""},{"id":478836829,"identity":"2023f938-fb36-4755-b77b-d487bee3b332","order_by":5,"name":"Kirsi Auro","email":"","orcid":"","institution":"National Institute for Health and Welfare","correspondingAuthor":false,"prefix":"","firstName":"Kirsi","middleName":"","lastName":"Auro","suffix":""},{"id":478836830,"identity":"a17408da-da49-415a-939f-60228eaa3adc","order_by":6,"name":"Anuja Java","email":"","orcid":"","institution":"Washington University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Anuja","middleName":"","lastName":"Java","suffix":""},{"id":478836831,"identity":"d0cdb5d1-bfd1-4bd5-b16e-29a75e1be468","order_by":7,"name":"Jane E. Salmon","email":"","orcid":"","institution":"Weill Medical College of Cornell University","correspondingAuthor":false,"prefix":"","firstName":"Jane","middleName":"E.","lastName":"Salmon","suffix":""},{"id":478836832,"identity":"b32e745b-31c1-4856-9c5a-15432425ef18","order_by":8,"name":"Seppo Heinonen","email":"","orcid":"","institution":"University of Helsinki and Helsinki University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Seppo","middleName":"","lastName":"Heinonen","suffix":""},{"id":478836833,"identity":"bd290bd8-006a-412e-b931-17bbdad4feb3","order_by":9,"name":"Eero Kajantie","email":"","orcid":"","institution":"Norwegian University of Health and Technology","correspondingAuthor":false,"prefix":"","firstName":"Eero","middleName":"","lastName":"Kajantie","suffix":""},{"id":478836834,"identity":"a02cc6d2-c86f-45ab-a130-15319d5c31db","order_by":10,"name":"Juha Kere","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Juha","middleName":"","lastName":"Kere","suffix":""},{"id":478836835,"identity":"b9dd864b-78e9-4ecb-97fe-60f09d4ad573","order_by":11,"name":"Riitta Lassila","email":"","orcid":"","institution":"University of Helsinki, Helsinki University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Riitta","middleName":"","lastName":"Lassila","suffix":""},{"id":478836836,"identity":"a9199a05-0980-4bdc-8ef8-0a4a69ba4baa","order_by":12,"name":"Mark Daly","email":"","orcid":"","institution":"University of Helsinki","correspondingAuthor":false,"prefix":"","firstName":"Mark","middleName":"","lastName":"Daly","suffix":""},{"id":478836837,"identity":"a9360f95-5e8f-41fc-86a0-dd2435374b9f","order_by":13,"name":"John P. Atkinson","email":"","orcid":"","institution":"Washington University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"John","middleName":"P.","lastName":"Atkinson","suffix":""},{"id":478836838,"identity":"50b60abc-4649-4331-8e0d-2503a02c9d63","order_by":14,"name":"Hannele Laivuori","email":"","orcid":"","institution":"Tampere University","correspondingAuthor":false,"prefix":"","firstName":"Hannele","middleName":"","lastName":"Laivuori","suffix":""},{"id":478836839,"identity":"df2d9f90-3a36-4a69-99e7-0bdaf69f05aa","order_by":15,"name":"Seppo Meri","email":"","orcid":"","institution":"University of Helsinki","correspondingAuthor":false,"prefix":"","firstName":"Seppo","middleName":"","lastName":"Meri","suffix":""}],"badges":[],"createdAt":"2024-12-20 15:38:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5685318/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5685318/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":86246752,"identity":"6fb0e6d5-04f2-49ea-bee0-9f5dd0cc3590","added_by":"auto","created_at":"2025-07-08 11:50:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":127253,"visible":true,"origin":"","legend":"\u003cp\u003eDomain structure of von Willebrand factor and ADAMTS13 with associating variants indicated with black arrows. Panel (A) von Willebrand factor (VWF) protein consists of eight functional classes of domains (29 in total, not shown) encoded by 52 exons (not shown). The domains in the propeptide region consisting of 741 amino acids are marked with sharp-cornered boxes and the domains that produce the mature VWF consisting of 2050 amino acids are marked by round-cornered boxes. The cleavage site of ADAMTS13 in the A2 domain is indicated with a dashed vertical line.\u003c/p\u003e\n\u003cp\u003ePanel (B). ADAMTS13 consists of 12 domains that are encoded by 29 exons. The domains of the ADAMTS13 are a signal peptide (S), a propeptide (P), a metalloprotease domain (MP), a disintegrin domain (DIS), 8 thrombospondin type 1 domains (1-8), a cysteine-rich region (CYS), a spacer domain and two CUB domains. The domains that bind VWF are marked with dashed outlines. The disintegrin and spacer domains cleave the VWF A2 domain. The thrombospondin type domains 5-8 and CUB domains bind D4 and CK domains of VWF.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5685318/v1/9ca22f9ad400064bcafc3128.png"},{"id":86246497,"identity":"b83b4bea-daf3-4717-979d-20e1f7693b9a","added_by":"auto","created_at":"2025-07-08 11:42:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":48961,"visible":true,"origin":"","legend":"\u003cp\u003eFrequency of blood groups of preeclampsia patients with any predisposing VWF/ADAMTS13 allele (pe; N=80) and in the Finnish population (fin; N=5536, source: Finnish Red Cross Blood Service). *** indicates p\u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5685318/v1/fe27f0e0c1f401395319f8ed.png"},{"id":86246501,"identity":"dbe8fa28-3c3a-4aef-a136-5a965e687829","added_by":"auto","created_at":"2025-07-08 11:42:42","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":74760,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic depiction of the proposed role of the ADAMTS13 Ala732Val variant in PE. In normal pregnancy (panel A), the cleavage of Weibel-Palade body-derived VWF from endothelial cells by ADAMTS13 prevents excessive VWF multimerization. In preeclampsia pregnancies (panel B) with rs41314453*T of \u003cem\u003eADAMTS13\u003c/em\u003e,the amount or enzymatic activity of ADAMTS13 is reduced thereby enhancing multimeric VWF and platelet aggregation. Created with BioRender.com.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5685318/v1/2267b55628742e7fe8cd61b8.png"},{"id":86247461,"identity":"bad0d129-3301-472f-a1fe-7bbb71e626ec","added_by":"auto","created_at":"2025-07-08 11:58:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1054051,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5685318/v1/0bf66160-6ad3-4611-8356-60b3e3aac366.pdf"},{"id":86246499,"identity":"43f8b418-333c-4364-950f-c8f1cb040082","added_by":"auto","created_at":"2025-07-08 11:42:42","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":79866,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarydataclean.docx","url":"https://assets-eu.researchsquare.com/files/rs-5685318/v1/1b897d01df8b1bacfdaf3a3d.docx"}],"financialInterests":"Competing interest reported. RL is a member of an advisor board and given lectures for Sanofi and Takeda. AJ serves on the scientific advisory boards of Alexion, AstraZeneca Rare Disease, and Novartis International AG, and serves as a consultant for Dianthus Therapeutics and Aurinia Pharmaceuticals. She has been a Principal Investigator for Apellis Pharmaceuticals and is a Principal Investigator for Novartis International AG. She also receives royalty from UptoDate. HL has received honoraria from Orion Corporation. JPA is in the Scientific Advisory Board of Complement Corporation and Kypha, Inc; Scientific Advisory Board. Furthermore, he serves as a consultant in Celldex Therapeutics, formerly Avant Immunotherapeutics, Inc., Biothera and Clinical Pharmacy Services, CDMI. SM has received honoraria from Alexion, AstraZeneca Rare Disease, Biogen, Merck, Pfizer and UCB, and research funding from Alexion. Other authors have no conflicts of interest to report.","formattedTitle":"Genetic association of preeclampsia to von Willebrand factor and its size-regulator ADAMTS13","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePreeclampsia (PE) is a common pregnancy-specific vascular disorder with diverse clinical characteristics. It affects approximately 3% of pregnancies and accounts for over 50,000 maternal and 900,000 perinatal deaths annually\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. No specific treatment, other than delivery, is available for PE. For prevention, low-dose aspirin administered from \u0026lt;\u0026thinsp;16 weeks of gestation has been suggested to reduce the risk of preterm PE (resulting in delivery before 37 wks of gestation) in women at high risk for PE, but its use remains controversial \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Despite common signs, proteinuria and hypertension, the etiology of PE could be heterogeneous, especially in a subset of cases.\u003c/p\u003e \u003cp\u003eThere is a familial predisposition to PE and strong epidemiological evidence suggests that the risk for PE is inherited \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. However, the individual variant effects of the candidate genes discovered thus far are modest. Finnish population presents an opportunity to study complex diseases, because the allele frequencies observed in the modern Finnish population result from several bottleneck events in the founder population which helps to identify relevant pathways for disease pathogenesis due to the enrichment of associating variants \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe coagulation system is activated by changes in the vascular endothelium, and by platelet activation, adhesion, aggregation and interaction among leukocytes. In these processes, platelet interactions with von Willebrand factor (VWF) are an important contributor. Dysregulation of the platelet activity and coagulation system may result in thrombotic microangiopathies, including hemolytic anemia, and thrombocytopenia in women with PE \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. No firm consensus regarding the role of platelets and coagulation biology in the development of PE has been reached \u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Early results linking common variants such as FV Leiden and the prothrombin 3\u0026prime; UTR variant to PE risk have not been replicated in larger studies \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo investigate the role of the genetic burden of coagulation proteins in PE, we designed a targeted exome sequencing study to screen the exons and splicing sites of genes involved in blood coagulation and its regulation.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eIn the 58 selected genes we discovered 107 annotated variants and 151 presumably benign variants (data not shown). Key results of this association analysis are shown in Table 2 (significant and borderline significant variants noted). The significantly associated variants in Table 2 are all listed as variant of unknown significance by the American College of Medical Genetics (ACMG) classification\u003csup\u003e10\u003c/sup\u003e. Overall, the most significant associations were available in the hemostasis axis, including VWF and its size-regulating ADAMTS13 enzyme. Also, two protective antithrombin variants were discovered.\u003c/p\u003e\n\u003cp\u003eThe gene coding for von Willebrand Factor (\u003cem\u003eVWF)\u0026nbsp;\u003c/em\u003ewasassociated with PE by three likely or probable LoF variants with significant p-values (Figure 1A). Rs1800385 (p.Val1565Leu)\u0026nbsp;in the middle of the \u003cem\u003eVWF\u003c/em\u003e gene is a missense variant that increases the risk for PE (OR=1.72, 95% confidence interval (CI) 1.27-2.32, p-value=3.57E-4). The intronic variant rs34444862 located 8 base pairs downstream of exon 35, and the second missense variant rs34230288 (p.Ala2178Ser)\u0026nbsp;increase the risk for PE (OR=2.30, 95%CI=1.19-4.35, p-value=0.01; OR=2.2, CI 1.11-4.17, p-value=0.017, respectively).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn \u003cem\u003eADAMTS13\u003c/em\u003e, the intronic variant rs36218903 increased the risk for PE (OR=3.06, CI 95%=1.42-6.53; p-value=0.002), while the splice region variant rs36219245 decreased risk (OR=0.57, 95% CI 0.40-0.80; p-value=8.62E-4), (Figure 1B). The missense variant rs41314453 (Ala732Val)\u0026nbsp;in \u003cem\u003eADAMTS13\u003c/em\u003e had a suggested increase in PE risk (OR=1.97, 95% CI=0.99-3.78; p-value=0.044).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe also found that in our cohorts rs5878 and rs5877 in\u0026nbsp;\u003cem\u003eSERPINC1\u0026nbsp;\u003c/em\u003eencoding for\u0026nbsp;antithrombin (III), a critical plasma protease inhibitor and a member of the serpin superfamily,\u0026nbsp;decreased the risk for PE (OR= 0.85 (95% CI=0.74 - 0.98), and 0.86 (95% CI=0.74-1), p-value=0.02 and 0.03, respectively).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eComparison of the frequency of blood groups between patients carrying \u003cem\u003eVWF\u0026nbsp;\u003c/em\u003eand/or \u003cem\u003eADAMTS13\u003c/em\u003e variants in the Finnish population revealed that women affected by PE blood group A are significantly more prevalent (Χ\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e= 16.227, p\u0026lt;0.0001; Figure 2). In contrast, blood group O was significantly underrepresented in the PE patients (Χ\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e= 21.403, p\u0026lt;0.0001).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur results suggest that genetic variants in \u003cem\u003eVWF\u003c/em\u003e and in its size and functional regulator ADAMTS13 associate with primary hemostasis abnormalities. Variants in genes coding for both proteins may predispose to PE. Women with blood group A are at particular risk of VWF-mediated PE, while mothers with blood group O have a lower incidence of PE.\u003c/p\u003e \u003cp\u003eThese observations further support the proposed causative role of platelet dysregulation in a specific subgroup of PE. Importantly, we found associations within the VWF and ADAMTS13 axis, that cooperates to promote platelet-vascular wall interactions. A decrease in ADAMTS13 activity and an increase in VWF levels have also been previously associated with PE \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, although the underlying and causative mechanisms in the VWF pathway have been under debate \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. It is possible that VWF abnormalities are particularly associated with PE with severe features \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Common genetic variants within other coagulation genes are associated with PE \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Two of the discovered common PE-associating variants rs5878 and rs5877 in \u003cem\u003eSERPINC1\u003c/em\u003e that encode antithrombin are related reduced generation of thrombin and formation of fibrin. While we were able to confirm the reported association between Factor V Leiden (rs6025) and PE, the literature provides sparse insight into the potential associations we discovered in other \u003cem\u003eF5\u003c/em\u003e loci or variants discovered in \u003cem\u003eF2\u003c/em\u003e, \u003cem\u003eF7\u003c/em\u003e, and \u003cem\u003eSERPINA5.\u003c/em\u003e Overall, the link between common coagulation variants, regulation of the coagulation system and an increased risk of preeclampsia\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e was strongly corroborated by our data.\u003c/p\u003e \u003cp\u003eVWF is a plasma, platelet and endothelial glycoprotein that maintains hemostasis by generating multimers, which induce platelet aggregation and bind several proteins on activated endothelial cells in the vascular wall. Thereby, the multimers can lead to loss of vascular endothelial integrity \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. This is particularly relevant in the placental vasculature due to its specific hemodynamic conditions. To prevent excessive platelet responses and coagulation, VWF oligomers emerging from endothelial cells or activated platelets are proteolytically cleaved by the ADAMTS13 enzyme \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. ADAMTS13 cleaves VWF between tyrosine and methionine at position 842\u0026ndash;843. Mutations in the \u003cem\u003eADAMTS13\u003c/em\u003e gene or, more commonly, autoantibodies against the ADAMTS13 enzyme cause thrombotic thrombocytopenic purpura (TTP).\u003c/p\u003e \u003cp\u003eThe variant rs34230288 results in the replacement of the alanine at position 2178 with a serine in VWF. This variant has been observed in a patient who was \u003cem\u003ein cis\u003c/em\u003e heterozygous for two \u003cem\u003eVWF\u003c/em\u003e mutations and suffering from a noncanonical type 2B von Willebrand disease characterized by low VWF activity\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Similarly, the variant rs1800385 results in the replacement of valine at position 1565 by leucine resulting in significantly elevated ADAMTS13 activity but available data is insufficient to ascertain it\u0026rsquo;s functional relevance \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Rs41314453 is the main genetic determinant of ADAMTS13 activity. It is important to note that it is in linkage disequilibrium with several intronic variants in \u003cem\u003eADAMTS13\u003c/em\u003e and variants in the regulatory regions of neighbouring genes \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. The total effect of rs41314453 is dependent on the sequence context, which may influence the extent and direction of its effect on gene expression\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. It has been estimated that the variant reduces ADAMTS13 levels by approximately 40% \u003csup\u003e23,24\u003c/sup\u003e. Although this magnitude of a decrease does not reach levels that are considered significant in TTP (\u0026lt;\u0026thinsp;10%), it may be significant in the context of the strong triggers such as pregnancy. The product of the \u003cem\u003eADAMTS13\u003c/em\u003e gene with the minor allele T of rs41314453 has up to 29% less VWF cleavage activity than the protein coded by the gene with the major allele \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Thereby, rs41314453 may increase the risk for platelet deposition by accumulation of ultralarge VWF multimers (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In TTP, the accumulation of platelet-super-adhesive ultralarge VWF multimers on vascular endothelium leads to the spontaneous formation of microthrombi. Pregnancy is also one of the well-known triggers to precipitate attacks of TTP\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWe recorded the blood groups of the women due to their role in association with VWF levels. Persons with blood group O have 30% lower VWF expression than the other blood groups, and blood group O has implications for platelet physiology\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Previously, blood groups A and more convincingly AB have been linked to a modestly increased risk of PE \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. In addition, blood group A has been found to predispose to severe COVID-19, while blood group O is protective against infection and microthrombosis \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Concurrently, blood group O carries a 30% lower level of VWF, which may be highly elevated in COVID-19 \u003csup\u003e29,30\u003c/sup\u003e. COVID-19 infection is also an independent risk factor for PE \u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Our observed genetic variants of VWF, ADAMTS13 and non-O blood groups, likely contribute to the pathogenesis of PE. Furthermore, these findings may be helpful in the future to risk stratify patients and target novel therapies based on the specific analysis of VWF and ADAMTS13 biomarkers \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe findings of our study may explain aspects of the pathophysiology of PE and clinical observations related to the preventive use of aspirin. In PE, the placental intervillous blood flow is perturbed due to the lack of vasodilation in the spiral arteries, and local high shear forces prevail, promoting platelet-VWF interactions \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. This also increases the risk of local red blood cell lysis and promotes the release of ADP and thromboxane A2, which are known to further activate platelets. ADP increases the expression and release of VWF on platelets \u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Associated activation of the complement system results in the formation of C5a and of membrane attack complexes, which can further activate platelets and induce release of VWF from endothelial cell Weibel-Palade bodies \u003csup\u003e\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. Subsequent reduced ability of ADAMTS13 to cleave VWF multimers would thus promote formation of platelet aggregates, which have been shown to be resistant to ADAMTS13 \u003csup\u003e38\u003c/sup\u003e. On the other hand, VWF has been shown to protect the endothelium from complement-mediated injury \u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. Aspirin has been shown to reduce expression of VWF on platelet surfaces \u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Thereby it may partially compensate for the procoagulant effect of rs41314453 on \u003cem\u003eADAMTS13\u003c/em\u003e. Reduced platelet activity may improve blood flow in the intervillous space and reduce local ischemia and the severity of PE. TTP is associated with adverse pregnancy outcomes including PE\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. Previously, a patient suffering from TTP due to a mutation in \u003cem\u003eADAMTS13\u003c/em\u003e experienced a successful pregnancy under prophylactic treatment by aspirin \u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. More recently, novel drugs to influence the VWF-ADAMTS13 axis have emerged. Drugs like caplacizumab or recombinant ADAMTS13 could thus potentially be used in severe cases that are linked to high level of VWF multimerization and thrombosis \u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn TMA, activation of the coagulation cascade and complement systems often go hand in hand \u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. Similarly, pregnancy is an inflammatory and procoagulative state. In a blood proteomic study, the most different expression patterns between preeclamptic patients and controls were observed in complement and coagulation pathways and platelet function and VWF were also implicated \u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. Thereby patients with a predisposing complement and/or coagulation pathway variants may present with TMA-like PE \u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis study was limited by unavailability to study VWF and ADAMTS13 activity or their biomarkers. Furthermore, complete blood cell counts were not measured routinely thereby rendering the analysis of this data inconclusive. The effect of blood group for PE risk in carriers of \u003cem\u003eVWF\u003c/em\u003e and \u003cem\u003eADAMTS13\u003c/em\u003e variants requires further investigation in other well-described case-control cohorts representing varied populations.\u003c/p\u003e \u003cp\u003eIn summary, our findings demonstrate a link between PE and two important and related hemostatic components VWF and ADAMTS13. Our results support the concept that in some cases, PE with severe features may present as a thrombotic microangiopathy \u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. The fact that PE-associated rs41314453 reduces ADAMTS13 level suggests that the ADAMTS13-VWF axis and regulated VWF size or multimerization are important in preventing PE. Our results may also relate to aspirin, which may show preventive properties against preeclampsia in high-risk individuals. However, in the future based on laboratory assessment of VWF and ADMTS13, novel medications, such as caplacizumab and recombinant ADAMTS13 should be evaluated in PE.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003ePatient cohorts\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo independent case-control cohorts, The Finnish Genetics of preeclampsia Consortium\u003cstrong\u003e\u0026nbsp;(\u003c/strong\u003eFINNPEC) cohort and the national FINRISK study cohort were investigated. The study rational is described in detail in the supplementary data. In the final association analyses, we included genotypes of FINNPEC and FINRISK population cohorts, leading to a combined total of 615 cases and 2094 controls. For FINNPEC, all women provided a written informed consent, and the FINNPEC study protocol was approved by the coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa. \u0026nbsp; (FINRISK license 8/2016)\u003csup\u003e46\u003c/sup\u003e. The patients and controls from the FINNPEC cohort are characterized in the Supplementary table S1. The National FINRISK Study description and ethical approvals are available online: https://www.thl.fi/en/web/thlfi-en/research-and-expertwork/population-studies/the-national-finrisk-study. This study was conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTargeted Sequencing and Capture Enrichment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLibraries from genomic DNA were prepared in-house (Washington University School of Medicine)\u003csup\u003e47\u003c/sup\u003e. Enzymes were purchased from Enzymatics (Beverly, MA). Briefly, the ends of sheared genomic DNA fragments were repaired by treatment with T4 DNA Polymerase and T4 DNA Polynucleotide Kinase, which phosphorylates the 5\u0026apos; hydroxyl. \u0026nbsp; Next, an adenosine was added to the 3\u0026apos; position at each end of the DNA fragment with Taq Polymerase. Illumina adapters with an overhanging \u0026ldquo;T\u0026rdquo; were ligated onto the DNA fragment followed by bead-based size selection to remove adapter-dimers and fragments below the desired size. A barcode consisting of a unique index sequence was added by PCR by targeting the two ligated universal adapters on each fragment end. Sequence capture hybridization and other laboratory methods are described in the Supplementary data. The studied genes and intronic loci of interest are listed in Table 1.\u003c/p\u003e\n\u003cp\u003eFisher\u0026rsquo;s exact t-test was used as the primary test of association, and differences in frequencies of variants with p-value \u0026lt; 0.05 were considered significant. Significant and borderline significant variants are listed in Table 2. In addition to the statistical probability test, odds ratios (OR) with 95% confidence intervals (CI95) were calculated for all variants.\u003c/p\u003e\n\u003cp\u003eComparison of the distribution of P values in benign (synonymous, intronic/intergenic; 151 observed variants) vs. annotated (missense, truncating, essential splice and splice region; 107 observed variants) variants indicate that the expected incidence of two annotated variants with p\u0026lt;0.001 is less than 0.01 in our data, compared with 0 observed variants with p\u0026lt;0.001. The lack of inflated P values indicates that confounders, such as stratification, are not causing false positives. Loss of function (LoF) analyses were done \u003cem\u003ein silico\u003c/em\u003e for all genes with associating variants by the Loss of Function \u0026ndash; tool of the Variant Effect Predictor (VEP) (https://github.com/ensembl-variation/VEP_plugins/blob/master/LoFtool.pm). In the LoF tool, the following annotations were calculated: LoF score \u0026lt; 0.2 indicates a probably damaging variant, LoF score 0.2-0.7 possibly damaging and LoF score \u0026lt; 0.7 a benign variant. 5/7 of the genes in Table 2 had scores \u0026lt; 0.2, suggesting a probable LoF.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData were analyzed using PlinkSeq, Plink \u003csup\u003e48\u003c/sup\u003e and R. Kaviar \u003csup\u003e49\u003c/sup\u003e. VEP Build 37 was used for additional annotations \u003csup\u003e50\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData-sharing statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study available from Professor Hannele Laivuori on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Elisha D.O. Roberson for assistance in data analysis (P30-AR073752).\u003c/p\u003e\n\u003cp\u003eFINNPEC study board consists of Hannele Laivuori (PI), Seppo Heinonen, Eero Kajantie, Juha Kere, Katja Kivinen, and Anneli Pouta. Eija Kortelainen and late Susanna Meht\u0026auml;l\u0026auml; provided technical assistance. We thank all the participants of the FINNPEC study as well as participants of FinMetSeq and FINRISK population cohort studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJPA and HL came up with the study question. SH, EK, JK and HL supervised the collection of the FINNPEC cohort. \u0026nbsp;MP and KA provided the FINRISK data. MT, JES, and JPA designed the targeted exomic sequencing method and MT conducted these laboratory analyses. AIL designed the data analysis with MD. AIL and JPA wrote the manuscript drafts in collaboration with SM and HL. MT, JES and JPA designed the targeted exomic sequencing method and MT conducted these laboratory analyses. ED performed the statistical analysis under the supervision of MK and MD. SM, AJ and RL are the specialists in the complement and coagulation pathways. All authors read and approved the final manuscript. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by Alfred Kordelin Foundation (AIL), Maud Kuistila Foundation, Jane and Aatos Erkko Foundation (HL), The Academy of Finland (121196 and 278941; HL), Sigrid Jus\u0026eacute;lius Foundation (HL, SM) and Special State Subsidy for Health Research (TYH2019311, TYH2022315; SM, TYH2020318; RL TYH2021315, TYH2022315; HL). This research reported in this publication was also supported by the National Institutes of Health under Award Numbers F30 HL103072 (MT), U54 HL112303 (JPA), R01 GM099111 (JPA), and P30 AR048335 (JPA). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Finnish Medical Foundation (HL), University of Helsinki Funds (HL), Sakari and P\u0026auml;ivikki Sohlberg Foundation (HL), Novo Nordisk Foundation and Signe and Ane Gyllenberg Foundation for Pediatric Research contributed to the FINNPEC sample collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from Professor Hannele Laivuori on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRL is a member of an advisor board and given lectures for Sanofi and Takeda.\u0026nbsp;\u003c/strong\u003eAJ serves on the scientific advisory boards of Alexion, AstraZeneca Rare Disease, and Novartis International AG, and serves as a consultant for Dianthus Therapeutics and Aurinia Pharmaceuticals. She has been a Principal Investigator for Apellis Pharmaceuticals and is a Principal Investigator for Novartis International AG. She also receives royalty from UptoDate. HL\u0026nbsp;has received honoraria from Orion Corporation.\u003cstrong\u003eJPA is in the Scientific Advisory Board of\u0026nbsp;\u003c/strong\u003eComplement Corporation and Kypha, Inc; Scientific Advisory Board. Furthermore, he serves as a consultant in Celldex Therapeutics, formerly Avant Immunotherapeutics, Inc., Biothera and Clinical Pharmacy Services, CDMI. SM has received honoraria from Alexion, AstraZeneca Rare Disease, Biogen, Merck, Pfizer and UCB, and research funding from Alexion. Other authors have no conflicts of interest to report.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eVan Lerberghe, W., Manuel, A., Matthews, Z. \u0026amp; Cathy, W. \u003cem\u003eThe World Health Report 2005 - Make Every Mother and Child Count\u003c/em\u003e. (2005).\u003c/li\u003e\n \u003cli\u003eRolnik, D. L. \u003cem\u003eet al.\u003c/em\u003e Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. \u003cem\u003eNew England Journal of Medicine\u003c/em\u003e (2017) doi:10.1056/nejmoa1704559.\u003c/li\u003e\n \u003cli\u003eSkjaerven, R. \u003cem\u003eet al.\u003c/em\u003e Recurrence of pre-eclampsia across generations: exploring fetal and maternal genetic components in a population based cohort. \u003cem\u003eBMJ\u003c/em\u003e \u003cstrong\u003e331\u003c/strong\u003e, 877 (2005).\u003c/li\u003e\n \u003cli\u003eLim, E. T. \u003cem\u003eet al.\u003c/em\u003e Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population. \u003cem\u003ePLoS Genet\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e, e1004494 (2014).\u003c/li\u003e\n \u003cli\u003eMcCrae, K. R. Thrombocytopenia in pregnancy. \u003cem\u003eHematology.American Society of Hematology.Education Program\u003c/em\u003e \u003cstrong\u003e2010\u003c/strong\u003e, 397\u0026ndash;402 (2010).\u003c/li\u003e\n \u003cli\u003eBoij, R. \u003cem\u003eet al.\u003c/em\u003e Biomarkers of coagulation, inflammation, and angiogenesis are independently associated with preeclampsia. \u003cem\u003eAm J Reprod Immunol\u003c/em\u003e \u003cstrong\u003e68\u003c/strong\u003e, 258\u0026ndash;270 (2012).\u003c/li\u003e\n \u003cli\u003eDehkordi, M. A. e. R., Soleimani, A., Haji-Gholami, A., Vardanjani, A. K. \u0026amp; Dehkordi, S. A. e. R. Association of deficiency of coagulation factors (Prs, Prc, ATIII) and FVL positivity with preeclampsia and/or eclampsia in pregnant women. \u003cem\u003eInt J Hematol Oncol Stem Cell Res\u003c/em\u003e (2014).\u003c/li\u003e\n \u003cli\u003eHan, L. \u003cem\u003eet al.\u003c/em\u003e Blood coagulation parameters and platelet indices: Changes in normal and preeclamptic pregnancies and predictive values for preeclampsia. \u003cem\u003ePLoS One\u003c/em\u003e (2014) doi:10.1371/journal.pone.0114488.\u003c/li\u003e\n \u003cli\u003eStaines-Urias, E. \u003cem\u003eet al.\u003c/em\u003e Genetic association studies in pre-eclampsia: systematic meta-analyses and field synopsis. \u003cem\u003eInt J Epidemiol\u003c/em\u003e \u003cstrong\u003e41\u003c/strong\u003e, 1764\u0026ndash;1775 (2012).\u003c/li\u003e\n \u003cli\u003eRichards, S. \u003cem\u003eet al.\u003c/em\u003e Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. (2015) doi:10.1038/gim.2015.30.\u003c/li\u003e\n \u003cli\u003eAref, S. \u0026amp; Goda, H. Increased VWF antigen levels and decreased ADAMTS13 activity in preeclampsia. \u003cem\u003eHematology\u003c/em\u003e \u003cstrong\u003e18\u003c/strong\u003e, 237\u0026ndash;241 (2013).\u003c/li\u003e\n \u003cli\u003eStepanian, A. \u003cem\u003eet al.\u003c/em\u003e Von Willebrand factor and ADAMTS13: a candidate couple for preeclampsia pathophysiology. \u003cem\u003eArterioscler Thromb Vasc Biol\u003c/em\u003e \u003cstrong\u003e31\u003c/strong\u003e, 1703\u0026ndash;1709 (2011).\u003c/li\u003e\n \u003cli\u003eMolvarec, A. \u003cem\u003eet al.\u003c/em\u003e Increased plasma von Willebrand factor antigen levels but normal von Willebrand factor cleaving protease (ADAMTS13) activity in preeclampsia. \u003cem\u003eThromb Haemost\u003c/em\u003e \u003cstrong\u003e101\u003c/strong\u003e, 305\u0026ndash;311 (2009).\u003c/li\u003e\n \u003cli\u003eZhang, D. \u003cem\u003eet al.\u003c/em\u003e Von Willebrand factor antigen and ADAMTS13 activity assay in pregnant women and severe preeclamptic patients. \u003cem\u003eJournal of Huazhong University of Science and Technology.Medical sciences = Hua zhong ke ji da xue xue bao.Yi xue Ying De wen ban = Huazhong keji daxue xuebao.Yixue Yingdewen ban\u003c/em\u003e \u003cstrong\u003e30\u003c/strong\u003e, 777\u0026ndash;780 (2010).\u003c/li\u003e\n \u003cli\u003eNieves-Col\u0026oacute;n, M. A. \u003cem\u003eet al.\u003c/em\u003e Clotting factor genes are associated with preeclampsia in high-altitude pregnant women in the Peruvian Andes. \u003cem\u003eThe American Journal of Human Genetics\u003c/em\u003e \u003cstrong\u003e109\u003c/strong\u003e, 1117\u0026ndash;1139 (2022).\u003c/li\u003e\n \u003cli\u003eWang, J., Ma, H. P., Ti, A. L. T. T. L., Zhang, Y. Q. \u0026amp; Zheng, H. Prothrombotic SERPINC1 Gene Polymorphism may Affect Heparin Sensitivity among Different Ethnicities of Chinese Patients Receiving Heart Surgery. \u003cem\u003eClinical and Applied Thrombosis/Hemostasis\u003c/em\u003e (2015) doi:10.1177/1076029614556744.\u003c/li\u003e\n \u003cli\u003eGao, C. \u003cem\u003eet al.\u003c/em\u003e Heparin promotes platelet responsiveness by potentiating alphaIIbbeta3-mediated outside-in signaling. \u003cem\u003eBlood\u003c/em\u003e \u003cstrong\u003e117\u003c/strong\u003e, 4946\u0026ndash;4952 (2011).\u003c/li\u003e\n \u003cli\u003eSadler, J. E. Biochemistry and genetics of von Willebrand factor. \u003cem\u003eAnnu Rev Biochem\u003c/em\u003e \u003cstrong\u003e67\u003c/strong\u003e, 395\u0026ndash;424 (1998).\u003c/li\u003e\n \u003cli\u003eDong, J. fei \u003cem\u003eet al.\u003c/em\u003e ADAMTS-13 metalloprotease interacts with the endothelial cell-derived ultra-large von Willebrand factor. \u003cem\u003eJ Biol Chem\u003c/em\u003e \u003cstrong\u003e278\u003c/strong\u003e, 29633\u0026ndash;29639 (2003).\u003c/li\u003e\n \u003cli\u003eXiang, Y., De Groot, R., Crawley, J. T. B. \u0026amp; Lane, D. A. Mechanism of von Willebrand factor scissile bond cleavage by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). \u003cem\u003eProc Natl Acad Sci U S A\u003c/em\u003e \u003cstrong\u003e108\u003c/strong\u003e, 11602\u0026ndash;11607 (2011).\u003c/li\u003e\n \u003cli\u003eSacco, M. \u003cem\u003eet al.\u003c/em\u003e Noncanonical type 2B von Willebrand disease associated with mutations in the VWF D\u0026rsquo;D3 and D4 domains. \u003cem\u003eBlood Adv\u003c/em\u003e \u003cstrong\u003e4\u003c/strong\u003e, 3405\u0026ndash;3415 (2020).\u003c/li\u003e\n \u003cli\u003eLasom, S. \u003cem\u003eet al.\u003c/em\u003e Protective effect of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 haplotype on coronary artery disease. \u003cem\u003eBlood Coagul Fibrinolysis\u003c/em\u003e \u003cstrong\u003e28\u003c/strong\u003e, 286\u0026ndash;294 (2017).\u003c/li\u003e\n \u003cli\u003eDe Vries, P. S. \u003cem\u003eet al.\u003c/em\u003e Genetic variants in the ADAMTS13 and SUPT3H genes are associated with ADAMTS13 activity. \u003cem\u003eBlood\u003c/em\u003e (2015) doi:10.1182/blood-2015-02-629865.\u003c/li\u003e\n \u003cli\u003ePlaimauer, B. \u003cem\u003eet al.\u003c/em\u003e Modulation of ADAMTS13 secretion and specific activity by a combination of common amino acid polymorphisms and a missense mutation. \u003cem\u003eBlood\u003c/em\u003e \u003cstrong\u003e107\u003c/strong\u003e, 118\u0026ndash;125 (2006).\u003c/li\u003e\n \u003cli\u003eWard, S. E., O\u0026rsquo;Sullivan, J. M. \u0026amp; O\u0026rsquo;Donnell, J. S. The relationship between ABO blood group, von Willebrand factor, and primary hemostasis. \u003cem\u003eBlood\u003c/em\u003e \u003cstrong\u003e136\u003c/strong\u003e, 2864\u0026ndash;2874 (2020).\u003c/li\u003e\n \u003cli\u003ePhaloprakarn, C. \u0026amp; Tangjitgamol, S. Maternal ABO blood group and adverse pregnancy outcomes. \u003cem\u003eJournal of Perinatology\u003c/em\u003e \u003cstrong\u003e33\u003c/strong\u003e, 107\u0026ndash;111 (2013).\u003c/li\u003e\n \u003cli\u003eAlpoim, P. N. \u003cem\u003eet al.\u003c/em\u003e Preeclampsia and ABO blood groups: A systematic review and meta-analysis. \u003cem\u003eMol Biol Rep\u003c/em\u003e (2013) doi:10.1007/s11033-012-2288-2.\u003c/li\u003e\n \u003cli\u003eLiu, N. \u003cem\u003eet al.\u003c/em\u003e The impact of ABO blood group on COVID-19 infection risk and mortality: A systematic review and meta-analysis. \u003cem\u003eBlood Rev\u003c/em\u003e \u003cstrong\u003e48\u003c/strong\u003e, (2021).\u003c/li\u003e\n \u003cli\u003eLadikou, E. E. \u003cem\u003eet al.\u003c/em\u003e Von Willebrand factor (vWF): marker of endothelial damage and thrombotic risk in COVID-19? \u003cem\u003eClinical Medicine\u003c/em\u003e \u003cstrong\u003e20\u003c/strong\u003e, e178 (2020).\u003c/li\u003e\n \u003cli\u003eGill, J. C., Endres-Brooks, J., Bauer, P. J., Marks, W. J. \u0026amp; Montgomery, R. R. The Effect of ABO Blood Group on the Diagnosis of von Willebrand Disease. \u003cem\u003eBlood\u003c/em\u003e \u003cstrong\u003e69\u003c/strong\u003e, 1691\u0026ndash;1695 (1987).\u003c/li\u003e\n \u003cli\u003ePapageorghiou, A. T. \u003cem\u003eet al.\u003c/em\u003e Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study. \u003cem\u003eAm J Obstet Gynecol\u003c/em\u003e \u003cstrong\u003e225\u003c/strong\u003e, 289.e1-289.e17 (2021).\u003c/li\u003e\n \u003cli\u003eBrosens, I. A., Robertson, W. B. \u0026amp; Dixon, H. G. The role of the spiral arteries in the pathogenesis of preeclampsia. \u003cem\u003eObstet Gynecol Annu\u003c/em\u003e (1972).\u003c/li\u003e\n \u003cli\u003eMody, N. A. \u0026amp; King, M. R. Platelet Adhesive Dynamics. Part II: High Shear-Induced Transient Aggregation via GPIb\u0026alpha;-vWF-GPIb\u0026alpha; Bridging. \u003cem\u003eBiophys J\u003c/em\u003e \u003cstrong\u003e95\u003c/strong\u003e, 2556 (2008).\u003c/li\u003e\n \u003cli\u003eParker, R. I. \u0026amp; Gralnick, H. R. Effect of aspirin on platelet-von Willebrand factor surface expression on thrombin and ADP-stimulated platelets. \u003cem\u003eBlood\u003c/em\u003e \u003cstrong\u003e74\u003c/strong\u003e, 2016\u0026ndash;2021 (1989).\u003c/li\u003e\n \u003cli\u003eMannes, M. \u003cem\u003eet al.\u003c/em\u003e Complement \u0026amp; platelets: Prothrombotic cell activation requires membrane attack complex induced release of danger signals. \u003cem\u003eBlood Adv\u003c/em\u003e (2023) doi:10.1182/BLOODADVANCES.2023010817.\u003c/li\u003e\n \u003cli\u003eAiello, S. \u003cem\u003eet al.\u003c/em\u003e C5a and C5aR1 are key drivers of microvascular platelet aggregation in clinical entities spanning from aHUS to COVID-19. \u003cem\u003eBlood Adv\u003c/em\u003e \u003cstrong\u003e6\u003c/strong\u003e, 866\u0026ndash;881 (2022).\u003c/li\u003e\n \u003cli\u003eTurner, N. A. \u0026amp; Moake, J. Assembly and Activation of Alternative Complement Components on Endothelial Cell-Anchored Ultra-Large Von Willebrand Factor Links Complement and Hemostasis-Thrombosis. \u003cem\u003ePLoS One\u003c/em\u003e \u003cstrong\u003e8\u003c/strong\u003e, e59372 (2013).\u003c/li\u003e\n \u003cli\u003eErcig, B. \u003cem\u003eet al.\u003c/em\u003e Conformational plasticity of ADAMTS13 in hemostasis and autoimmunity. \u003cem\u003eJ Biol Chem\u003c/em\u003e \u003cstrong\u003e297\u003c/strong\u003e, (2021).\u003c/li\u003e\n \u003cli\u003eNoone, D. G. \u003cem\u003eet al.\u003c/em\u003e Von Willebrand factor regulates complement on endothelial cells. \u003cem\u003eKidney Int\u003c/em\u003e \u003cstrong\u003e90\u003c/strong\u003e, 123\u0026ndash;134 (2016).\u003c/li\u003e\n \u003cli\u003eScully, M. How to evaluate and treat the spectrum of TMA syndromes in pregnancy. \u003cem\u003eHematology Am Soc Hematol Educ Program\u003c/em\u003e \u003cstrong\u003e2021\u003c/strong\u003e, (2021).\u003c/li\u003e\n \u003cli\u003eMoatti-Cohen, M. \u003cem\u003eet al.\u003c/em\u003e Unexpected frequency of Upshaw-Schulman syndrome in pregnancy-onset thrombotic thrombocytopenic purpura. \u003cem\u003eBlood\u003c/em\u003e \u003cstrong\u003e119\u003c/strong\u003e, 5888\u0026ndash;5897 (2012).\u003c/li\u003e\n \u003cli\u003eCoppo, P. \u0026amp; Joly, B. S. Caplacizumab: A game changer also in pregnancy-associated immune-mediated thrombotic thrombocytopenic purpura? \u003cem\u003eBr J Haematol\u003c/em\u003e (2023) doi:10.1111/BJH.18915.\u003c/li\u003e\n \u003cli\u003eMeri, S. Complement activation in diseases presenting with thrombotic microangiopathy. \u003cem\u003eEur J Intern Med\u003c/em\u003e \u003cstrong\u003e24\u003c/strong\u003e, 496\u0026ndash;502 (2013).\u003c/li\u003e\n \u003cli\u003eYoussef, L. \u003cem\u003eet al.\u003c/em\u003e Complement and coagulation cascades activation is the main pathophysiological pathway in early-onset severe preeclampsia revealed by maternal proteomics. \u003cem\u003eSci Rep\u003c/em\u003e \u003cstrong\u003e11\u003c/strong\u003e, 3048 (2021).\u003c/li\u003e\n \u003cli\u003eLokki, A. I. \u0026amp; Heikkinen-Eloranta, J. Pregnancy induced TMA in severe preeclampsia results from complement-mediated thromboinflammation. \u003cem\u003eHum Immunol\u003c/em\u003e \u003cstrong\u003e82\u003c/strong\u003e, 371\u0026ndash;378 (2021).\u003c/li\u003e\n \u003cli\u003eBorodulin, K. \u003cem\u003eet al.\u003c/em\u003e Forty-year trends in cardiovascular risk factors in Finland. \u003cem\u003eEur J Public Health\u003c/em\u003e (2015) doi:10.1093/eurpub/cku174.\u003c/li\u003e\n \u003cli\u003eTriebwasser, M. Excessive Complement Activation Due to Genetic Haploinsufficiency of Regulators in Multiple Human Diseases. \u003cem\u003eWashington University in St.Louis, Arts \u0026amp; Sciences Electronic Theses and Dissertations.\u003c/em\u003e (2015). doi:http://dx.doi.org/10.7936/K7V69GR4.\u003c/li\u003e\n \u003cli\u003ePurcell, S. \u0026amp; Sham, P. Genetic Power Calculator. \u003cem\u003ePower\u003c/em\u003e \u003cstrong\u003e8\u003c/strong\u003e, 2005\u0026ndash;2008 (2007).\u003c/li\u003e\n \u003cli\u003eGlusman, G., Caballero, J., Mauldin, D. E., Hood, L. \u0026amp; Roach, J. C. Kaviar: an accessible system for testing SNV novelty. \u003cem\u003eBioinformatics\u003c/em\u003e \u003cstrong\u003e27\u003c/strong\u003e, 3216\u0026ndash;3217 (2011).\u003c/li\u003e\n \u003cli\u003eMcLaren, W. \u003cem\u003eet al.\u003c/em\u003e Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. \u003cem\u003eBioinformatics\u003c/em\u003e \u003cstrong\u003e26\u003c/strong\u003e, 2069\u0026ndash;2070 (2010).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Targeted coagulation-associated genes and intronic loci.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"524\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" rowspan=\"2\" style=\"width: 327px;\"\u003e\n \u003cp\u003eCoagulation-associated genes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 196px;\"\u003e\n \u003cp\u003eCoagulation loci\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003eGene\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003eSNP\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cem\u003eABO\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cem\u003eF7\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cem\u003eKLKB1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cem\u003eSERPINA5\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cem\u003eF2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003ers1799963\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cem\u003eADAMTS13\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cem\u003eF8\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cem\u003eKNG1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cem\u003eSERPINB2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cem\u003eF5\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003ers6020 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cem\u003eADRA2A\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cem\u003eF9\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cem\u003eMRVI1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cem\u003eSERPINC1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cem\u003eSERPINE1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003ers2227631 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cem\u003eCD36\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cem\u003eFGA\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cem\u003ePEAR1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cem\u003eSERPIND1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cem\u003eF10\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cem\u003eFGB\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cem\u003ePIK3CG\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cem\u003eSERPINE1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cem\u003eF11\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cem\u003eFGG\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cem\u003ePLAT\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cem\u003eSERPINE2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cem\u003eF12\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cem\u003eGP1BA\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cem\u003ePLAU\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cem\u003eSHH\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cem\u003eF13B\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cem\u003eGP1BB\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cem\u003ePLG\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cem\u003eSTX2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cem\u003eF2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cem\u003eGP5\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cem\u003ePROC\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cem\u003eSTXBP5\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cem\u003eF2R\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cem\u003eGP6\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cem\u003ePROCR\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cem\u003eSVIL\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cem\u003eF2RL1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cem\u003eGP9\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cem\u003ePROS1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cem\u003eTFPI\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cem\u003eF2RL2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cem\u003eIPCEF1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cem\u003ePROZ\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cem\u003eTFPI2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cem\u003eF2RL3\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cem\u003eITGA2B\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cem\u003eSELP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cem\u003eVSGI4\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cem\u003eF3\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cem\u003eITGB3\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cem\u003eSERPINA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;VWF\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cem\u003eF5\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cem\u003eJMJD1C\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cem\u003eSERPINA10\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 2. Variants with significant or suggestive associations to preeclampsia within genes coding for coagulation proteins. Loss of function (LoF) is given per gene. All variants in Table 2 had a The American College of Medical Genetics and Genomics classification of variant of uncertain significance due to not enough evidence.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"1002\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRSID number\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGene name\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR (95% confidence interval)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMAF\u003csub\u003ecases\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMAF\u003csub\u003econtrols\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConsequence (distance from exon, base pairs)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLoFtool*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003ers1800385\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cem\u003eVWF\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e3.57E-4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e1.72 (1.27 - 2.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.059\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.035\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003emissense variant, V1565L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003ers34444862\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cem\u003eVWF\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e2.30 (1.19 - 4.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003eintron variant (-8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003ers34230288\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cem\u003eVWF\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e2.18 (1.11 - 4.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003emissense variant, A2178S\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003ers36219245\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cem\u003eADAMTS13\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e8.62E-4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e0.57 (0.40 - 0.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.089\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003esplice region variant (+4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003ers36218903\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cem\u003eADAMTS13\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e2.28E-3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e3.06 (1.42 - 6.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003eintron variant (-33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003ers41314453\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cem\u003eADAMTS13\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e1.97 (0.99 - 3.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003emissense variant, A732V\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003ers5898\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cem\u003eF2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e1.31 (1.01 - 1.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.077\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.060\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003esynonymous variant, P395P\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003ers2301515\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cem\u003eF5\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e8.06E-3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e1.21 (1.05 - 1.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003eintron variant (-50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003ers6023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cem\u003eF5\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e1.48 (1.07 - 2.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.050\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.034\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003esplice region variant (+7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003ers6025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cem\u003eF5\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e1.49 (1.01 \u0026ndash; 2.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.030\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003emissense variant, R534Q\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003ers9332688\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cem\u003eF5\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e2.10 (1.07 - 3.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003eintron variant (-32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003ers900258823\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cem\u003eF5\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e1.49 (1.01 - 2.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.030\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003eintron variant (-7098)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003ers6042\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cem\u003eF7\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e1.32 (1.04 - 1.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.086\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.067\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003esynonymous variant, H176H\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003ers6109\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cem\u003eSERPINA5\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e5.70E-3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e1.22 (1.06 - 1.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.313\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.272\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003eintron variant (-34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003ers6115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cem\u003eSERPINA5\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e1.15 (1.01 - 1.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.367\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.335\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003emissense variant, S64N\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003ers5878\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cem\u003eSERPINC1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e1.17 (1.02 - 1.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.316\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.282\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003esynonymous variant, Q337Q\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003ena\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003ers5877\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cem\u003eSERPINC1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e1.17 (1.01- 1.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.301\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e0.269\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 291px;\"\u003e\n \u003cp\u003esynonymous variant, V327V\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003ena\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*LoF tool \u0026ndash; (loss of function tool); score of LoF susceptibility per gene \u0026lt; 0.2 = probably damaging, 0.2-0.7 = possibly damaging, \u0026gt; 0.7 = benign\u003c/p\u003e\n\u003cp\u003ena \u0026ndash; not available\u003c/p\u003e\n\u003cp\u003eRSID \u0026ndash; Single nucleotide polymorphism identifier, OR \u0026ndash; Odds Ratio, MAF - Minor Allele Frequency\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"preeclampsia, pregnancy, coagulation cascade, von willebrand factor, ADAMTS13, genetic association","lastPublishedDoi":"10.21203/rs.3.rs-5685318/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5685318/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePreeclampsia is a common pregnancy-specific vascular disorder that develops during the second half of pregnancy. Preeclampsia shares features with thrombotic microangiopathies. Here we analyzed whether sequence variants in the coagulation system genes predispose to preeclampsia. We performed targeted exomic sequencing of 58 genes in a total of 615 preeclamptic women and 2094 controls. A common missense variant rs1800385 (Val1565Leu) in the gene coding for von Willebrand Factor (\u003cem\u003eVWF)\u003c/em\u003e (OR=1.72, p-value=3.57E-4) and a low-frequency missense variant rs41314453 (Ala732Val) in the gene coding for a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) (OR=1.97, p-value=0.044) were associated with preeclampsia. rs41314453 is known to decrease ADAMTS13 expression and activity. Thus, the reduced enzyme activity could promote the formation of large vWF polymers on endothelial cells and platelets and thereby increase vascular prothrombotic activity in preeclampsia. Our results support a role for an impaired ability of ADAMTS13 to limit VWF polymerization in the pathogenesis of PE. Ultralarge multimers of VWF could mediate platelet accumulation in the turbulent intervillous spaces in preeclamptic placentae, calling upon novel therapeutics to control the VWF-ADAMTS13 axis in severe cases having low ADAMTS13 in the presence of high VWF levels and multimerization.\u003c/p\u003e","manuscriptTitle":"Genetic association of preeclampsia to von Willebrand factor and its size-regulator ADAMTS13","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-08 11:42:38","doi":"10.21203/rs.3.rs-5685318/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"88d309f4-bfd8-4e17-b7c3-5e3516ec879a","owner":[],"postedDate":"July 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":50839378,"name":"Biological sciences/Genetics"},{"id":50839379,"name":"Health sciences/Diseases"},{"id":50839380,"name":"Health sciences/Medical research"},{"id":50839381,"name":"Health sciences/Molecular medicine"},{"id":50839382,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2025-07-08T11:42:38+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-08 11:42:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5685318","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5685318","identity":"rs-5685318","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}