{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T06:33:44Z","timestamp":1789022024090,"version":"build-2803163510"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T00:00:00Z","timestamp":1747267200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T00:00:00Z","timestamp":1747267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Genom. Inform."],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Deep vein thrombosis (DVT) is a clinically significant condition characterized by the formation of thrombi in deep venous structures, leading to high morbidity and potential mortality.\u00a0Identifying reliable biomarkers for DVT risk prediction remains challenging due to the intricate genetic and molecular mechanisms underlying the disease. This study aims to investigate the best biomarker for DVT. Our study utilized genome-wide association studies (GWAS) findings coupled with a\u00a0functional annotation scoring system to identify and prioritize genetic markers with strong associations to DVT. Furthermore, gene expression levels were analyzed to determine the most promising genetic markers. Several databases were utilized, including the GWAS Catalog, HaploReg 4.2, WebGestalt, Enrichr, and the GTEx Portal. Through the comprehensive analysis, we found 5 potential biomarkers and highlighted thrombomodulin (THBD) and Factor V (F5) as the\u00a0best blood-based biomarkers. THBD and F5 genes were selected based on their elevated expression levels in blood and the presence of eQTLs. Functionally, THBD modulates coagulation via protein C activation, while F5 is pivotal in thrombin formation and clot stabilization, underscoring their mechanistic relevance to DVT pathogenesis,\u00a0and rendering them suitable for non-invasive clinical assessment. Our findings emphasize the potential of genetic biomarkers to transform DVT risk assessment and support advancements in precision medicine for thrombotic disorders.\n<\/jats:p>","DOI":"10.1186\/s44342-025-00047-2","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T15:10:21Z","timestamp":1747321821000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Genome-wide association study-driven identification of thrombomodulin and factor V as the best biomarker combination for deep vein thrombosis"],"prefix":"10.1186","volume":"23","author":[{"given":"Usi","family":"Sukorini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisca Ajeng Widya","family":"Ninggar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Hendra Setia","family":"Lesmana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lalu","family":"Irham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wirawan","family":"Adikusuma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hegaria","family":"Rahmawati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nur Imma Fatimah","family":"Harahap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiou-Feng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahmat Dani","family":"Satria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,15]]},"reference":[{"issue":"5","key":"47_CR1","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1161\/ATVBAHA.124.320151","volume":"44","author":"A Wendelboe","year":"2024","unstructured":"Wendelboe A, Weitz JI. Global health burden of venous thromboembolism. Arterioscler Thromb Vasc Biol. 2024;44(5):1007\u201311.","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"11","key":"47_CR2","doi-asserted-by":"publisher","first-page":"2363","DOI":"10.1161\/ATVBAHA.114.304488","volume":"34","author":"GE Raskob","year":"2014","unstructured":"Raskob GE, Angchaisuksiri P, Blanco AN, Buller H, Gallus A, Hunt BJ, et al. Thrombosis: a major contributor to global disease burden. Arterioscler Thromb Vasc Biol. 2014;34(11):2363\u201371.","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"June","key":"47_CR3","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.thromres.2023.06.011","volume":"228","author":"V Lo Faro","year":"2023","unstructured":"Lo Faro V, Johansson T, H\u00f6glund J, Hadizadeh F, Johansson \u00c5. Polygenic risk scores and risk stratification in deep vein thrombosis. Thromb Res. 2023;228(June):151\u201362.","journal-title":"Thromb Res"},{"issue":"4","key":"47_CR4","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/s41569-022-00787-6","volume":"20","author":"PL Lutsey","year":"2023","unstructured":"Lutsey PL, Zakai NA. Epidemiology and prevention of venous thromboembolism. Nat Rev Cardiol. 2023;20(4):248\u201362.","journal-title":"Nat Rev Cardiol"},{"issue":"12","key":"47_CR5","doi-asserted-by":"publisher","first-page":"1988","DOI":"10.1161\/CIRCRESAHA.121.318322","volume":"128","author":"RA Baylis","year":"2021","unstructured":"Baylis RA, Smith NL, Klarin D, Fukaya E. Epidemiology and genetics of venous thromboembolism and chronic venous disease. Circ Res. 2021;128(12):1988\u20132002.","journal-title":"Circ Res"},{"key":"47_CR6","doi-asserted-by":"crossref","unstructured":"Shaw JR, Nopp S, Stavik B, Youkhana K, Michels AL, Kennes S, et al. Thrombosis, translational medicine, and biomarker research: moving the needle. J Am Heart Assoc. 2025;14(1). Available from: https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.124.038782.","DOI":"10.1161\/JAHA.124.038782"},{"key":"47_CR7","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.thromres.2019.12.018","volume":"186","author":"M Lundbech","year":"2020","unstructured":"Lundbech M, Krag AE, Christensen TD, Hvas AM. Thrombin generation, thrombin-antithrombin complex, and prothrombin fragment F1+2 as biomarkers for hypercoagulability in cancer patients. Thromb Res. 2020;186:80\u20135 Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0049384819305511\n.","journal-title":"Thromb Res"},{"issue":"18","key":"47_CR8","doi-asserted-by":"publisher","first-page":"14179","DOI":"10.3390\/ijms241814179","volume":"24","author":"CL Hvas","year":"2023","unstructured":"Hvas CL, Larsen JB. The fibrinolytic system and its measurement: history, current uses and future directions for diagnosis and treatment. Int J Mol Sci. 2023;24(18):14179 Available from: https:\/\/www.mdpi.com\/1422-0067\/24\/18\/14179\n.","journal-title":"Int J Mol Sci"},{"issue":"12","key":"47_CR9","doi-asserted-by":"publisher","first-page":"3142","DOI":"10.1111\/jth.15052","volume":"18","author":"AR Rezaie","year":"2020","unstructured":"Rezaie AR, Giri H. Anticoagulant and signaling functions of antithrombin. J Thromb Haemost. 2020;18(12):3142\u201353.","journal-title":"J Thromb Haemost"},{"issue":"7488","key":"47_CR10","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/nature12873","volume":"506","author":"Y Okada","year":"2014","unstructured":"Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506(7488):376\u201381.","journal-title":"Nature"},{"issue":"11","key":"47_CR11","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1001\/jama.299.11.1306","volume":"299","author":"ID Bezemer","year":"2008","unstructured":"Bezemer ID. Gene variants associated with deep vein thrombosis. J Am Med Assoc. 2008;299(11):1306 Available from: http:\/\/jama.jamanetwork.com\/article.aspx?doi=10.1001\/jama.299.11.1306\n.","journal-title":"J Am Med Assoc"},{"issue":"1","key":"47_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41435-022-00192-6","volume":"24","author":"SJ Virolainen","year":"2023","unstructured":"Virolainen SJ, VonHandorf A, Viel KCMF, Weirauch MT, Kottyan LC. Gene\u2013environment interactions and their impact on human health. Genes Immun. 2023;24(1):1\u201311.","journal-title":"Genes Immun"},{"issue":"D1","key":"47_CR13","doi-asserted-by":"publisher","first-page":"D877","DOI":"10.1093\/nar\/gkv1340","volume":"44","author":"LD Ward","year":"2016","unstructured":"Ward LD, Kellis M. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res. 2016;44(D1):D877-81 Available from: https:\/\/academic.oup.com\/nar\/article-lookup\/doi\/10.1093\/nar\/gkv1340\n.","journal-title":"Nucleic Acids Res"},{"issue":"10","key":"47_CR14","doi-asserted-by":"publisher","first-page":"1877","DOI":"10.1111\/j.1538-7836.2011.04443.x","volume":"9","author":"NA Zakai","year":"2011","unstructured":"Zakai NA, Mcclure LA. Racial differences in venous thromboembolism. J Thromb Haemost. 2011;9(10):1877\u201382. https:\/\/doi.org\/10.1111\/j.1538-7836.2011.04443.x.","journal-title":"J Thromb Haemost"},{"key":"47_CR15","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1007\/s10875-022-01289-3","volume":"42","author":"SG Tangye","year":"2022","unstructured":"Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human inborn errors of immunity: 2022 update on the classification from the international union of immunological societies expert committee. Journal of Clinical Immunology. 2022;42:1473\u2013507. https:\/\/doi.org\/10.1007\/s10875-022-01289-3. Springer US.","journal-title":"Journal of Clinical Immunology"},{"issue":"2019","key":"47_CR16","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.ijcard.2019.01.090","volume":"286","author":"MK Christiansen","year":"2019","unstructured":"Christiansen MK, Larsen SB, Nyegaard M, Neergaard-Petersen S, W\u00fcrtz M, Grove EL, et al. The ABO locus is associated with increased platelet aggregation in patients with stable coronary artery disease. Int J Cardiol. 2019;286(2019):152\u20138. https:\/\/doi.org\/10.1016\/j.ijcard.2019.01.090.","journal-title":"Int J Cardiol"},{"issue":"3","key":"47_CR17","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/s41588-022-01286-7","volume":"55","author":"J Ghouse","year":"2023","unstructured":"Ghouse J, Tragante V, Ahlberg G, Rand SA, Jespersen JB, Lein\u00f8e EB, et al. Genome-wide meta-analysis identifies 93 risk loci and enables risk prediction equivalent to monogenic forms of venous thromboembolism. Nat Genet. 2023;55(3):399\u2013409 Available from: https:\/\/www.nature.com\/articles\/s41588-022-01286-7\n.","journal-title":"Nat Genet"},{"issue":"2","key":"47_CR18","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1161\/ATVBAHA.119.313137","volume":"40","author":"Y Zhang","year":"2020","unstructured":"Zhang Y, Zhang Z, Wei R, Miao X, Sun S, Liang G, et al. IL (Interleukin)-6 contributes to deep vein thrombosis and is negatively regulated by miR-338-5p. Arterioscler Thromb Vasc Biol. 2020;40(2):323\u201334.","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"1","key":"47_CR19","doi-asserted-by":"publisher","DOI":"10.1016\/j.rpth.2024.102330","volume":"8","author":"AK Mohapatra","year":"2024","unstructured":"Mohapatra AK, Todaro AM, Castoldi E. Factor V variants in bleeding and thrombosis. Res Practn Thrombosis and Haemostasis. 2024;8(1): 102330. https:\/\/doi.org\/10.1016\/j.rpth.2024.102330. Available from:","journal-title":"Res Practn Thrombosis and Haemostasis"},{"issue":"7","key":"47_CR20","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1177\/1076029618779136","volume":"24","author":"J Sokol","year":"2018","unstructured":"Sokol J, Skerenova M, Ivankova J, Simurda T, Stasko J. Association of genetic variability in selected genes in patients with deep vein thrombosis and platelet hyperaggregability. Clin Appl Thromb. 2018;24(7):1027\u201332.","journal-title":"Clin Appl Thromb"},{"issue":"11","key":"47_CR21","doi-asserted-by":"publisher","first-page":"1802","DOI":"10.1111\/j.1538-7836.2009.03544.x","volume":"7","author":"Y Li","year":"2009","unstructured":"Li Y, Bezemer ID, Rowland CM, Tong CH, Arellano AR, Catanese JJ, et al. Genetic variants associated with deep vein thrombosis: the F11 locus. J Thromb Haemost. 2009;7(11):1802\u20138.","journal-title":"J Thromb Haemost"},{"issue":"August","key":"47_CR22","first-page":"1","volume":"14","author":"G Motta","year":"2023","unstructured":"Motta G, Juliano L, Chagas JR. Human plasma kallikrein: roles in coagulation, fibrinolysis, inflammation pathways, and beyond. Front Physiol. 2023;14(August):1\u201312.","journal-title":"Front Physiol"},{"issue":"10","key":"47_CR23","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1016\/j.bcp.2011.06.023","volume":"82","author":"J Devalli\u00e8re","year":"2011","unstructured":"Devalli\u00e8re J, Charreau B. The adaptor Lnk (SH2B3): an emerging regulator in vascular cells and a link between immune and inflammatory signaling. Biochem Pharmacol. 2011;82(10):1391\u2013402 Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0006295211004060\n.","journal-title":"Biochem Pharmacol"},{"issue":"12","key":"47_CR24","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1038\/s41436-018-0322-z","volume":"20","author":"S Zhang","year":"2018","unstructured":"Zhang S, Taylor AK, Huang X, Luo B, Spector EB, Fang P, et al. Venous thromboembolism laboratory testing (factor V Leiden and factor II c.*97G>A), 2018 update: a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2018;20(12):1489\u201398. https:\/\/doi.org\/10.1038\/s41436-018-0322-z.","journal-title":"Genet Med"},{"issue":"10","key":"47_CR25","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.1111\/j.1538-7836.2008.03118.x","volume":"6","author":"AP Reiner","year":"2008","unstructured":"Reiner AP, Carty CL, Jenny NS, Nievergelt C, Cushman M, Stearns-Kurosawa DJ, et al. PROC, PROCR andPROS1 polymorphisms, plasma anticoagulant phenotypes, and risk of cardiovascular disease and mortality in older adults: the cardiovascular health study. J Thromb Haemost. 2008;6(10):1625\u201332 Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1538783622139668\n.","journal-title":"J Thromb Haemost"},{"issue":"6","key":"47_CR26","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1161\/01.ATV.0000130465.23430.74","volume":"24","author":"N Mackman","year":"2004","unstructured":"Mackman N. Role of tissue factor in hemostasis, thrombosis, and vascular development. Arterioscler Thromb Vasc Biol. 2004;24(6):1015\u201322.","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"47_CR27","doi-asserted-by":"publisher","unstructured":"Lobato RL, White WD, Mathew JP, Newman MF, Smith PK, McCants CB, et al. Thrombomodulin gene variants are associated with increased mortality after coronary artery bypass surgery in replicated analyses. Circulation. 2011;124(SUPPL. 1: S143-S148). https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.110.00833.","DOI":"10.1161\/CIRCULATIONAHA.110.00833"},{"issue":"Suppl 3","key":"47_CR28","doi-asserted-by":"publisher","first-page":"S276","DOI":"10.21037\/cdt.2017.09.01","volume":"7","author":"J Stone","year":"2017","unstructured":"Stone J, Hangge P, Albadawi H, Wallace A, Shamoun F, Knuttien MG, et al. Deep vein thrombosis: pathogenesis, diagnosis, and medical management. Cardiovasc Diagn Ther. 2017;7(Suppl 3):S276\u201384.","journal-title":"Cardiovasc Diagn Ther"},{"issue":"23","key":"47_CR29","doi-asserted-by":"publisher","first-page":"3497","DOI":"10.1182\/blood.V126.23.3497.3497","volume":"126","author":"Q Wang","year":"2015","unstructured":"Wang Q, Tang L, Hu B, Hu Y, Liu H. Thrombomodulin gene mutations associated with thromboembolic diseases. Blood. 2015;126(23):3497\u20133497 Available from: https:\/\/ashpublications.org\/blood\/article\/126\/23\/3497\/90955\/Thrombomodulin-Gene-Mutations-Associated-with\n.","journal-title":"Blood"},{"issue":"1","key":"47_CR30","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.jtha.2022.10.014","volume":"21","author":"GW Moore","year":"2023","unstructured":"Moore GW, Castoldi E, Teruya J, Morishita E, Adcock DM. Factor V Leiden-independent activated protein C resistance: communication from the plasma coagulation inhibitors subcommittee of the International Society on Thrombosis and Haemostasis Scientific and Standardisation Committee. J Thromb Haemost. 2023;21(1):164\u201374. https:\/\/doi.org\/10.1016\/j.jtha.2022.10.014.","journal-title":"J Thromb Haemost"},{"key":"47_CR31","doi-asserted-by":"publisher","unstructured":"Kujovich JL. Factor V Leiden thrombophilia. Genet Med. 2011;13(1):1-16. https:\/\/doi.org\/10.1097\/GIM.0b013e3181faa0f2. PMID: 21116184.","DOI":"10.1097\/GIM.0b013e3181faa0f2"},{"issue":"2","key":"47_CR32","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1007\/s11239-020-02203-7","volume":"51","author":"Y Zhang","year":"2021","unstructured":"Zhang Y, Zhang Z, Shu S, Niu W, Xie W, Wan J, et al. The genetics of venous thromboembolism: a systematic review of thrombophilia families. J Thromb Thrombolysis. 2021;51(2):359\u201369 Available from: https:\/\/link.springer.com\/10.1007\/s11239-020-02203-7\n.","journal-title":"J Thromb Thrombolysis"}],"container-title":["Genomics &amp; Informatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s44342-025-00047-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s44342-025-00047-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s44342-025-00047-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T15:10:23Z","timestamp":1747321823000},"score":1,"resource":{"primary":{"URL":"https:\/\/genomicsinform.biomedcentral.com\/articles\/10.1186\/s44342-025-00047-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,15]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["47"],"URL":"https:\/\/doi.org\/10.1186\/s44342-025-00047-2","relation":{},"ISSN":["2234-0742"],"issn-type":[{"value":"2234-0742","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,15]]},"assertion":[{"value":"16 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 April 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 May 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"For research involving secondary data analysis of public datasets, consent and ethical clearance were deemed not applicable, as the data were anonymized and publicly available for research use.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"11"}}