{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T09:18:35Z","timestamp":1791364715360,"version":"4.3.1"},"reference-count":35,"publisher":"American Medical Association (AMA)","issue":"16","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA"],"published-print":{"date-parts":[[2025,4,22]]},"abstract":"Importance<\/jats:title>Clinical decision-making in thrombotic disorders is impeded by long-standing uncertainty regarding the magnitude of venous and arterial thrombosis risk associated with low protein S. Population-scale multiomic datasets offer an unprecedented opportunity to answer questions regarding the epidemiology and clinical impacts of protein S deficiency.<\/jats:p><\/jats:sec>Objective<\/jats:title>To evaluate the risk associated with protein S deficiency across multiple thrombosis phenotypes.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>Cross-sectional study using longitudinal population cohorts derived from the UK Biobank (n\u2009=\u2009426\u202f436) and the US National Institutes of Health All of Us (n\u2009=\u2009204\u202f006) biorepositories. UK Biobank participants were enrolled in 2006-2010 (last follow-up, May 19, 2020) and underwent whole exome sequencing, with a subset (n\u2009=\u200944\u202f431) having protein S levels measured by high-throughput plasma proteomics. Recruitment for All of Us began in 2017 and is ongoing, with participants receiving germline whole genome sequencing. Both cohorts include individual-level data on demographics, laboratory measurements, and clinical outcomes.<\/jats:p><\/jats:sec>Exposure<\/jats:title>Presence of rare germline genetic variants in PROS1<\/jats:italic>, segmented by functional impact score (FIS), an in silico prediction of the probability that a genetic variant will disrupt protein activity.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>Firth logistic regression and linear regression modeling were used to evaluate the thrombosis risk associated with low plasma protein S levels and PROS1<\/jats:italic> variants across a range of FIS ratings.<\/jats:p><\/jats:sec>Results<\/jats:title>The UK Biobank cohort was 54.3% female, with a median age of 58.3 (IQR, 50.5-63.7) years at enrollment. Most participants (95.6%) were of European ancestry, and 18\u202f011 had experienced a venous thromboembolism (VTE). In this population cohort, heterozygosity for the highest-risk PROS1<\/jats:italic> variants with an FIS of 1.0 (nonsense, frameshift, and essential splice site disruptions) was rare (adjusted prevalence, 0.0091% in the UK and 0.0178% in the US) and associated with markedly increased risk of VTE (odds ratio [OR], 14.01; 95% CI, 6.98-27.14; P<\/jats:italic>\u2009=\u20099.09\u2009\u00d7\u200910\u221211<\/jats:sup>). Plasma proteomics (n\u2009=\u200944\u202f431) demonstrated that carriers of these variants had total protein S levels that were 48.0% of normal (P<\/jats:italic>\u2009=\u2009.02 compared with noncarriers). In contrast, less damaging missense variants (FIS \u22650.7) occurred more commonly (adjusted prevalence, 0.22% in the UK and 0.20% in the US) and were associated with marginally reduced plasma protein S concentrations and a smaller point estimate for VTE risk (OR, 1.977; 95% CI, 1.552-2.483; P<\/jats:italic>\u2009=\u20091.95\u2009\u00d7\u200910\u22127<\/jats:sup>). Associations between PROS1<\/jats:italic> and VTE at both FIS cutoffs were independently validated in the All of Us cohort with similar effect sizes. No association was detected between the presence of coding PROS1<\/jats:italic> variants and 3 forms of arterial thrombosis: myocardial infarction, peripheral artery disease, and noncardioembolic ischemic stroke. The presence of PROS1<\/jats:italic> variants correlated poorly with low plasma protein S levels, and protein S deficiency was significantly associated with VTE and peripheral artery disease regardless of PROS1<\/jats:italic> variant carrier status. The elevated risk of VTE associated with germline loss of function in PROS1<\/jats:italic> was evident in Kaplan-Meier survival analysis and appeared to persist throughout life (log-rank P<\/jats:italic>\u2009=\u2009.0005).<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>True inherited loss of function in PROS1<\/jats:italic> is rare but represents a stronger risk factor for VTE in the general population than previously understood. Acquired, environmental, or trans-acting genetic factors are more likely to cause circulating protein S deficiency than coding variation in PROS1<\/jats:italic>, and low plasma protein S is associated with VTE.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jama.2025.0155","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T16:01:45Z","timestamp":1741017705000},"page":"1423","source":"Crossref","is-referenced-by-count":32,"title":["Population-Scale Studies of Protein S Abnormalities and Thrombosis"],"prefix":"10.1001","volume":"333","author":[{"given":"Sharjeel A.","family":"Chaudhry","sequence":"first","affiliation":[{"name":"Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, Massachusetts"},{"name":"Department of Surgery, Division of Vascular and Endovascular Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts"},{"name":"Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia K.","family":"Haj","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Harvard Medical School, Boston, Massachusetts"},{"name":"Department of Pathology, Massachusetts General Hospital, Boston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justine","family":"Ryu","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Section of Hematology, Yale School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean J.","family":"Jurgens","sequence":"additional","affiliation":[{"name":"Cardiology Division, Massachusetts General Hospital, Boston"},{"name":"Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, University of Amsterdam, Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso","family":"Rodriguez Espada","sequence":"additional","affiliation":[{"name":"Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, Massachusetts"},{"name":"Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Hoan","family":"Choi","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Sanna-Cherchi","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Columbia University Irving Medical School, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven P.","family":"Grover","sequence":"additional","affiliation":[{"name":"UNC Blood Research Center, Division of Hematology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth A.","family":"Bauer","sequence":"additional","affiliation":[{"name":"Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, Massachusetts"},{"name":"Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick T.","family":"Ellinor","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Harvard Medical School, Boston, Massachusetts"},{"name":"Cardiology Division, Massachusetts General Hospital, Boston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavan K.","family":"Bendapudi","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, Massachusetts"},{"name":"Harvard Medical School, Boston, Massachusetts"},{"name":"Division of Hematology and Blood Transfusion Service, Massachusetts General Hospital, Boston"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"6","key":"joi250001r1","doi-asserted-by":"publisher","first-page":"2082","DOI":"10.1172\/JCI111632","article-title":"Familial protein S deficiency is associated with recurrent thrombosis.","volume":"74","author":"Comp","year":"1984","journal-title":"J Clin Invest"},{"issue":"24","key":"joi250001r2","doi-asserted-by":"publisher","first-page":"1525","DOI":"10.1056\/NEJM198412133112401","article-title":"Recurrent venous thromboembolism in patients with a partial deficiency of protein S.","volume":"311","author":"Comp","year":"1984","journal-title":"N Engl J Med"},{"issue":"6","key":"joi250001r3","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1182\/blood.V64.6.1297.1297","article-title":"Plasma protein S deficiency in familial thrombotic disease.","volume":"64","author":"Schwarz","year":"1984","journal-title":"Blood"},{"issue":"6","key":"joi250001r4","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1111\/j.1365-2516.2008.01775.x","article-title":"Protein S deficiency: a clinical perspective.","volume":"14","author":"ten Kate","year":"2008","journal-title":"Haemophilia"},{"issue":"4","key":"joi250001r5","doi-asserted-by":"publisher","first-page":"498","DOI":"10.3324\/haematol.12691","article-title":"Protein S deficiency.","volume":"93","author":"D\u2019Angelo","year":"2008","journal-title":"Haematologica"},{"issue":"4","key":"joi250001r6","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1182\/blood-2003-05-1551","article-title":"Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex.","volume":"103","author":"Rezende","year":"2004","journal-title":"Blood"},{"issue":"11","key":"joi250001r7","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.5858\/2002-126-1349-AROTTD","article-title":"A review of the technical, diagnostic, and epidemiologic considerations for protein S assays.","volume":"126","author":"Goodwin","year":"2002","journal-title":"Arch Pathol Lab Med"},{"issue":"1","key":"joi250001r8","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1111\/jth.15109","article-title":"Recommendations for clinical laboratory testing for protein S deficiency: communication from the SSC committee plasma coagulation inhibitors of the ISTH.","volume":"19","author":"Marlar","year":"2021","journal-title":"J Thromb Haemost"},{"issue":"21","key":"joi250001r9","doi-asserted-by":"publisher","first-page":"5314","DOI":"10.1182\/blood-2008-10-184879","article-title":"Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives.","volume":"113","author":"Lijfering","year":"2009","journal-title":"Blood"},{"issue":"10","key":"joi250001r10","doi-asserted-by":"publisher","first-page":"2756","DOI":"10.1182\/blood.V85.10.2756.bloodjournal85102756","article-title":"Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study).","volume":"85","author":"Koster","year":"1995","journal-title":"Blood"},{"issue":"1","key":"joi250001r11","doi-asserted-by":"publisher","first-page":"8","DOI":"10.7326\/0003-4819-128-1-199801010-00002","article-title":"Clarification of the risk for venous thrombosis associated with hereditary protein S deficiency by investigation of a large kindred with a characterized gene defect.","volume":"128","author":"Simmonds","year":"1998","journal-title":"Ann Intern Med"},{"issue":"7","key":"joi250001r12","doi-asserted-by":"publisher","first-page":"2353","DOI":"10.1182\/blood.V92.7.2353","article-title":"Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families.","volume":"92","author":"Martinelli","year":"1998","journal-title":"Blood"},{"issue":"6","key":"joi250001r13","doi-asserted-by":"publisher","first-page":"1935","DOI":"10.1182\/blood.V95.6.1935","article-title":"Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S.","volume":"95","author":"Makris","year":"2000","journal-title":"Blood"},{"issue":"18","key":"joi250001r14","doi-asserted-by":"publisher","first-page":"3210","DOI":"10.1182\/blood-2013-04-499335","article-title":"Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study.","volume":"122","author":"Pintao","year":"2013","journal-title":"Blood"},{"issue":"3","key":"joi250001r15","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1055\/s-0037-1614334","article-title":"Hormonal state rather than age influences cut-off values of protein S: reevaluation of the thrombotic risk associated with protein S deficiency.","volume":"82","author":"Liberti","year":"1999","journal-title":"Thromb Haemost"},{"issue":"4","key":"joi250001r16","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.121.023018","article-title":"Classic thrombophilias and thrombotic risk among middle-aged and older adults: a population-based cohort study.","volume":"11","author":"Manderstedt","year":"2022","journal-title":"J Am Heart Assoc"},{"issue":"7","key":"joi250001r17","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1056\/NEJMsr1809937","article-title":"The \u201cAll of Us\u201d research program.","volume":"381","author":"Denny","year":"2019","journal-title":"N Engl J Med"},{"issue":"7726","key":"joi250001r18","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","article-title":"The UK Biobank resource with deep phenotyping and genomic data.","volume":"562","author":"Bycroft","year":"2018","journal-title":"Nature"},{"issue":"3","key":"joi250001r19","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1038\/s41588-021-01011-w","article-title":"Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank.","volume":"54","author":"Jurgens","year":"2022","journal-title":"Nat Genet"},{"issue":"7809","key":"joi250001r20","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans.","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"issue":"1","key":"joi250001r23","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1161\/CIRCGENETICS.115.001211","article-title":"Interaction of hereditary thrombophilia and traditional cardiovascular risk factors on the risk of arterial thromboembolism: pooled analysis of four family cohort studies.","volume":"9","author":"Mahmoodi","year":"2016","journal-title":"Circ Cardiovasc Genet"},{"issue":"1","key":"joi250001r24","doi-asserted-by":"publisher","first-page":"37","DOI":"10.14740\/jh478","article-title":"Protein S deficiency and arterial thromboembolism: a case report and review of the literature.","volume":"8","author":"Fearon","year":"2019","journal-title":"J Hematol"},{"issue":"5","key":"joi250001r25","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1097\/MOH.0000000000000663","article-title":"Protein S: function, regulation, and clinical perspectives.","volume":"28","author":"Majumder","year":"2021","journal-title":"Curr Opin Hematol"},{"issue":"4","key":"joi250001r26","doi-asserted-by":"publisher","first-page":"2512","DOI":"10.1073\/pnas.78.4.2512","article-title":"High molecular weight complex in human plasma between vitamin K-dependent protein S and complement component C4b-binding protein.","volume":"78","author":"Dahlb\u00e4ck","year":"1981","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"15","key":"joi250001r27","doi-asserted-by":"publisher","first-page":"3310","DOI":"10.1016\/j.febslet.2005.03.001","article-title":"The anticoagulant protein C pathway.","volume":"579","author":"Dahlb\u00e4ck","year":"2005","journal-title":"FEBS Lett"},{"issue":"5","key":"joi250001r28","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1160\/TH15-02-0141","article-title":"Classic thrombophilic gene variants.","volume":"114","author":"Mannucci","year":"2015","journal-title":"Thromb Haemost"},{"issue":"1","key":"joi250001r29","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1046\/j.1365-2141.2000.02039.x","article-title":"Prevalence of factor V Leiden and prothrombin G20210A mutations in unselected patients with venous thromboembolism.","volume":"110","author":"de Moerloose","year":"2000","journal-title":"Br J Haematol"},{"issue":"4","key":"joi250001r30","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1055\/s-0038-1625983","article-title":"Risk of venous thrombosis in antithrombin deficiency: a systematic review and bayesian meta-analysis.","volume":"44","author":"Croles","year":"2018","journal-title":"Semin Thromb Hemost"},{"issue":"5","key":"joi250001r32","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1055\/s-0038-1665408","article-title":"Free protein S deficiency is a risk factor for venous thrombosis.","volume":"78","author":"Faioni","year":"1997","journal-title":"Thromb Haemost"},{"issue":"5","key":"joi250001r33","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1002\/ajh.21992","article-title":"Protein S abnormalities: a diagnostic nightmare.","volume":"86","author":"Marlar","year":"2011","journal-title":"Am J Hematol"},{"issue":"3","key":"joi250001r34","doi-asserted-by":"publisher","first-page":"561","DOI":"10.3324\/haematol.2013.092023","article-title":"Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population.","volume":"99","author":"Kim","year":"2014","journal-title":"Haematologica"},{"key":"joi250001r35","first-page":"S249","article-title":"Protein S deficiency is common in a healthy Thai population.","volume":"88","author":"Akkawat","year":"2005","journal-title":"J Med Assoc Thai"},{"key":"joi250001r31","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/B978-0-12-813726-0.00151-3","volume-title":"Transfusion Medicine and Hemostasis","author":"Roshal","year":"2019","edition":"3rd ed"},{"key":"joi250001r21","unstructured":"UK Office of National Statistics. Official census and labor market statistics: RM032\u2014ethnic group by sex by age. Accessed September 9, 2024. https:\/\/www.nomisweb.co.uk\/query\/construct\/summary.asp?reset=yes&mode=construct&dataset=2132&version=0&anal=1"},{"key":"joi250001r22","unstructured":"US Census Bureau. National population by characteristics: 2020-2023. Accessed September 9, 2024. https:\/\/www.census.gov\/data\/tables\/time-series\/demo\/popest\/2020s-national-detail.html"}],"container-title":["JAMA"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jama\/articlepdf\/2831018\/jama_chaudhry_2025_oi_250001_1744313628.00462.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T15:04:38Z","timestamp":1745334278000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jama\/fullarticle\/2831018"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,22]]},"references-count":35,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2025,4,22]]}},"URL":"https:\/\/doi.org\/10.1001\/jama.2025.0155","relation":{},"ISSN":["0098-7484"],"issn-type":[{"value":"0098-7484","type":"print"}],"subject":[],"published":{"date-parts":[[2025,4,22]]}}}