{"id":27944,"date":"2025-05-08T04:23:00","date_gmt":"2025-05-07T20:23:00","guid":{"rendered":"https:\/\/csccm.org.cn\/?p=27944"},"modified":"2025-05-08T05:22:22","modified_gmt":"2025-05-07T21:22:22","slug":"jama%e5%8f%91%e8%a1%a8%e8%ae%ba%e6%96%87%ef%bc%9a%e8%9b%8b%e7%99%bds%e5%bc%82%e5%b8%b8%e4%b8%8e%e8%a1%80%e6%a0%93%e5%bd%a2%e6%88%90%e7%9a%84%e4%ba%ba%e7%be%a4%e7%a0%94%e7%a9%b6","status":"publish","type":"post","link":"https:\/\/csccm.org.cn\/?p=27944","title":{"rendered":"[JAMA\u53d1\u8868\u8bba\u6587]\uff1a\u86cb\u767dS\u5f02\u5e38\u4e0e\u8840\u6813\u5f62\u6210\u7684\u4eba\u7fa4\u7814\u7a76"},"content":{"rendered":"\n

Original Investigation <\/p>\n\n\n\n

March 3, 2025<\/p>\n\n\n\n

Population-Scale Studies of Protein S Abnormalities and Thrombosis<\/h1>\n\n\n\n

Sharjeel A. Chaudhry, Amelia K. Haj, Justine Ryu, et al<\/h3>\n\n\n\n

JAMA. <\/em>Published online March 3, 2025. doi:10.1001\/jama.2025.0155<\/h3>\n\n\n\n

<\/a>Key Points<\/p>\n\n\n\n

Question<\/strong>  What is the thrombosis risk conferred by deficiency in protein S?<\/p>\n\n\n\n

Findings<\/strong>  In this analysis of more than 600\u202f000 individuals, we found that deleterious missense and complete loss-of-function variants in PROS1<\/em> are significantly associated with venous thromboembolism (odds ratios, 1.98 and 14.01, respectively). Complete heterozygous loss of function in PROS1<\/em> occurs in approximately 1 in 10\u202f000 people. Low plasma protein S is associated with venous thromboembolism and peripheral artery disease regardless of whether a coding variant in PROS1<\/em> is present.<\/p>\n\n\n\n

Meaning<\/strong>  Genetically defined protein S deficiency is rarer and more closely linked to venous thrombosis than previously appreciated in cross-sectional studies; low circulating protein S levels are associated with 2 thrombosis phenotypes.<\/a><\/p>\n\n\n\n

Abstract<\/p>\n\n\n\n

Importance<\/strong>  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.<\/p>\n\n\n\n

Objective<\/strong>  To evaluate the risk associated with protein S deficiency across multiple thrombosis phenotypes.<\/p>\n\n\n\n

Design, Setting, and Participants<\/strong>  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.<\/p>\n\n\n\n

Exposure<\/strong>  Presence of rare germline genetic variants in PROS1<\/em>, segmented by functional impact score (FIS), an in silico prediction of the probability that a genetic variant will disrupt protein activity.<\/p>\n\n\n\n

Main Outcomes and Measures<\/strong>  Firth logistic regression and linear regression modeling were used to evaluate the thrombosis risk associated with low plasma protein S levels and PROS1<\/em> variants across a range of FIS ratings.<\/p>\n\n\n\n

Results<\/strong>\u00a0\u00a0The 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\u00a0PROS1<\/em>\u00a0variants 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;\u00a0P<\/em>\u2009=\u20099.09\u2009\u00d7\u200910\u221211<\/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<\/em>\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;\u00a0P<\/em>\u2009=\u20091.95\u2009\u00d7\u200910\u22127<\/sup>). Associations between\u00a0PROS1<\/em>\u00a0and 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\u00a0PROS1<\/em>\u00a0variants and 3 forms of arterial thrombosis: myocardial infarction, peripheral artery disease, and noncardioembolic ischemic stroke. The presence of\u00a0PROS1<\/em>\u00a0variants correlated poorly with low plasma protein S levels, and protein S deficiency was significantly associated with VTE and peripheral artery disease regardless of\u00a0PROS1<\/em>\u00a0variant carrier status. The elevated risk of VTE associated with germline loss of function in\u00a0PROS1<\/em>\u00a0was evident in Kaplan-Meier survival analysis and appeared to persist throughout life (log-rank\u00a0P<\/em>\u2009=\u2009.0005).<\/p>\n\n\n\n

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Conclusions and Relevance<\/strong>  True inherited loss of function in PROS1<\/em> 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<\/em>, and low plasma protein S is associated with VTE.<\/p>\n","protected":false},"excerpt":{"rendered":"

Original Investigation  March 3, 2025 Po […]<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[32,23],"tags":[],"_links":{"self":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/27944"}],"collection":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=27944"}],"version-history":[{"count":2,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/27944\/revisions"}],"predecessor-version":[{"id":28247,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/27944\/revisions\/28247"}],"wp:attachment":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=27944"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=27944"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=27944"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}