基因定义的蛋白S缺乏症很罕见，但与静脉血栓形成密切相关
基因定义的蛋白S缺乏症很罕见，但与静脉血栓形成密切相关
作者： 小柯机器人 发布时间：2025/3/4 15:30:11
本期文章：《美国医学会杂志》：Online/在线发表
美国麻省理工学院和哈佛大学Pavan K. Bendapudi小组提出了蛋白S异常与血栓形成的人口规模研究。该项研究成果发表在2025年3月3日出版的《美国医学会杂志》上。
与低蛋白S相关的静脉和动脉血栓形成风险的长期不确定性阻碍了血栓性疾病的临床决策。人口规模的多组学数据集为回答有关蛋白S缺乏的流行病学和临床影响的问题提供了前所未有的机会。
为了评估多种血栓形成表型与蛋白S缺乏相关的风险，研究组使用来自英国生物库（n=426436）和美国国立卫生研究院All of US（n=204006）生物库的纵向人群队列进行横断面研究。英国生物库参与者于2006-2010年（最后一次随访，2020年5月19日）入组，并接受了全外显子组测序，其中一个子组（n=44431）的蛋白S水平通过高通量血浆蛋白质组学测量。All of Us生物库的招募始于2017年，目前仍在进行中，参与者接受了种系全基因组测序。这两个队列都包括关于人口统计学、实验室测量和临床结果的个人层面数据。
暴露因素为PROS1中存在罕见的种系遗传变异，通过功能影响评分（FIS）进行分段，这是对遗传变异破坏蛋白质活性概率的计算机预测。主要结局为Firth逻辑回归和线性回归模型评估的一系列FIS评分中与低血浆蛋白S水平和PROS1变异相关的血栓形成风险。
英国生物库队列中54.3%为女性，入组时的中位年龄为58.3岁（IQR，50.5-63.7）。大多数参与者（95.6%）是欧洲血统，18011人经历过静脉血栓栓塞症（VTE）。在该人群队列中，FIS为1.0的最高风险PROS1变异的杂合性（无义、移码和必需剪接位点中断）很少见（调整后的患病率，英国为0.0091%，美国为0.0178%），并且与VTE风险显著增加有关（比值比[OR]，14.01；95%CI，6.98-27.14；P=0.09×10 -11 ）。
血浆蛋白质组学（n=44431）表明，这些变异的携带者的总蛋白S水平为正常水平的48.0%（与非携带者相比P=0.02）。相比之下，损伤较小的错义变异（FIS≥0.7）更常见（调整后的患病率，英国为0.22%，美国为0.20%），与血浆蛋白S浓度略有降低和VTE风险的较小点估计值相关（OR，1.977；95%CI，1.552-2.483；P=0.95×10 -7 ）。
在具有相似效应大小的All of Us队列中，独立验证了FIS临界值下PROS1和VTE之间的关联。编码PROS1变异的存在与3种形式的动脉血栓形成之间没有关联：心肌梗死、外周动脉疾病和非心源性栓塞缺血性卒中。PROS1变异的存在与低血浆蛋白S水平相关性较差，蛋白S缺乏与VTE和外周动脉疾病显著相关，无论PROS1变异携带者状态如何。Kaplan-Meier生存分析显示，PROS1中与种系功能丧失相关的VTE风险升高是显而易见的，并且似乎在一生中持续存在（时序P = .0005）。
研究结果表明，PROS1中真正的遗传性功能丧失很少见，但在普通人群中代表了比以前理解的更强的VTE风险因素。获得性、环境性或反式作用的遗传因素比PROS1的编码变异更有可能导致循环蛋白S缺乏，低血浆蛋白S与VTE有关。
附：英文原文
Title: Population-Scale Studies of Protein S Abnormalities and Thrombosis
Author: Sharjeel A. Chaudhry, Amelia K. Haj, Justine Ryu, Sean J. Jurgens, Alfonso Rodriguez Espada, Xin Wang, Seung Hoan Choi, Simone Sanna-Cherchi, Steven P. Grover, Kenneth A. Bauer, Patrick T. Ellinor, Pavan K. Bendapudi
Issue&Volume: 2025-03-03
Abstract:
Importance 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.
Objective To evaluate the risk associated with protein S deficiency across multiple thrombosis phenotypes.
Design, Setting, and Participants Cross-sectional study using longitudinal population cohorts derived from the UK Biobank (n=426436) and the US National Institutes of Health All of Us (n=204006) biorepositories. UK Biobank participants were enrolled in 2006-2010 (last follow-up, May 19, 2020) and underwent whole exome sequencing, with a subset (n=44431) 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.
Exposure Presence of rare germline genetic variants in PROS1, segmented by functional impact score (FIS), an in silico prediction of the probability that a genetic variant will disrupt protein activity.
Main Outcomes and Measures Firth logistic regression and linear regression modeling were used to evaluate the thrombosis risk associated with low plasma protein S levels and PROS1 variants across a range of FIS ratings.
Results 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 18011 had experienced a venous thromboembolism (VTE). In this population cohort, heterozygosity for the highest-risk PROS1 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=9.09×1011). Plasma proteomics (n=44431) demonstrated that carriers of these variants had total protein S levels that were 48.0% of normal (P=.02 compared with noncarriers). In contrast, less damaging missense variants (FIS ≥0.7) 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=1.95×107). Associations between PROS1 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 variants and 3 forms of arterial thrombosis: myocardial infarction, peripheral artery disease, and noncardioembolic ischemic stroke. The presence of PROS1 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 variant carrier status. The elevated risk of VTE associated with germline loss of function in PROS1 was evident in Kaplan-Meier survival analysis and appeared to persist throughout life (log-rank P=.0005).
Conclusions and Relevance True inherited loss of function in PROS1 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, and low plasma protein S is associated with VTE.
DOI: 10.1001/jama.2025.0155
Source: https://jamanetwork.com/journals/jama/fullarticle/2831018