Lin Yu, Louca Panayiotis, Bowyer Ruth C E, Kouraki Afroditi, Rossi Niccolò, Ni Lochlainn Mary, Kelly Anthony, Georgopoulos Vasileios, Williams Frances M K, Steves Claire J, Falchi Mario, Valdes Ana M, Menni Cristina
Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
Academic Rheumatology Clinical Sciences Building, Nottingham City Hospital, University of Nottingham, Nottingham, UK.
Commun Med (Lond). 2025 Jul 20;5(1):301. doi: 10.1038/s43856-025-01012-4.
Chronic inflammation is linked to frailty and deprivation, both of which are comorbid with cardiovascular diseases (CVD). This study aims to identify inflammatory proteins associated with both socioeconomic deprivation and frailty, and assess their role in mediating cardiovascular risk in a large cohort with independent replication.
We included 2144 TwinsUK females aged 37-84 with concurrent measures of frailty (frailty index), index of multiple deprivation (IMD), cardiovascular risk (ASCVD score), and 74 proteins (Olink inflammation panel). A random forest model with SHapley Additive exPlanations identified shared proteomic markers of frailty and deprivation. Linear mixed models assessed associations between selected proteins, IMD, frailty, and ASCVD score. Findings were validated in 57 females from the Nottingham Osteoarthritis study. Mixed-effects Cox regression evaluated associations with 10-year ischemic heart disease risk, and mediation analysis assessed the role of proteins in linking IMD and frailty to ASCVD risk.
We identify ten pro-inflammatory proteins associated with both frailty and area-level social deprivation. Four of those (TNFSF14, HGF, CDCP1, and CCL11) are consistently positively correlated with ASCVD score in both two cohorts. CDCP1 is also associated with higher incident ischemic heart disease risk (HR [95%CI] = 1.82 [1.17, 2.85]). TNFSF14, HGF, and CDCP1 mediate the association between IMD and ASCVD, as well as between frailty and ASCVD.
Our findings indicate that inflammatory proteins involved in cellular signalling, growth, and migration are associated with frailty, socioeconomic deprivation, and CVD risk, suggesting that these pathways mediate the impact of socioeconomic deprivation and ageing on CVD risk.
慢性炎症与身体虚弱和社会经济剥夺相关，而这两者都与心血管疾病（CVD）并存。本研究旨在确定与社会经济剥夺和身体虚弱均相关的炎症蛋白，并在一个大型队列中评估它们在介导心血管风险方面的作用，同时进行独立复制验证。
我们纳入了2144名年龄在37 - 84岁的英国双胞胎女性，她们同时接受了身体虚弱（虚弱指数）、多重剥夺指数（IMD）、心血管风险（ASCVD评分）以及74种蛋白质（Olink炎症检测板）的检测。采用带有SHapley加性解释的随机森林模型来识别虚弱和剥夺的共同蛋白质组学标志物。线性混合模型评估所选蛋白质、IMD、虚弱和ASCVD评分之间的关联。研究结果在诺丁汉骨关节炎研究的57名女性中得到验证。混合效应Cox回归评估与10年缺血性心脏病风险的关联，中介分析评估蛋白质在将IMD和虚弱与ASCVD风险联系起来方面的作用。
我们确定了十种与虚弱和地区层面社会剥夺均相关的促炎蛋白。其中四种（肿瘤坏死因子配体超家族成员14、肝细胞生长因子、CUB结构域蛋白1和嗜酸粒细胞趋化蛋白Eotaxin-1）在两个队列中均与ASCVD评分持续呈正相关。CUB结构域蛋白1还与更高的缺血性心脏病发病风险相关（风险比[95%置信区间]=1.82[1.17, 2.85]）。肿瘤坏死因子配体超家族成员14、肝细胞生长因子和CUB结构域蛋白1介导了IMD与ASCVD之间以及虚弱与ASCVD之间的关联。
我们的研究结果表明，参与细胞信号传导生长和迁移的炎症蛋白与虚弱、社会经济剥夺和CVD风险相关，这表明这些途径介导了社会经济剥夺和衰老对CVD风险的影响。
