Common inflammatory proteins linking frailty and area-level deprivation as key drivers of cardiovascular risk in women

Background: 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. Methods: 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. Results: 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. Conclusions: 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.