Dynamic changes in hs-CRP and risk of all-cause mortality among middle-aged and elderly adults: findings from a nationwide prospective cohort and mendelian randomization.

Introduction: The general population experiences mortality rates that are related to high levels of high-sensitivity C-reactive protein (hs-CRP). We aim to assess the linkage of longitudinal trajectories in hs-CRP levels with all-cause mortality in Chinese participants.

Methods: We utilized data from the China Health and Retirement Longitudinal Study (CHARLS). The exposures were dynamic changes in the hs-CRP and cumulative hs-CRP from 2012 to 2015, and the outcome was all-cause mortality. All participants were categorized into four trajectories according to hs-CRP levels. Multivariable logistic regression analysis, adjusted for potential confounders, was employed to evaluate the relationship of different trajectories of hs-CRP with mortality risk. A two-sample Mendelian randomization (TSMR) method and SHapley Additive exPlanations (SHAP) for identifying determinants of mortality risk were also employed.

Results: The study included 5,445 participants with 233 deaths observed, yielding a mortality proportion of 4.28%. Compared to individuals maintaining low, stable levels of hs-CRP (Class 1), individuals with sustained elevated levels of hs-CRP (Class 4), those experiencing a progressive rise in hs-CRP levels (Class 2), or those transitioning from elevated to reduced hs-CRP levels (Class 3) all faced a significantly heighted death risk, with adjusted Odds Ratios (ORs) ranging from 2.34 to 2.47 across models. Moreover, a non-linear relationship was found between them. Further TSMR analysis also supported these findings. SHAP showed that hs-CRP was the fifth most important determinant of mortality risk.

Conclusions: Our study shows all-cause mortality increases with dynamic changes in hs-CRP levels among middle-aged and elderly adults in China, and cumulative hs-CRP shows an L-shaped relationship with all-cause mortality.