Abstract Body (Do not enter title and authors here): Background: Hypertension (HTN) is a leading cause of cardiovascular disease (CVD) worldwide. While the prevalence of HTN increases with age, the biological mechanisms underlying its development and age-related progression are incompletely understood.
Hypothesis: We hypothesized that longitudinal profiling of the plasma proteome and integration with human genetics would identify novel determinants of age-related increases in systolic blood pressure (SBP) and CVD risk.
Methods: Plasma proteins (n=2,944) were measured using the OLINK 3k protein assay in 2,006 adults (mean age=58 years, 52% women) from the Multi-Ethnic Study of Atherosclerosis (MESA) at 3 visits (baseline, 10 and 15 years). Systolic blood pressure (SBP) was measured at each timepoint and adjusted for BP medication usage. We evaluated the association between relative protein abundance and SBP at each visit through time-updating linear mixed models (LMM) with an interaction term for protein X time. Proteins whose associations with SBP strengthened over time were evaluated for their potential causal roles in SBP using cis-Mendelian Randomization (cis-MR). Time-varying SBP proteins were tested for associations with incident CVD (coronary heart disease, stroke and heart failure) using Cox proportional hazards regression. A false discovery rate of <5% was used for all analyses.
Results: Serial profiling identified 236 proteins with time-varying associations with SBP, including proteins with known roles in vascular remodeling such as VEGF-D (LMM β=1.9, p=3E-12) and novel circulating markers such as NADK (LMM β=2.7, p=5.8E-25), a protein with key roles in nitric oxide production and reactive oxygen species formation. cis-MR using the inverse variance weighted method supported potential causal roles for 10 of these proteins in BP regulation (Table 1). These included ASPN (IVW β=0.61, p=2.3E-12), a negative regulator of the TGF-B signaling pathway and previously associated with arterial stiffness. Finally, levels of 79/236 proteins were associated with incident CVD in MESA, suggesting shared molecular pathways between age-related SBP changes and development of CVD.
Conclusions: Serial profiling of the plasma proteome helped detect proteomic markers of age-related BP progression and CVD, several of which were supported with genetic evidence for causal roles in BP regulation. These proteins may help identify dysregulated pathways contributing to age-dependent risk of hypertension and CVD.