Associations of Circulating Protein Levels With Lipid Fractions in the General Population

Abstract

Objective: Revealing patterns of associations between circulating protein and lipid levels could improve biological understanding of cardiovascular disease. In this study, we investigated associations between proteins related to cardiovascular disease, and triglyceride (TG), total cholesterol (TC), LDL and HDL cholesterol (LDL-C and HDL-C) levels in individuals from the general population. Approach and Results: We measured plasma protein levels using the Olink ProSeek CVD I or II+III arrays and analyzed 57 proteins available in three population-based cohorts: EpiHealth (n=2,029 52% women, median age 61 years), PIVUS (n=790 51% women, all aged 70 years) and ULSAM (n=551, all men aged 77 years). A discovery analysis was performed in EpiHealth in a regression framework (adjusted for sex, age, BMI, smoking, glucose levels, systolic blood pressure, blood pressure medication, diabetes medication and CVD history) and associations with FDR<0.05 were further tested in PIVUS and ULSAM, where p-value of 0.05 was considered a successful replication (validation FDR of 0.1%). We used summary statistics from a genome-wide association study (GWAS) on each protein biomarker (meta-analysis of EpiHealth, PIVUS, ULSAM and IMPROVE) and publicly available data from Global Lipids Genetics Consortium (GLGC) to perform Mendelian randomization (MR) analyses to address possible causality of protein levels. Out of 57 tested proteins, 42 demonstrated an association with at least one lipid fraction; 35 were associated with TG, 15 with TC, 9 with LDL-C, and 24 with HDL-C. Among these associations, we found kidney injury molecule (KIM-1), tumor necrosis factor receptor 1 and 2 (TNF-R1 and TNF-R2), TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) and resistin (RETN) to be associated with all four lipid fractions. Further, 15 proteins were related to both TG and HDL-C in a consistent and biologically expected manner, i.e. higher TG and lower HDL-C or vice versa. Another common pattern of associations was concomitantly higher TG, TC and LDL-C, which is associated with higher CVD risk. We did not find evidence of causal links for protein levels. Conclusions: Our comprehensive analysis of plasma proteins and lipid fractions of 3,370 individuals from the general population provides new information about lipid metabolism.

Cardiovascular Disease-Related Serum Proteins in Workers Occupationally Exposed to Polycyclic Aromatic Hydrocarbons

“…Another suggested mechanism is through oxidative stress resulted from homocysteine metabolism imbalance (Marti-Carvajal et al , 2017). It should be noted that KIM-1 (kidney injury molecule-1) was positively associated with cholesterol, LDL, and triglycerides in both chimney sweeps and controls ( p < .05), which is in line with a previous study (Figarska et al., 2018). However, this protein was not differentially expressed.…”

Identification of endothelial-derived proteins in plasma associated with cardiovascular risk factors

“…Other screening technologies for CVD relevant plasma proteins are available, such as commercial aptamer-based technology (www.somalogic.com) and proximity extension assays (PEA)(53). Such assays have been used to identify biomarkers associated with CVD risk factor exposure, such as blood lipids and BMI (54, 55), but these CVD screening panels are still primarily configured to detect proteins with known functions in pathophysiological processes and pathways involved in CVD (e.g. inflammation, coagulation, lipid metabolism), and thus have limited overlap with our screening panel, which has a greater focus on biomarker source, rather than previous links to CVD.…”

“…Conversely, proteins negatively associated with multiple CVD risk factors, HEG1, ADAMTSL4, FBLN2 and ANGPT2 are all normally secreted (69-72). Other studies have examined plasma protein association with CVD risk factor exposure and prediction using pre-designed PEA CVD panels; 102 proteins were identified as associated with baseline BMI in a study of weight loss over time, of which 88 were positively associated and 14 negatively associated (54) and 42 candidates were associated with at least one lipid fraction (triglycerides and total, LDL or HDL cholesterol) with multiple proteins overlapping groups (55). In a study of 899 participants without overt CVD in the Framingham Heart study Offspring cohort, 1129 proteins were measured, of which 156 were (positively or negatively) associated with Framingham risk score (73).…”

“…candidates were associated with at least one lipid fraction (triglycerides and total, LDL or HDL cholesterol) with multiple proteins overlapping groups (55). In a study of 899 participants without overt CVD in the Framingham Heart study Offspring cohort, 1129 proteins were measured, of which 156 were (positively or negatively) associated with Framingham risk score (73).…”

Analysis Ofsome Components of Blood Proteome in “Healthy Population” of Russian Megapolis

“…C-reactive protein, which belongs to the category of acute phase proteins, is one of the markers of inflammatory reaction [4,5]. In addition, its level is considered as a predictor of various chronic diseases, including cardiovascular disease and degenerative diseases of the musculoskeletal system [16,17].…”