Identification of Endothelial Proteins in Plasma Associated With Cardiovascular Risk Factors

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  Figure 1.. Candidate plasma protein levels are associated with cardiovascular disease (CVD) risk factors. Two hundred sixteen proteins with predicted endothelial cell (EC)-enriched expression were measured in plasma samples from male (n=498) and female (n=507) participants in the SCAPIS (Swedish Cardiopulmonary Bioimage Study) pilot. Candidates associated with the CVD risk factors body mass index (BMI), total cholesterol (CHO), LDL (low-density lipoprotein), smoking, hypertension, or diabetes were identified (age- and sex-adjusted linear model). A, Summary of EC-derived plasma proteins associated with CVD risk factors. Proteins associated with a single risk factor are displayed in adjacent red or green boxes, indicating a positive association (ie, higher protein levels associated with increased risk, for example, higher BMI, smoking) or a negative association (ie, lower protein levels associated with reduced risk profile, for example, lower BMI, lower blood LDL), respectively. Gray bubbles show the number of proteins associated with the (multiple) risk factors linked by the corresponding dotted line. B, Provides further details of these multiple risk factor–associated proteins, indicating…

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  Figure 2.. Candidate plasma protein levels can be associated with multiple cardiovascular disease (CVD) risk factors. Two hundred sixteen proteins with predicted endothelial cell (EC)–enriched expression were measured in plasma samples from male (n=498) and female (n=507) participants in the SCAPIS (Swedish Cardiopulmonary Bioimage Study) pilot (N=1005). Candidate proteins associated with CVD risk factors: body mass index (BMI), total cholesterol (CHO), LDL (low-density lipoprotein), hypertension (HYP), smoking, or diabetes (DIAB) were identified (age- and sex-adjusted linear model, [Bonferroni corrected P value]). Illustrative plots of relative plasma levels of proteins positively: (A) GPR4 (G-protein–coupled receptor 4; B) TRPC6 (transient receptor potential cation channel subfamily C), or negatively: (C) HEG1 (heart development protein with EGF like domains 1), associated with CVD risk factors, in (i) all, (ii) male or (iii) female-only samples. D, Heatmap matrix showing Spearman correlation coefficients between relative plasma levels of proteins associated with ≥2 risk factors across samples. Scale on right side of heatmap. P value *<0.05 **<0.01 ***<0.001 ****<0.0001 vs normal for BMI,…

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  Figure 3.. Candidate plasma protein levels can be sex-specifically associated with cardiovascular disease risk factors. Two hundred sixteen proteins with predicted endothelial cell (EC)–enriched expression were measured in plasma samples from male (n=498) or female (n=507) participants in the SCAPIS (Swedish Cardiopulmonary Bioimage Study) pilot. Candidates associated with body mass index (BMI), total cholesterol (CHO), LDL (low-density lipoprotein), hypertension (HYP), or smoking (SMK) predominantly in (A) females or (B) males were identified. Red or green text indicates a positive or negative association, respectively, between the protein levels and the annotated risk factor. Example plots show relative protein levels of candidates highlighted in large bold text. *<0.05 **<0.01 ***<0.001 ****<0.0001 vs normal for BMI, and vs low for CHO, unless otherwise indicated (ANOVA followed by Tukey multiple comparisons, or unpaired t test [HYP]). Female and male tissue sections from human heart, esophagus, lung, liver, or kidney were stained for CLDN5 (claudin 5), LAMC1 (laminin subunit gamma 1), or COL15A1 (collagen type XV alpha 1 chain); arrows indicate positive staining in blood vessels. BMI:…

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  Figure 4.. Candidate plasma protein levels are associated with the Framingham risk score (FRS). Two hundred sixteen proteins with predicted endothelial cell (EC)–enriched expression were measured in plasma samples from male and female participants in the SCAPIS (Swedish Cardiopulmonary Bioimage Study) pilot (N=1005). Candidates associated with body mass index, total cholesterol, LDL (low-density lipoprotein), smoking, hypertension, or diabetes were identified (age- and sex-adjusted linear model). FRS were calculated for each individual. Summary of EC proteins (A) positively or (B) negatively associated with ≥1 risk factor (adjacent red or green dots indicate number) and corresponding association between protein levels and the Framingham Risk scores across samples (linear model). Example plots show relative levels in plasma across the FRS groups for proteins positively (red box) or negatively (green box) associated with FRS. C, A bidirectional stepwise algorithm was used to identify EC proteins with an additive cumulative association with the FRS in (i) the whole cohort, or in (ii) female or (iii) male subgroup analysis. Direction of protein association with cardiovascular disease risk is…