A targeted proteomics investigation of the obesity paradox in venous thromboembolism

Abstract

The obesity paradox, the controversial finding that obesity promotes disease development but protects against sequelae in patients, has been observed in venous thromboembolism (VTE). The aim of this investigation was to identify a body mass–related proteomic signature in VTE patients and to evaluate whether this signature mediates the obesity paradox in VTE patients. Data from the Genotyping and Molecular Phenotyping in Venous ThromboEmbolism Project, a prospective cohort study of 693 VTE patients, were analyzed. A combined end point of recurrent VTE or all-cause death was used. Relative quantification of 444 proteins was performed using high-throughput targeted proteomics technology. Measurements were performed in samples collected during the acute VTE event and at 12-month follow-up. An 11-protein signature (CLEC4C, FABP4, FLT3LG, IL-17C, LEP, LYVE1, MASP1, ST2, THBS2, THBS4, TSLP) for body mass in VTE patients was identified. The signature did not significantly mediate the obesity paradox (change in hazard ratio [HR]: 0.04; likelihood ratio test of nested models = 7.7; P = .74), but its main constituent protein, leptin, was inversely associated with recurrent VTE or death (adjusted HR [95% confidence interval] per standard deviation increase: 0.66 [0.46-0.94]). This relationship was significantly (P = .007) modified by markers of leptin resistance (ie, high body mass index and high circulating matrix metalloproteinase-2 levels). Although the signature did not substantially explain the obesity paradox, leptin appears to be protective against disease recurrence and death in VTE patients. This protective effect was abrogated under conditions of leptin resistance and hence was unrelated to the obesity paradox.

Proteomics in thrombosis research

“…Four larger “exploratory panels” targeting approximately 1500 unique proteins have become available, with a focus on cardiometabolic‐, oncology‐, neurology‐, and inflammation‐associated biomarkers, and more recently a combined Explore 3072 panel targeting approximately 2950 unique proteins has been launched. This technology has been applied to biomarker profiling studies of VTE 24‐26 …”

“…Target specificity for the corresponding Olink assays was validated using cis pQTL analysis. In a subsequent study, using the same Olink panels to analyze VTE patients sampled at diagnosis and at 12 months after the index event in GMP‐VTE, they identified a body mass‐associated proteomic signature of 11 proteins that were consistently related to body mass index in plasma of VTE patients sampled at diagnosis and at 12 months after the index event 25 . However, this signature did not explain the obesity paradox in VTE patients, but leptin was inversely associated with the combined endpoint of recurrent VTE and death.…”

“…Panova et al (OC 10.4) analyzed plasma proteomics profiles using PEA in 652 individuals from GMP‐VTE study, of which 82 had cancer. Using the same Olink panels as in two previous reports based on the same study, 24,25 they identified 60 unique proteins (13% of interrogated proteins) that in a model together (with nine other variables, not described) differentiate between cancer‐associated thrombosis (CAT) and noncancer VTE with an area under the curve (AUC) of 0.89. The 60 proteins were primarily related to complement, coagulation, angiogenesis, immune response, and cell growth regulation, which could reflect the preselection biases of the PEA panels (e.g., Cardiovascular, Immune Response).…”

“…However, compared with other disease states, a limited number of plasma proteomics studies has been reported, where novel biomarker candidates for VTE are identified. 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 Today, several of the plasma proteins reportedly associated with VTE, and subsequently evaluated when incorporated into risk scores, have emerged from hypothesis driven analysis of a single, or limited set, of proteins based on known links to thrombosis (e.g., P‐selectin 30 ). Systematic profiling of a larger portion of circulating plasma proteins could lead to discovery of novel protein biomarkers with potential clinical utility for VTE diagnosis and/or prediction.…”

“…Because VTE is a disease of the intravascular compartment, the blood proteome could reflect combined environmental, genetic, and epigenetic contributors to risk variation between individuals. However, compared with other disease states, a limited number of plasma proteomics studies has been reported, where novel biomarker candidates for VTE are identified 22‐29 . Today, several of the plasma proteins reportedly associated with VTE, and subsequently evaluated when incorporated into risk scores, have emerged from hypothesis driven analysis of a single, or limited set, of proteins based on known links to thrombosis (e.g., P‐selectin 30 ).…”