VEGF beta is a candidate biomarker for cardiovascular risk stratification
Authors: Schulte C , Mueller C , Escobar J D , Tong T , Lackner K , Schulze A , Blankenberg S , Salomaa V , Wild P , Zeller T 
Published: October 2022

Abstract

Background
The blood-based transcriptome changes in relation to body weight but longitudinal data on specific transcripts are rare. Monocytes play a crucial role in the development of atherosclerosis and coronary artery disease. Monitoring monocytic gene expression patterns could aid to identify biomarkers for improved cardiovascular risk stratification. BMI and diabetes mellitus (T2DM) are associated with coronary artery disease (CAD). There are mRNAs associated with the development of atherosclerosis and CAD, which can be detected in circulating cells. The exact pathways and direct targets have not been explored.

Objective
To apply transcriptome screening and validation analysis to identify novel biomarker candidates associated with longitudinal changes of BMI as cardiovascular risk factors and test association with clinical endpoints.

Methods
Transcriptome-wide monocytic gene expression changes were screened in relation to changes in BMI over a time period of 5 years in 1,092 participants of the Gutenberg Health Study with available transcriptomics data at baseline investigation and at 5-years follow-up. Functional enrichment of BMI-related genes (FDR &lt;0.01) was tested based on pathway databases and selected gene sets. Serum VEGFB levels were quantified and validated in serum from n=1,895 individuals from an independent cohort study (FinRisk). In-vitro, THP1 cells were stimulated with recombinant VEGFB.

Results
143 transcripts showed a significant association with change in BMI over 5 years. Decreased VEGFB mRNA levels strongly associated with increased BMI (p=2.8x10–9). Lower levels of VEGFB mRNA were associated with increased mortality (HRperSD=0.757, 95% CI: 0.647–0.885, p=0.0005) following adjustment for age and sex and incident diabetes (p=0.01). Circulating VEGFB levels inversely correlated with VEGFB mRNA (r=−0.2, p=0.0024) and positively correlated with an increase in BMI (beta=0.226, p=8.4x10–6), type 2 diabetes mellitus risk (HRperSD=1.279, 95% CI: 1.148–1.425, p=7.8x10–6) and all-cause mortality (HRperSD=1.184, 95% CI: 1.045–1.342, p=0.008). Further exploration in n=1,895 individuals from FinRisk revealed an association of increased VEGFB levels with increased risk for heart failure (HRperSD=1.373, 95% CI: 1.210–1.560, p=1.0x10–6) and coronary artery disease (HR=1.018, 95% CI: 1.003–1.034, p=0.019), even after adjustment for BMI. In THP-1 culture, stimulation with VEGFB resulted in downregulation of VEGFB mRNA levels.

Conclusion
Decreased monocytic gene expression of VEGFB is related to increased BMI, increased risk of T2DM and all-cause mortality. Vice versa,circulating VEGFB levels associates positively with BMI, diabetes, mortality as well as heart failure and coronary heart disease. We hypothesize that monocytes regulate VEGFB expression by a negative feed-back mechanism based. Circulating VEGFB is a potential novel biomarker candidate for weight-related diabetes risk and cardiovascular risk evaluation.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DZHK