Linking genetically dysregulated adipose tissue with coronary artery disease risk

• Applicant: Dr. Zhifen Chen
• Subject Area: Endocrinology, Diabetology, Metabolism ; General Genetics and Functional Genome Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 510049865

The global pandemic of obesity threatens public health and quality of individual lives. It is one of top risk factors for coronary artery disease (CAD), a lead cause of death worldwide. Across the spectrum from overweight to obesity CAD risk increases by 20% to 75%, as compared to individuals with normal weight [1][2], suggesting a detrimental role of too much or malfunctional adipose tissue (fat) in cardiovascular health. The mechanisms linking adipose tissue with CAD risk have not been fully elucidated. Recently, we performed the first transcriptome-wide association study (TWAS) to systematically identify genes with genetically driven differential expression in CAD cases and controls. Our study identified 32 genes affecting CAD risk via expression in visceral (VAT) and/or subcutaneous (SAT) adipose tissues. Among them, nine genes have not been associated with CAD risk before and therefore are novel susceptibility genes, including FAM114A1, WASF1, FOCAD, TSPAN11, TXNRD3, MGP, CAND1, KPTN, and RGS19. Extensive bioinformatic analyses on these genes using genomic, transcriptomic, and phenotypic data from humans and mice indicated their involvement in causal pathways and processes resulting in CAD. Co-expression network of the nine genes in human VAT suggested shared pathological pathways. Genetic knockdown of one of the genes, KPTN, led to protective phenotypes, indicating therapeutic potentials. Here I propose to investigate the biological underpinnings of the nine genes that firstly affect functions of adipose tissue and secondly are linked to CAD risk using state-of-art genome editing screening and in vitro and in vivo model systems. Specifically, I hope to identify novel mechanisms linking dysregulated adipose tissue with CAD risk. Based on these findings, I expect to discover potential biomarkers and/or therapeutic targets for overweight or obese CAD patients and to facilitate personalized medicine for this high-risk group.

• DFG Programme: Research Grants