Genetic association between inflammatory factors and abdominal aortic calcification: Insights from a genome-wide...

Current studies have indicated an association between inflammatory factor and vascular calcification. This study aimed to investigate the potential causal association between circulating inflammatory factor and abdominal aortic calcification (AAC) risk, and to identify potential drug targets for AAC.

We utilized genetic summary data for analysis, which included 91 circulating inflammatory factors from a genome-wide association study (GWAS) of 14,824 individuals of European descent, and AAC from a GWAS of 38,264 individuals of European descent from UK Biobank database. We investigated the potential causal association between circulating inflammatory factors and AAC risk using Mendelian randomization (MR) and assessed MR assumptions in sensitivity analyses and experimental validation. Additionally, protein-protein interaction, pathway enrichment analysis and drug target information summarized from Drugbank database were conducted to further identify the potential drug targets of AAC.

We found strong evidence that plasma FLT3LG and TNFRSF9 are positive associated with AAC risk, and plasma CX3CL1 and KITLG are negative associated with AAC risk. KITLG and TNFRSF9 may be potential drug targets for AAC. And no other significant associations for these inflammatory factors were observed in the PheWAS analysis, except FLT3LG. Additionally, consistent with the MR findings, experimental validation indicated FLT3LG and TNFRSF9 mRNA levels were significantly upregulated in human vascular smooth cells under calcifying conditions. The results of pathway enrichment analysis showed that these four inflammatory factors were mainly enriched in inflammation-related pathways, such as MAPK, PI3K-AKT, and Ras pathways.

Our genetic evidence links FLT3LG, CX3CL1, KITLG, and TNFRSF9 to AAC risk, with KITLG and TNFRSF9 emerging as potential candidates for future studies. Experimental validation confirmed elevated FLT3LG and TNFRSF9 mRNA in calcified model. These results may provide the evidence to support the role of circulating inflammatory factors in the pathogenesis of AAC. However, larger-scale GWAS, basic research and clinical studies are needed to assess these potential causal associations.