Integrative genome-wide association studies, proteome-wide Mendelian randomization, and single-cell RNA sequencing identify interleukin-6 receptor protein as a therapeutic target in aortic aneurysm

Abstract

Aortic aneurysm (AA) is a genetic cardiovascular disease marked by progressive weakening and dilation of the aortic wall, often resulting in high mortality if untreated. Early diagnosis and prevention remain challenging. This study integrated genome-wide association studies (GWAS), proteome-wide Mendelian randomization (PW-MR), and single-cell RNA sequencing data from large-scale cohorts (FinnGen, deCODE Genetics, and UK Biobank Pharma Proteomics Project) to identify new biomarkers and therapeutic targets for AA. Analyzing genetic data from 8125 AA patients and 381,977 controls, we identified four significant loci (ADAMTS8, PLCE1, NOC3L, and SPSB1). PW-MR highlighted numerous plasma proteins, with interleukin-6 receptor (IL6R) showing strong association and colocalization in both deCODE and UK Biobank Pharma Proteomics Project (UKB-PPP) datasets. Multi-trait colocalization analysis supports IL6R's role, suggesting that drugs targeting IL6R, such as tocilizumab, may benefit AA treatment, though potential side effects warrant consideration. Single-cell analysis indicated that macrophages are crucial in AA progression, particularly through the IL6R-mediated inflammatory response. These findings emphasize IL6R as a potential target for early intervention and AA prevention. By integrating genetic associations, proteomic evidence, and single-cell insights, this study offers new strategies for identifying biomarkers, understanding disease mechanisms, and developing targeted therapies for aortic aneurysm.

Keywords: Aortic aneurysm; Genome-wide association studies; Proteome-wide Mendelian randomization.