Abstract
The investigation of new strategies to prevent acute viral respiratory infections(ARI) is essential for reducing the global disease burden. Genetic association studies are valuable in identifying the susceptibility risk factors for diseases, and genetic evidence can expedite drug approval. To date, few studies have been conducted to reveal the susceptibility risks of ARI and identify novel drug targets through multi-omics genetic association analysis. This study aimed to integrate traditional Chinese medicine(TCM) into ARI prevention by identifying novel susceptibility risk loci across multi-ancestry populations and screening potential traditional Chinese medicines targeting these loci. First, with influenza and coronavirus disease 2019(COVID-19) as examples, the data of proteomics, genomics, transcriptomics, DNA methylation, and RNA alternative splicing were integrated to screen the susceptibility risk loci for ARI in European, East Asian, and South Asian populations. The screening was conducted by proteome-wide Mendelian randomization, gene-based association analyses, transcriptome-wide association analyses, and SMR & HEIDI methods. Then, SNPnexus was used to analyze the conservation and biological functions of key susceptibility risk targets for ARI. The druggability of these targets was explored by druggability analysis and phenome-wide association analysis. Potential traditional Chinese medicines targeting the druggable key susceptibility risk loci were screened. RESULTS:: showed that COL15A1 was a key susceptibility risk locus for influenza in European populations. MAN1A2 and RAB1A were identified as key susceptibility risk loci for COVID-19 in East Asian populations, while PPIE, MFGE8, VWA2, FCER2, TREML2, BMP8B, U2AF1L4, and IGFLR1 were identified as key susceptibility risk loci for COVID-19 in South Asian populations. In European populations, ABO was a key susceptibility risk locus for COVID-19. The mutations in these loci were highly deleterious and pathogenic. These loci mainly regulated the signaling pathways in the immune system, interleukin family, and some regulated the coagulation cascade, platelet activation, signaling, and aggregation. COL15A1, MAN1A2, RAB1A, PPIE, MFGE8, VWA2, FCER2, TREML2, BMP8B, and ABO were potential preventive drug targets for ARI. TCM with the effects of replenishing Qi and supplementing essence had the potential of targeting the key susceptibility risk loci. This study presents a new research idea for identifying susceptibility risk loci of ARI and a novel prevention strategy of ARI with TCM.
Published Version
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