(WHS-P1.02) LINKING HUMAN GENETICS AND WOUND INFECTION WITH TRANSCRIPTOME-WIDE ASSOCIATIONS
Friday, May 17, 2024
10:30 AM – 11:30 AM East Coast USA Time
Introduction: Microbes are believed to be key contributors to wound chronicity, yet our understanding about the reasons for inter-patient variation in the species infecting chronic wounds remains unclear. Previous investigations reveal that human genetic variation may partially explain differences in infection and may have to do with how our genetic variation encodes variation in wound bed cellular phenotypes. Because the wound bed is comprised of multiple cell and tissue types, we conducted a microbiome transcriptome-wide association study to investigate how patient genetic variation determines tissue-specific expression and in turn relates to infection. Significant and repeatable gene expression associations may provide insights into the mechanistic details of chronic wound bacterial infection.
Methods: In a deidentified fashion, consenting patients provided buccal swabs and wound debridement samples. The buccal swabs were genotyped at ~660k loci, and chronic wound bacterial microbiota were characterized via 16S sequencing. Whole genome imputation was performed to increase genomic coverage and improve subsequent gene expression imputation. Single nucleotide polymorphisms (SNPs) were used to predict patients’ gene expression levels and splicing patterns for artery, blood, fibroblast, skeletal muscle, skin, subcutaneous fat, and nerve tissue. A balanced and race-stratified two-cohort design of 458 patients was used. Across tissues, there was an average of 12,217 expressed genes and 30,100 splice variants considered. The effect of these genes on transformed relative abundances of 68 bacterial species was evaluated. Results and
Conclusion: The genetically regulated expression of more than 200 differentially expressed genes and splice variants were found to be significantly associated with bacterial relative abundances and reproducible across both cohorts (Bonferroni corrected p<0.05). Fifty-six species had significantly associated genes (median number of significant associations per bacterium = 4.5; first quartile = 1; third quartile = 10). Notably, significant genes had roles in cell adhesion and attachment, cell migration, cytokinesis, cytoskeletal integrity, and cytoskeletal dynamics. Findings inform how individual genetic variation translates to differences in bacterial colonization of chronic wounds. Future work will focus on predictive value of SNPs and gene expression for specific infection types.