Abstract
The clinical importance of microbiomes to the chronicity of wounds is widely appreciated, yet little is understood about patient-specific processes shaping wound microbiome composition. Here, a two-cohort microbiome-genome wide association study is presented through which patient genomic loci associated with chronic wound microbiome diversity were identified. Further investigation revealed that alternative TLN2 and ZNF521 genotypes explained significant inter-patient variation in relative abundance of two key pathogens, Pseudomonas aeruginosa and Staphylococcus epidermidis. Wound diversity was lowest in Pseudomonas aeruginosa infected wounds, and decreasing wound diversity had a significant negative linear relationship with healing rate. In addition to microbiome characteristics, age, diabetic status, and genetic ancestry all significantly influenced healing. Using structural equation modeling to identify common variance among SNPs, six loci were sufficient to explain 53% of variation in wound microbiome diversity, which was a 10% increase over traditional multiple regression. Focusing on TLN2, genotype at rs8031916 explained expression differences of alternative transcripts that differ in inclusion of important focal adhesion binding domains. Such differences are hypothesized to relate to wound microbiomes and healing through effects on bacterial exploitation of focal adhesions and/or cellular migration. Related, other associated loci were functionally enriched, often with roles in cytoskeletal dynamics. This study, being the first to identify patient genetic determinants for wound microbiomes and healing, implicates genetic variation determining cellular adhesion phenotypes as important drivers of infection type. The identification of predictive biomarkers for chronic wound microbiomes may serve as risk factors and guide treatment by informing patient-specific tendencies of infection.
Highlights
Chronic wounds, defined as wounds failing to show signs of healing within three weeks, are a significant and increasing burden on the health care system, resulting in several billion dollars in annual health care costs in the United States alone [1]
Non-healing, wounds represent a costly burden to patients, and bacterial infection of wounds is an important driver of chronicity
Genetic variation in the TLN2 and Zinc Finger 521 (ZNF521) genes was found to be associated with both the number of bacteria observed in wounds and the abundance of common pathogens
Summary
Chronic wounds, defined as wounds failing to show signs of healing within three weeks, are a significant and increasing burden on the health care system, resulting in several billion dollars in annual health care costs in the United States alone [1]. Chronic wound microbiomes can be dynamic through time [11] with bacterial diversity increasing at resolution of infection [12], and stable microbial communities being correlated with delayed healing [4, 12]. Despite these findings, the clinical importance of many taxa and the diversity of community compositions observed among wound infections remains unclear
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