Research Project
10203567
PROJECT SUMMARY Chronic wounds are an epidemic afflicting several million people in the United States, and many million more worldwide. The elderly, the obese and those with diabetes have much higher incidence of chronic wounds, and the proportion of the population that fall into these categories is rising. Chronic wounds are associated with considerable reductions in quality of life, including increased rates of depression and mortality, among others. The expansion of the chronic wound epidemic is also reflected in rapidly rising medical costs. The non- healing nature of these wounds is heavily influenced by microbial infection, and multiple bacterial species are commonly found to simultaneously occur in wounds as microbial communities. A recent study provided evidence that one's genetics shape the bacterial species that inhabit their chronic wounds and these species were consequential to healing rates. Recognizing the biomedical importance of understanding this relationship, the specific aims of the project are to: 1) Identify patient genomic loci associated with chronic wound microbiome characteristics; 2) Establish the feasibility of predictive modeling for chronic wound infections; and, 3) Functionally validate associated loci. The study design consists of comparing patients' chronic wound microbiomes to their genomes through a microbiome-genome wide association study. The design includes a discovery cohort of greater than 1,000 samples, regional imputation around lead SNPs and Bayesian fine-mapping to identify credible sets including likely causal variants. Based on results of association studies, specific genomic regions will be used to build the first predictive models for bacterial species occurrence in chronic wounds; it is anticipated that such models will eventually find application in predictive and therapeutic medicine. Model development will be accomplished by using the Bayesian credible sets of SNPs from associated regions to inform latent variables in a structural equation modeling framework. An independent validation cohort of greater than 250 samples will be used to assess the predictive power of these models. Also, wet lab functional validation experiments of SNPs most likely to be causal are expected to yield new mechanistic insights about host-microbe interactions consequential to chronic wounds. The long-term goal of this work is to leverage individual genetics to combat chronic wounds and improve public health outcomes.
