Characterisation of gene-environment interactions in acne vulgaris

Introduction: Acne is the 8th most prevalent disease in the world and peaks in prevalence in adolescence when it impacts confidence, academic performance and quality of life. Understanding the key components of acne development is essential for developing effective treatment strategies. Acne arises due to a complex interplay between a genetic predisposition to follicular hyperkeratinization, or blocked pores, and inflammation driven by the bacteria Cutibacterium acnes, hormones and other environmental factors. Challenge the project addresses: Genome-wide association studies (GWAS) have uncovered the genetic basis of acne vulgaris, which indicate that cellular programs governing the maintenance of hair follicle and skin formation, are central to its development. Acne has been linked to environmental triggers such as hormonal and dietary factors in epidemiological studies, where large populations have been surveyed. However, clear causality and mechanisms that explain why certain exposures are linked to acne remain lacking. Therefore, treatment strategies aimed at targeting modifiable exposures are limited and lack evidence-base. Our project aims to leverage insights from our recent genome-wide association meta-analysis of acne, which has identified genes that are implicated in acne, to identify causal circulating factors using Mendelian randomisation (MR), an analytical approach which uses understanding of genetic variants to identify causes of disease. We will then identify pathogenic cell types in which genetic mechanisms of acne are enriched and generate an lab-based in vitro model system for acne in which can be used to validate the impact of genetic and environmental perturbations. Aim: To characterise gene-environment interactions in acne vulgaris. Objectives: Identification of causal serum biomarkers of acne vulgaris using bidirectional Mendelian Randomisation (MR) approaches Identification of cell-type specific genetic perturbations through the integration of GWAS and single-cell RNA sequencing data Generation of an in vitro model of acne informed by identified genetic and environmental factors, which will provide both functional validation and a model system for future studies. Potential applications and benefits: This approach will add both specificity and detail to our understanding of both genetics as well as environmental factors in acne pathogenesis. Identification of circulating factors has two benefits; firstly, these circulating factors could represent new treatment targets. Secondly, new circulating factors or 'biomarkers' could be used clinically to help distinguish sub-types of acne vulgaris, which could be treated using different approaches. And finally, we aim to leverage our knowledge of genetic and environmental factors to develop an in vitro culture model of acne, which will functionally validate these genetic discoveries as well as provide a lab-based model system for future studies in acne vulgaris, which is currently lacking