Repair of adult tissues involves a complex interplay of several key cell lineages and inevitably leads to formation of a fibrotic collagenous scar, whereas embryonic tissues heal perfectly without any resulting scar deposition. This dramatic difference in repair efficiency between embryonic versus neonatal/adult tissues has been instrumental is guiding us towards potential causes of scarring. Indeed, we now believe that one major driver of scarring is the wound inflammatory response which doesn't initiate until a transition period in foetal development which, in turn, coincides with the developmental onset of tissue scarring. This insight has led us towards further mechanistic cell and molecular studies in model organisms, such as mouse and zebrafish, which help us better understand the scarring process and how one might modulate the wound inflammatory response in order to improve or prevent scarring.
Whilst these approaches, motivated by comparing embryonic versus adult healing, have been fruitful, it is clear that scarring is a complex, multifactorial response likely driven by a number of interacting mechanisms. We would like to use a conceptually similar comparative approach to gain further insights into the fundamental cell and molecular mechanisms of scarring by analysing differences in degree of scarring, not between embryo and adult, but rather across human adult populations since we know there is a range of “scarring phenotypes” from “minimal scarrer” to keloid scarring individuals. This use of human phenotypic variation in a population based, using an integrative approach: genetic variation (genetic association, genomewide association studies – GWAS), gene silencing (methylation, epigenetic association studies - EWAS), gene expression (transcriptomics, transcriptome-wide association studies - TWAS), has the potential not only to yield gene variant correlates of scarring, but also to point towards specific biological contributions to wound healing, both at causative and regulatory and levels.
The use of natural human experiments (e.g. Bacillus Calmette–Guérin (BCG) vaccination wound healing, Caesarean section (C-section) wound scarring and examples of human disease related fibroses) has never before been used for identification of scarring genes, even though the approach has proven to be powerful for discovering genes associated elsewhere with a wide variety of complex health outcomes (www.ebi.ac.uk/gwas/).
Fibrosis and scarring are closely related processes that involve the formation of excess fibrous connective tissue in organs or tissues, typically in response to injury or chronic inflammation. Fibrosis is defined as the accumulation of excess extracellular matrix components, particularly collagen, in and around damaged or inflamed tissues. Scarring is the end result of this process, where fibrous tissue replaces normal, functional tissue. In early stages, fibrosis may be reversible if the underlying cause is treated. However, advanced fibrosis and scarring are often permanent and irreversible. Fibrosis can occur in virtually any organ, including the lungs (pulmonary fibrosis), liver (cirrhosis), kidneys, heart, and skin. Fibrosis can be caused by various factors, including chronic inflammation, autoimmune diseases, infections, toxins, and radiation exposure. In some cases, the cause is unknown (idiopathic).
Furthermore, alongside a growing number of catalogues charting the results of human genetic association studies for health outcomes and intermediates there are tools able to consider (in frameworks of causal analysis) the existence of potentially causal and modifiable relationships between exposures of interest (e.g. inflammation, differential wound repair or scar) and health outcomes (e.g. wound healing, recovery, and disease).
Using human genetic data to help explore the potential of biological pathways contributing to health and disease in applied epidemiological designs is an approach that we have refined and developed and is an integrated approach to health research that has yielded important clinically relevant insights but has also indicated opportunities (e.g. associated signalling pathways for targeting) to unify basic science approaches with human population-based health data.
Understanding fibrosis and scarring is crucial for developing effective treatments for a wide range of chronic diseases. While advanced fibrosis remains a challenging medical problem, early intervention and new therapeutic approaches offer hope for improved outcomes.
In this study, we will use several strategies:
• We will investigate a more comprehensive number of variants in genes, using the topmed reference panel, given its diverse sample population from both Europeans and non-Europeans, with a total of 97,256 high-coverage genomes, to help identifying variants responsible for scarring and fibrosis.
• With a focus on those that are not that frequent in the population (frequency under 1%), we will investigate whole genome and exome sequencing variants, to help identifying variants responsible for scarring and fibrosis phenotypes.
• We will investigate regulation pathways of scarring and fibrosis phenotypes using the information provided by epigenetic and expression arrays.