Establishing the contributions of monogenic etiologies to hidradenitis suppurativapathogenesis

Pathological inflammation is a source of substantial morbidity underlying clinically diverse diseases that are marked by irreversible tissue damage. Hidradenitis suppurativa (HS) is a prevalent inflammatory skin disease that shares features with these other disorders, including repeated bouts of unprovoked inflammation causing pain, hyperplasia, aberrant healing, and fibrosis. HS is debilitating, difficult to manage, and has many unmet medical needs. Notably, HS is in dire need of new treatments, with the lone FDA-approved drug failing to illicit a clinical response in ~35% of patients. Human genetic studies help to identify and prioritize drug targets and improve drug development success rates. However, relatively few human genetic studies have been performed for HS and these have been conducted in small cohorts. Furthermore, although African Americans are at three times the risk of HS, they have been excluded from those studies. Importantly, no GWAS or exome wide studies have been published for HS. To date, four monogenic etiologies have been described for HS, one of which implicates an inborn error of immunity (IEI). IEI are single-gene disorders comprising a class of nearly 500 extensively studied genes that cause improper function of the immune system, resulting in pathological inflammation, autoimmunity, and/or increased susceptibility to infection. IEI underlie a range of phenotypes that span multi-organ dysfunction to more focal outcomes, and some include HS and/or clinical features that overlap with HS. There is immunological and clinical overlap between HS and IEI, and yet IEI have not been rigorously investigated with HS genetic studies. Furthermore, IEI contribute to the genetic architecture of prevalent multifactorial disorders and can have important clinical implications for the patients that harbor them by presenting opportunities for targeted interventions and individualized screening. As was found to be the case for other inflammatory diseases such as inflammatory bowel disease and atopic dermatitis, we hypothesize IEI are important components of HS pathogenesis. Specifically, we will first test the hypothesis that some people with an HS diagnosis have an IEI by generating exome data and performing a diagnostic analysis followed by validation of identified mutations. Next, we will test the hypothesis that IEI pathways are a component of HS pathogenesis. We will use burden testing with exome data and genome-wide association studies to identify genes, pathways, and cell types that are relevant to HS and then determine the prevalence of IEI genes and pathways in HS. Our approach is to leverage large HS cohorts with ancestral diversity that we have built with clinical collaborators who specialize in HS treatment and industry partners running HS clinical trials. The successful completion of these studies will help to identify subsets of HS research participants with IEI (some of which will have immediate clinical relevance), will determine the prevalence of IEI in HS, and will identify IEI pathways that are relevant to HS patients without an IEI. Together these results will provide the rationale for drug repurposing in HS and may also help to improve strategies for managing pathogenic inflammation.