Identification of Specific Immune Responses in African American Female Patients with Hidradenitis Suppurativa

Project Summary Hidradenitis suppurativa (HS) is a multifactorial chronic, debilitating, inflammatory skin disorder characterized by painful nodules, abscesses, sinus tracts, and scar formation in intertriginous skin. Most HS patients experience low quality of life likely due to the associated pain, disease severity, comorbidity conditions, and psychological discomfort. HS affects all races; however, sex and racial disparities exist with a female to male ratio about 3:1 and increased prevalence, severity, and dermatologic care in African American and Hispanic/Latino patients compared to White patients. Despite these differences, contributing factors to these disparities in HS are largely understudied. Although multiple studies have provided evidence of genetic contribution to HS, only one genome-wide association study of HS susceptibility has been published, creating a gap in our knowledge of the pathogenesis of HS. Our main hypotheses are as follows: germline variation contributes to HS risk in African American, Hispanic/Latino, and White patients; ancestral differences in genetic risk loci likely account for the racial disparity in HS risk; and sex-specific genetic risk loci partially influence the sex disparity in HS. We will use whole-genome sequencing (WGS) to comprehensively assess the associations of rare and common genetic variants across the genome with HS. We will leverage data from our unique cohorts and other existing genetic resources including the All of Us WGS data to test our hypothesis through the following specific aims. In Aim 1, we will perform WGS analysis of HS in African American, Hispanic/Latino, and White individuals via single-variant and rare-variant burden association tests for each population. We will determine the effect of genetic ancestries on HS risk and identify the variation in regional chromosomal ancestries associated with HS in admixed individuals (African Americans and Hispanic/Latino Americans) via admixture mapping. In Aim 2 we will conduct trans-ethnic meta- analyses of WGS data to identify both shared and population-specific genetic risk loci and determine whether HS-associated variants are shared between females and males or sex specific. In Aim 3, we will seek to identify cell-specific immune related genetic loci, and through comprehensive multi-omics analysis identify functionally relevant variants to be validated mechanistically. Successful completion of this proposal will provide insights into the genetic contributions to risk of HS, including mechanistic exploration of the genes identified that will lead to the development of new therapeutic targets and treatments in HS.