Keloids are benign fibrotic dermal tumors that form during prolonged wound healing. Keloids are characterized by an exaggerated response to injury and a prevalence disparity between African and non-African populations. Keloids occur in ~1/30 African Americans (AAs) with a 20-fold higher risk in AAs than in European Americans (EAs). Evidence supporting a genetic basis for keloids includes familial forms of keloids and racial and ethnic disparities in keloid prevalence. Several studies have attempted to identify keloid genes, but few genetic risk factors have been found. In a recent genome-wide association study (GWAS) in a Japanese population, four single nucleotide polymorphisms (SNPs) in three regions (1q41, 3q22.3-23, 15q21.3) associated with keloid risk. SNPs in 1q41 and 15q21.3 were validated in a Chinese cohort, supporting a role of these regions in keloid risk among East Asians. Due to the high prevalence of keloids among AA and evidence that keloids are heritable, we conducted admixture mapping to determine if local ancestry associated with keloid risk. We observed strong evidence of ancestry associating with keloid risk at chr15q21.2-22.3 that included NEDD4, a gene previously implicated with keloids. However, the strongest associations were in a nearby gene, MYO1E. Evaluation of MYO1E expression showed increased expression in fibroblasts from keloid relative to normal scar tissue. Our analyses of the region showed multiple genes associated with keloid risk that have associated with other fibroproliferative conditions. This study is the frst implicating this region with keloids in AAs; however, it is unclear whether the signal is coming from a single or multiple causative variants in the region. We hypothesize that genetic determinants of keloids are located in chr15q21.2-22.3.
Our Specific Aims are to:
Aim 1. Identify novel variants associated with keloids by resequencing genes in chr15q21.2-22.3 and validate in an independent cohort. Using 250 keloid cases and controls we will do targeted resequencing of genes located in chr15q21.2-22.3 prioritizing those: a) identified using admixture mapping, b) showing altered expression in keloid versus normal scar fibroblasts, or c) associated with a fibroproliferative disorder. We will then test 300 identified variants in an independent Yoruban cohort (750 cases and 750 controls) for association.
Aim 2. Evaluate the biological relevance of candidate keloid loci or genes associated with keloid formation. Using well-characterized fibroblast strains from keloids and normal scars up to ten genes will be evaluated to see what effects manipulation of their expression has on keloid and normal phenotypes in culture. These genes will include those with the strongest evidence for association with keloids from admixture mapping and gene expression studies, as well as additional genes validated in Aim 1. We propose an efficient and cost-effective approach to fine map and characterize genetic risk factors for keloids, taking advantage of strong preliminary data and DNA and fibroblasts from existing cohorts. Our study will increase understanding of the mechanisms of AA keloid formation and aid in identifying novel therapeutic approaches.
Keloid formation, a form of abnormal wound healing, is a major public health problem that disproportionately impacts African Americans and has no satisfactory treatment. Despite federal research agencies, including the NIAMS, recognizing keloids as a research priority, the literature about the genetics of keloids is meager. This proposed study that includes leveraging strong preliminary data, targeted next-generation resequencing experiments, functional tests, and replication of study findings will make a significant contribution to elucidating the genetic bases of keloids and may suggest effective methods of prevention and treatment.
|Hellwege, Jacklyn N; Russell, Shirley B; Williams, Scott M et al. (2018) Gene-based evaluation of low-frequency variation and genetically-predicted gene expression impacting risk of keloid formation. Ann Hum Genet 82:206-215|
|Hellwege, Jacklyn N; Torstenson, Eric S; Russell, Shirley B et al. (2017) Evidence of selection as a cause for racial disparities in fibroproliferative disease. PLoS One 12:e0182791|