Evaluating Genetic Risk For Keloids in African Ancestry Individuals

 描述（由申请人提供） 瘢痕疙瘩是在长期伤口愈合过程中形成的良性纤维化皮肤肿瘤。瘢痕疙瘩的特点是对伤害的反应过度，非洲和非非洲人群之间的患病率差异。瘢痕疙瘩发生在约1/30的非洲裔美国人（AAs）中，AAs的风险比欧洲裔美国人（EAs）高20倍。支持瘢痕疙瘩遗传基础的证据包括瘢痕疙瘩的家族形式和瘢痕疙瘩患病率的种族和民族差异。最近的一项日本人群全基因组关联研究（GWAS）发现，1 q41，3q22.3-23，15q21.3三个区域的四个单核苷酸多态性（SNP）与瘢痕疙瘩的发病风险相关。1 q41和15q21.3中的SNP在中国队列中得到验证，支持这些区域在东亚人瘢痕疙瘩风险中的作用。由于瘢痕疙瘩在AA中的高患病率以及瘢痕疙瘩具有遗传性的证据，我们进行了混合作图以确定当地血统是否与瘢痕疙瘩风险相关。我们在chr15q21.2-22.3处观察到与瘢痕疙瘩风险相关的祖先的强有力证据，其中包括NEDD 4，一个先前与瘢痕疙瘩有关的基因。然而，最强的关联是在附近的基因MYO 1 E中。MYO 1 E表达的评估显示，相对于正常瘢痕组织，瘢痕疙瘩成纤维细胞中MYO 1 E的表达增加。我们对该区域的分析显示，与瘢痕疙瘩风险相关的多个基因与其他纤维增生性疾病相关。这项研究是第一次暗示该区域与AAs中的瘢痕疙瘩有关;然而，目前还不清楚该信号是来自该区域的单个还是多个致病变体。我们推测瘢痕疙瘩的遗传决定因素位于chr15q21.2-22.3。我们的具体目标是：目标1。通过chr15q21.2-22.3基因重测序鉴定与瘢痕疙瘩相关的新变异，并在独立队列中进行验证。使用250例瘢痕疙瘩病例和对照，我们将对位于chr 15 q21.2 -22.3的基因进行靶向重测序，优先考虑：a）使用混合作图鉴定，B）显示瘢痕疙瘩与正常瘢痕成纤维细胞表达改变，或c）与纤维增生性疾病相关。然后，我们将在一个独立的约鲁班队列（750例病例和750例对照）中测试300个已识别的变异。目标2.评价瘢痕疙瘩形成相关基因或候选瘢痕疙瘩基因座的生物学相关性。使用来自瘢痕疙瘩和正常瘢痕的良好表征的成纤维细胞株，将评估多达10个基因，以观察操纵它们的表达对培养物中的瘢痕疙瘩和正常表型的影响。这些基因将包括来自混合物定位和基因表达研究的与瘢痕疙瘩相关的最有力证据，以及在Aim 1中验证的其他基因。我们提出了一种有效且具有成本效益的方法来精细绘制和表征瘢痕疙瘩的遗传风险因素，利用现有队列的强有力的初步数据以及DNA和成纤维细胞。我们的研究将增加对AA瘢痕疙瘩形成机制的理解，并有助于确定新的治疗方法。

 DESCRIPTION (provided by applicant) 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.