Evaluating Genetic Risk For Keloids in African Ancestry Individuals

 描述(由申请人提供) 瘢痕疙瘩是一种良性纤维性皮肤肿瘤，在伤口长期愈合过程中形成。瘢痕疙瘩的特点是对伤害的反应夸张，非洲人和非非洲人之间的患病率存在差异。瘢痕疙瘩发生在约1/30的非洲裔美国人(AAs)中，其风险是欧洲裔美国人(EAs)的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。有几项研究试图确定瘢痕疙瘩的基因，但几乎没有发现遗传风险因素。最近在日本人群的全基因组关联研究中发现，3个区域(1q41、3q22.3-23、15q21.3)上的4个单核苷酸多态(SNPs)与瘢痕疙瘩风险相关。1q41和15q21.3的SNP在中国队列中得到验证，支持这些区域在东亚人的瘢痕疙瘩风险中所起的作用。由于再生障碍性关节炎中瘢痕疙瘩的高患病率，以及有证据表明瘢痕疙瘩是可遗传的，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有关。我们在chr15q21.2-22.3处观察到了与瘢痕疙瘩风险相关的祖先的强有力证据，其中包括NEDD4基因，这是一个先前与瘢痕疙瘩有关的基因。然而，最强烈的关联是在附近的一个基因MYO1E中。对MYO1E表达的评估显示，与正常瘢痕组织相比，瘢痕疙瘩成纤维细胞中MYO1E的表达增加。我们对该区域的分析表明，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。这项研究是第一次将这一区域与AAS中的瘢痕疙瘩联系在一起；然而，目前尚不清楚该信号来自该区域的单个还是多个致病变异。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：目的1.通过对chr15q21.2-22.3中的基因重新测序并在一个独立的队列中验证，确定与瘢痕疙瘩相关的新变异体。使用250例瘢痕疙瘩病例和对照，我们将对位于chr15q21.2-22.3中的基因进行有针对性的重新测序，优先考虑：a)通过混合图谱确定，b)在瘢痕疙瘩成纤维细胞中显示与正常瘢痕成纤维细胞相比的表达变化，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个病例和750个对照)中测试300个已识别的变异，以进行关联。目的2.评估与瘢痕疙瘩形成相关的候选基因座或基因的生物学相关性。使用特征良好的瘢痕疙瘩和正常瘢痕成纤维细胞株，将对多达10个基因进行评估，看看它们的表达对培养的瘢痕疙瘩和正常表型有什么影响。这些基因将包括从混合作图和基因表达研究中获得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。我们提出了一种高效且经济高效的方法来精细定位和表征瘢痕疙瘩的遗传风险因素，利用强大的初步数据和现有队列中的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了解，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.