Evaluating Genetic Risk For Keloids in African Ancestry Individuals

评估非洲血统个体的瘢痕疙瘩遗传风险

• 批准号: 9353290
• 负责人: Digna R Velez Edwards
• 金额: $ 13.9万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353290
• 关键词: 1q41; Address; African; African American; American; Asians; Benign; Biological; CCNB2 gene; Cell Culture Techniques; Chinese People; Cicatrix; Code; DNA; DNA Resequencing; Data; Dermal Neoplasm; Disease; European; Evaluation; Event; Fibroblasts; Frequencies; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Risk; Genotype; Goals; Heritability; High Prevalence; Individual; Japanese Population; Keloid; Link; Literature; Logistic Regressions; Maps; Methods; Mutation; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Phenotype; Population; Predisposition; Prevalence; Prevention; Public Health; Research; Research Priority; Risk; Role; Sample Size; Signal Transduction; Single Nucleotide Polymorphism; Somatic Mutation; Targeted Resequencing; Testing; Tissues; Validation; Variant; Work; Wound Healing; admixture mapping; base; case control; cohort; cost effective; ethnic difference; experimental study; gene discovery; genetic risk factor; genome wide association study; high risk; next generation; novel; novel therapeutic intervention; public health relevance; racial and ethnic disparities; racial difference; racial health disparity; repository; response to injury; skin disorder

 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.

 描述（由申请人提供） 疤痕疙瘩是良性纤维化真皮肿瘤，在长期伤口愈合过程中形成。疤痕疙瘩的特点是对损伤的过度反应以及非洲和非非洲人群之间的患病率差异。约 1/30 的非洲裔美国人 (AA) 会出现瘢痕疙瘩，其中 AA 的风险比欧洲裔美国人 (EA) 高 20 倍。支持疤痕疙瘩遗传基础的证据包括疤痕疙瘩的家族形式以及疤痕疙瘩患病率的种族和民族差异。一些研究试图鉴定疤痕疙瘩基因，但很少发现遗传风险因素。在最近一项针对日本人群的全基因组关联研究 (GWAS) 中，三个区域（1q41、3q22.3-23、15q21.3）的四个单核苷酸多态性 (SNP) 与瘢痕疙瘩风险相关。 1q41 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 AA 中疤痕疙瘩的患病率很高，而且有证据表明疤痕疙瘩是可遗传的，我们进行了混合图谱分析，以确定当地血统是否与疤痕疙瘩风险相关。我们在 chr15q21.2-22.3 处观察到了与疤痕疙瘩风险相关的血统证据，其中包括 NEDD4（一种先前与疤痕疙瘩有关的基因）。然而，最强的关联是附近的基因 MYO1E。 MYO1E 表达的评估显示，与正常疤痕组织相比，瘢痕疙瘩成纤维细胞中的表达增加。我们对该区域的分析显示，多个与疤痕疙瘩风险相关的基因也与其他纤维增殖性疾病相关。这项研究首次将该区域与 AA 中的瘢痕疙瘩联系起来；然而，尚不清楚该信号是来自该区域的单个还是多个致病变异。我们假设疤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. 通过对 chr15q21.2-22.3 中的基因进行重新测序来识别与疤痕疙瘩相关的新变异，并在独立队列中进行验证。使用 250 个疤痕疙瘩病例和对照，我们将对位于 chr15q21.2-22.3 的基因进行有针对性的重测序，优先考虑以下基因：a) 使用混合图谱识别，b) 显示疤痕疙瘩与正常疤痕成纤维细胞相比的表达改变，或 c) 与纤维增殖性疾病相关。然后，我们将在一个独立的约鲁巴队列（750 个病例和 750 个对照）中测试 300 个已识别的变异是否存在关联。目标 2. 评估与瘢痕疙瘩形成相关的候选瘢痕疙瘩基因座或基因的生物学相关性。使用来自疤痕疙瘩和正常疤痕的充分表征的成纤维细胞菌株，将评估多达十个基因，以了解其表达操作对培养中的疤痕疙瘩和正常表型有何影响。这些基因将包括那些从混合图谱和基因表达研究中获得与疤痕疙瘩相关的最有力证据的基因，以及在目标 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，利用强大的初步数据以及来自现有队列的 DNA 和成纤维细胞，对疤痕疙瘩的遗传风险因素进行精细图谱和表征。我们的研究将增进对 AA 瘢痕疙瘩形成机制的了解，并有助于确定新的治疗方法。