Genetic Etiology of Abdominal Hernia Susceptibility

腹部疝气易感性的遗传病因学

• 批准号: 10006003
• 负责人: Nadav Ahituv
• 金额: $ 59.27万
• 依托单位: KAISER FOUNDATION RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006003
• 关键词: Address; Adult; Affect; Aging; Alleles; Biological; Biological Assay; CRISPR/Cas technology; ChIP-seq; Chromatin; Collaborations; Congenital exomphalos; Connective Tissue; Development; Diagnosis; Disease; Elements; Emergency Situation; Enhancers; Etiology; Family Study; Femoral Hernia; First Degree Relative; Foundations; Gene Expression Regulation; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic study; Genomics; Health; Health Care Costs; Hernia; Hernia of abdominal cavity; Human; Human Genetics; Imprisonment; In Vitro; Individual; Inguinal Hernia; Intestines; Lead; Link; Linkage Disequilibrium; Literature; Methods; Modernization; Mus; Mutation; Nucleic Acid Regulatory Sequences; Nucleotides; Operative Surgical Procedures; Patients; Phenotype; Predisposition; Procedures; Public Health; Recurrence; Regulation; Regulator Genes; Regulatory Element; Risk; Role; Series; Single Nucleotide Polymorphism; Surgical complication; Testing; Transposase; Untranslated RNA; Variant; Ventral Hernia; WT1 gene; Woman; chronic pain; clinical phenotype; clinical practice; cohort; common treatment; cost; experience; experimental study; genetic analysis; genetic epidemiology; genetic risk factor; genetic variant; genomic locus; improved; in vivo; innovation; insight; men; mortality risk; multidisciplinary; novel; precision medicine; repaired; risk variant; tool; trait

Abdominal hernias are some of the most frequently diagnosed conditions in clinical practice, with more than twenty million hernia repair surgeries performed annually around the world. Many patients experience serious post-surgical complications, including chronic pain (6%) and hernia recurrence (10%). Delaying treatment carries the risk of bowel incarceration, which requires emergency hernia repair surgery and is associated with a substantial risk of mortality. Because the risks associated with hernias must be balanced against the risks associated with their treatment, there is a clear need for a better understanding of hernia etiology and improved treatment options. We conducted the first large-scale genetic study of hernia risk and identified noncoding variants at four novel genetic loci underlying the risk of inguinal hernia—the most common type of hernia—and showed that four genes in these loci (EFEMP1, WT1, EBF2, and ADAMTS6) are expressed in mouse connective tissue. Here, we will extend our findings by identifying genetic risk loci underlying additional abdominal hernia subtypes, locating and characterizing regulatory elements within these loci, and demonstrating, using both in vitro and in vivo assays, how nucleotide variation within these elements can lead to their altered regulation and hernia susceptibility. By linking specific genetic variants in hernia risk loci to their functional effect on gene regulation, we can begin to understand the biological mechanisms that lead to hernia susceptibility. Our study will fill an important gap in the literature by identifying genetic loci underlying hernia subtypes and provide insights into the specific biological mechanisms that lead to hernia development. An improved understanding of the mechanisms through which hernias develop can guide a modern `precision medicine' approach for hernia treatment that will lead to preventative non-surgical treatments.

腹疝是临床实践中最常诊断的疾病之一，超过 全世界每年进行两千万例疝气修复手术。许多患者经历了严重的 术后并发症，包括慢性疼痛（6%）和疝气复发（10%）。延误治疗 存在肠嵌顿的风险，需要紧急疝气修复手术，并且与 巨大的死亡风险。因为与疝气相关的风险必须与以下风险进行权衡 与其治疗相关，显然需要更好地了解疝气的病因和 改进的治疗方案。 我们进行了首次大规模的疝气风险基因研究，并在四个新的基因中发现了非编码变异。 腹股沟疝（最常见的疝气类型）风险的遗传位点，并表明四个 这些基因座（EFEMP1、WT1、EBF2 和 ADAMTS6）中的基因在小鼠结缔组织中表达。这里， 我们将通过识别其他腹部疝气亚型的遗传风险位点来扩展我们的发现， 定位和表征这些基因座内的调控元件，并使用体外和体内证明 体内测定，这些元件内的核苷酸变异如何导致其调节改变和疝气 易感性。通过将疝气风险位点中的特定遗传变异与其对基因调控的功能影响联系起来， 我们可以开始了解导致疝气易感性的生物学机制。 我们的研究将通过识别疝气亚型和潜在的遗传位点来填补文献中的一个重要空白。 提供对导致疝气发展的特定生物学机制的见解。一个改进的 了解疝气发生的机制可以指导现代“精准医学” 疝气治疗方法将导致预防性非手术治疗。