Genetic Etiology of Abdominal Hernia Susceptibility

腹疝是临床实践中最常诊断的疾病， 全世界每年进行两千万例疝修补手术。许多患者经历了严重的 术后并发症，包括慢性疼痛（6%）和疝复发（10%）。延误治疗 有肠嵌顿的风险，需要紧急疝修补手术，并与 有很大的死亡风险因为疝气的风险必须与 与其治疗相关，显然需要更好地了解疝的病因， 改善治疗选择。 我们进行了第一次大规模的疝气风险遗传研究，并在四个新的基因组中鉴定了非编码变异。 腹股沟疝是最常见的疝类型， 这些基因座中的基因（EFEMP1、WT 1、EBF2和ADAMTS6）在小鼠结缔组织中表达。在这里， 我们将通过鉴定其他腹疝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 体内分析，这些元件内的核苷酸变异如何导致其调节改变和疝 易感性通过将疝风险基因座中的特定遗传变异与其对基因调控的功能效应联系起来， 我们就可以开始了解导致疝气易感性的生物学机制。 我们的研究将通过确定疝亚型的遗传位点填补文献中的一个重要空白， 提供深入了解导致疝气发展的特定生物学机制。一种改进 对疝气形成机制的了解可以指导现代“精确医学” 这将导致预防性非手术治疗的疝治疗方法。

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.