Genetic Etiology of Abdominal Hernia Susceptibility

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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.