Discovery of genetic risk factors for diverticulosis and diverticulitis

高达50%的60岁以上的人受到憩室病的影响，其中10 - 25%的患者进展为憩室炎或出血。严重并发症如脓肿、穿孔和急性出血发生在约15%的憩室炎病例中，导致年死亡率为2.5/100，000。憩室病的发病率在过去的几十年中大幅增加。由于其高患病率和相关的并发症，憩室病代表了第五个最重要的胃肠道疾病的直接和间接成本。在瑞典的一项双胞胎研究中，憩室病的遗传率估计约为42%。丹麦的一项基于人群的流行病学研究证实了这一高遗传率估计为53%。尽管这种强大的和确定的遗传因素在疾病的病因学，没有系统的或全基因组的遗传研究已经在疾病中进行到现在。该项目建议使用每1,700例憩室病、憩室炎和无憩室对照患者以及适当的验证实验进行第一次全基因组关联研究。我们期望通过比较对照组与憩室病组以及憩室炎与憩室病组的成对关联分析，分别识别出肠壁完整性/运动性和肠屏障功能的不同风险位点。该提案使用D-A-CH机制将大型互补患者队列与德国和奥地利群体的现有基因型资源（总计15，000名患者和2，300名现有GWAS数据）汇集在一起。只有通过DFG和FWF这两个机构将患者资源和资金选择结合起来，才能实现竞争性实验。纳入德国国家队列的两个中心和一个在憩室病和肠动力方面具有强大功能专业知识的小组，为未来开发基于人群的综合风险模型和机制随访研究提供了条件，以将风险基因的发现转化为新的病理生理学见解。鉴于双胞胎和人群分析中确定的憩室病遗传成分以及完全缺乏以前的研究，强大的基因发现产生对其遗传疾病病因更深入了解的机会非常高。我们预期憩室病和憩室炎有不同的病因学途径。两者都将使人们对这些常见疾病的病因学和新的预防和治疗选择有令人兴奋的新见解。

Up to 50% of individuals over 60 years of age are affected by diverticulosis and 10 to 25% of these patients progress to develop diverticulitis or bleeding. Severe complications such as abscess, perforation and acute bleeding occur in approximately 15% of diverticulitis cases resulting in an annual mortality 2.5 per 100,000. The incidence of diverticular disease has increased substantially over the last decades. Due to its high prevalence and the associated complications, diverticular disease represents the 5th most important gastrointestinal disease in terms of direct and indirect cost. The heritability of diverticulosis was estimated at ~42% in a Swedish twin study. A Danish population-based epidemiological study confirmed this high heritability estimate at 53%. Despite this strong and established genetic component in the etiology of the disease, no systematic or genome-wide genetic studies have been performed in the disease up to now. This project proposes to perform the first genome-wide association study using each 1,700 patients with diverticulosis, diverticulitis and diverticular-free controls plus the appropriate validation experiments. We expect the identification of distinct risk loci for intestinal wall integrity / motility and intestinal barrier function from the pair-wise association analysis comparing controls vs. diverticulosis and diverticulitis vs. diverticulosis, respectively. This proposal uses the D-A-CH mechanism to bring together large and complementary patient cohorts and existing genotype resources of German and Austrian groups (in total 15,000 patients and 2,300 with existing GWAS data). Only this combination of the patient resources and funding options through the two agencies DFG and FWF enables a competitive experiment. Inclusion of two centers of the German National Cohort and a group with strong functional expertise in diverticulosis and intestinal motility provide for the future development of integrated, population-based risk models and for mechanistic follow-up studies to translate the risk genes findings into novel pathophysiological insights. Given the firmly established heritable component of diverticulosis from twin and population analyses and the complete lack of previous studies, the chances for robust gene discoveries to yield a deeper understanding of its genetic disease etiology are very high. We expect distinct etiological pathways for diverticular disease and diverticulitis. Both will allow exciting new insights into disease etiology and novel prevention and treatment options for these common disorders.