Discovery of genetic risk factors for diverticulosis and diverticulitis

多达50%的60岁以上的人受到憩室病的影响，其中10%到25%的患者进展为憩室炎或出血。大约15%的憩室炎病例会出现严重的并发症，如脓肿、穿孔和急性出血，每年死亡率为2.5/100,000。在过去的几十年里，憩室病的发病率大幅增加。由于其高患病率和相关的并发症，憩室病在直接和间接成本方面是第五大最重要的胃肠道疾病。在瑞典的一项双胞胎研究中，憩室病的遗传度估计为~42%。丹麦一项以人群为基础的流行病学研究证实了这一高遗传率估计为53%。尽管在该病的病因学中存在这种强有力的、公认的遗传成分，但到目前为止，还没有对该病进行系统的或全基因组的遗传学研究。该项目建议对每1,700名憩室病、憩室炎和无憩室对照患者进行首次全基因组相关性研究，并进行适当的验证实验。我们期望通过对比对照组与憩室病、憩室炎与憩室病的配对关联分析，确定不同的肠壁完整性/动力和肠屏障功能的危险部位。这项建议使用D-A-CH机制，将德国和奥地利群体的大型和互补的患者队列和现有的基因资源(总共15,000名患者和2,300名现有的Gwas数据)聚集在一起。只有通过DFG和FWF这两个机构的患者资源和资金选择的这种组合才能使实验具有竞争力。纳入德国国家队列的两个中心和一个在憩室和肠道运动方面拥有强大功能专业知识的小组，为基于人群的综合风险模型的未来发展和将风险基因发现转化为新的病理生理学见解的机械性后续研究提供了基础。鉴于双胞胎和群体分析中确定的憩室病的可遗传成分，以及完全缺乏先前的研究，强有力的基因发现对其遗传疾病病因产生更深层次理解的机会非常高。我们期望憩室病和憩室炎有不同的病因途径。两者都将为这些常见疾病提供令人兴奋的新病因学见解和新的预防和治疗选择。

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.