Discovery of genetic risk factors for diverticulosis and diverticulitis

60岁以上人群中高达50%患有憩室病，其中10%至25%的患者发展为憩室炎或出血。严重的并发症，如脓肿、穿孔和急性出血发生在大约15%的憩室炎病例中，导致每年死亡率为每10万人2.5人。憩室病的发病率在过去几十年里显著增加。由于憩室病的高患病率和相关并发症，就直接和间接成本而言，憩室病是第五大胃肠道疾病。在一项瑞典双胞胎研究中，憩室病的遗传率估计约为42%。一项基于丹麦人群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有很强的和确定的遗传成分，但到目前为止还没有对该病进行系统或全基因组的遗传研究。本项目拟对每1700例憩室病、憩室炎和无憩室对照患者进行首次全基因组关联研究，并进行相应的验证实验。我们期望分别从对照与憩室病、憩室炎与憩室病的双相关分析中识别出不同的肠壁完整性/运动性和肠屏障功能的风险位点。该建议使用D-A-CH机制将德国和奥地利群体的大型互补患者队列和现有基因型资源（总共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，才能进行有竞争力的实验。纳入德国国家队列的两个中心和一个在憩室病和肠道蠕动方面具有强大功能专业知识的小组，为未来综合的、基于人群的风险模型的发展和机制随访研究提供了基础，将风险基因发现转化为新的病理生理学见解。鉴于从双胞胎和群体分析中确定的憩室病的遗传成分，以及以前的研究完全缺乏，对其遗传疾病病因有更深入了解的强有力的基因发现的机会非常高。我们期望憩室疾病和憩室炎的不同病因途径。两者都将为这些常见疾病的病因和新的预防和治疗选择提供令人兴奋的新见解。

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.