Regional replication, refinement and functional characterisation of GWAs variants in alcoholic and non-alcoholic chronic pancreatitis

慢性胰腺炎（CP）是一种进行性炎症性疾病，其特征是反复发作或持续腹痛，可导致外分泌和/或内分泌功能不全。由于发病率为每10万居民3.5-10人，CP对卫生保健和社会系统来说是一个巨大的负担。最主要的原因是酗酒和吸烟。在没有这些贡献者的患者中，已经描述了几种遗传关联，然而，在高达50%的这些患者中，没有确定潜在的遗传决定因素。为了阐明与酒精相关性CP （ACP）和非酒精相关性CP （NACP）相关的常见遗传变异，我们对2,813例CP患者进行了全基因组关联（GWA）研究。在ACP中，我们发现了5个具有全基因组意义的关联信号，包括CTRB1/CTRB2和EIF3A中的两个新位点。为了完善这些关联并描述功能后果，我们将使用Sanger测序技术研究复杂的CTRB1/CTRB2位点。在NACP中，我们将在第二组患者和对照组中使用多重方法研究p值为bb0.1 x 10-5的30个最佳GWAs snp，以确定新的风险位点。我们进行了复杂的生物统计学分析，包括顺式调控元件的转录结合位点模式，并将在不同细胞类型的体外实验中描述CTRB1/CTRB2位点的7个变体的功能特性。此外，还将分析EIF3A位点的其他变异和与NACP相关的变异。通过我们的策略，我们将获得关于CP发病机制的新见解，并解释相关变异的功能后果。

Chronic pancreatitis (CP) is a progressive inflammatory disease characterized by recurrent episodes or persisting abdominal pain that can lead to exocrine and/or endocrine insufficiency. Due to incidence rates of 3.5-10 per 100.000 inhabitants CP is a huge debit for health care and social systems. The most predominant contributors are alcohol abuse and smoking. In patients without these contributors several genetic associations have been described, however, in up to 50% of these patients no underlying genetic determinants can be identified. To elucidate common genetic variants associated with alcohol-related CP (ACP) and non alcohol-related CP (NACP) we have conducted a genome wide association (GWA) study in 2,813 CP patients. In ACP we identified five association signals with genome wide significance including two novel loci in CTRB1/CTRB2 as well as in EIF3A. To refine these associations and to characterise the functional consequences we will investigate the complex CTRB1/CTRB2 locus with Sanger sequencing technology. In NACP we will investigate the 30 best GWAs SNPs with a p-value of >1 x 10-5 with multiplex methods in a second cohort of patients and controls to identify new risk loci. We have performed complex biostatistical analyses including transcription binding site patterns of cis-regulatory elements and will characterize the functional properties of seven variants in the CTRB1/CTRB2 locus in vitro in distinct cell types. Further variants of the EIF3A locus and variants associated with NACP will be analysed in addition. With our strategy we will gain new insights in the pathogenesis of CP and explain the functional consequences of associated variants.