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

酒精性和非酒精性慢性胰腺炎 GWA 变异的区域复制、细化和功能表征

• 批准号: 321033801
• 负责人: Professor Dr. Jonas Rosendahl
• 金额: --
• 依托单位: Universitätsklinik und Poliklinik für Innere Medizin I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/321033801?language=en
• 关键词: Regional; replication; refinement; functional; characterisation

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.

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是卫生保健和社会系统的一笔巨额债务。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相关性，然而，在高达50%的这些患者中，无法确定潜在的遗传决定因素。为了阐明与酒精相关CP（ACP）和非酒精相关CP（NACP）相关的常见遗传变异，我们在2，813名CP患者中进行了全基因组关联（GWA）研究。在ACP中，我们发现了五个具有全基因组意义的关联信号，包括CTRB 1/CTRB 2以及EIF 3A中的两个新基因座。为了进一步研究这些关联和功能性结果，我们将用桑格测序技术研究复杂的CTRB 1/CTRB 2基因座。在NACP中，我们将在第二组患者和对照中采用多重方法研究30个p值>1 x 10-5的最佳GWA SNP，以确定新的风险基因座。我们已经进行了复杂的生物统计分析，包括转录结合位点的顺式调控元件的模式，并将在不同的细胞类型的CTRB 1/CTRB 2基因座在体外的功能特性的特征。此外，还将分析EIF 3A基因座的其他变体和与NACP相关的变体。通过我们的策略，我们将在CP的发病机制中获得新的见解，并解释相关变体的功能后果。

项目成果

Variants in the pancreatic CUB and zona pellucida-like domains 1 (CUZD1) gene in early-onset chronic pancreatitis - A possible new susceptibility gene.

• DOI: 10.1016/j.pan.2022.04.015
• 发表时间: 2022-06
• 期刊: PANCREATOLOGY
• 影响因子: 3.6
• 作者: Rygiel, Agnieszka Magdalena;Unger, Lara Sophie;Sorgel, Franziska Lena;Masson, Emmanuelle;Matsumoto, Ryotaro;Ewers, Maren;Chen, Jian-Min;Bugert, Peter;Buscail, Louis;Gambin, Tomasz;Oracz, Grzegorz;Winiewska-Szajewska, Maria;Mianowska, Agnieszka;Poznanski, Jaroslaw;Kosinska, Joanna;Stawinski, Piotr;Ploski, Rafa;Koziel, Dorota;Gluszek, Stanislaw;Laumen, Helmut;Lindgren, Fredrik;Lohr, J. Matthias;Orekhova, Anna;Rebours, Vinciane;Rosendahl, Jonas;Parniczky, Andrea;Hegyi, Peter;Sasaki, Akira;Kataoka, Fumiya;Tanaka, Yu;Hamada, Shin;Sahin-Toth, Miklos;Hegyi, Eszter;Ferec, Claude;Masamune, Atsushi;Witt, Heiko
• 通讯作者: Witt, Heiko

Sequencing of the complex CTRB1-CTRB2 locus in chronic pancreatitis.

慢性胰腺炎复杂 CTRB1-CTRB2 位点的测序

• DOI: 10.1016/j.pan.2020.09.017
• 发表时间: 2020
• 期刊: Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]
• 作者: Seltsam K;Pentner C;Weigl F;Sutedjo S;Zimmer C;Beer S;Bugert P;Ewers M;Ruffert C;Michl P;Laumen H;Witt H;Rosendahl J
• 通讯作者: Rosendahl J

Common variants in glyoxalase I do not increase chronic pancreatitis risk

乙二醛酶 I 的常见变异不会增加慢性胰腺炎的风险

• DOI: 10.1371/journal.pone.0222927
• 发表时间: 2019
• 期刊: PLoS ONE
• 影响因子: 3.7
• 作者: Kaune T;Hollenbach M;Keil B;Chen JM;Masson E;Becker C;Damm M;Ruffert C;Grützmann R;Hoffmeister A;Te Morsche RHM;Cavestro GM;Zuppardo RA;Saftoiu A;Malecka-Panas E;Głuszek S;Bugert P;Lerch MM;Weiss FU;Zou WB;Liao Z;Hegyi P;Drenth JP
• 通讯作者: Drenth JP

Colocalization analysis of pancreas eQTLs with risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS suggests potential disease causing mechanisms.

胰腺 eQTL 与酒精性和新型非酒精性慢性胰腺炎 GWAS 风险位点的共定位分析表明潜在的致​​病机制

• DOI: 10.1016/j.pan.2022.03.007
• 发表时间: 2022
• 期刊: Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]
• 作者: Schmidt AW;Kühnapfel A;Kirsten H;Grallert H;Hellerbrand C;Kiefer F;Mann K;Mueller S;Nöthen MM;Peters A;Ridinger M;Frank J;Rietschel M;Soranzo N;Soyka M;Wodarz N;Malerba G;Gambaro G;Gieger C;Scholz M;Krug S;Michl P;Ewers M;Witt H
• 通讯作者: Witt H

Genetic analysis of pancreatic phospholipase A2 (PLA2G1B) in patients with chronic pancreatitis.

慢性胰腺炎患者胰腺磷脂酶A2（PLA2G1B）的基因分析

• DOI: 10.1016/j.pan.2022.01.003
• 发表时间: 2022
• 期刊: Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]
• 作者: Ewers M;Epple D;Bugert P;Rosendahl J;Witt H
• 通讯作者: Witt H