Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis.
Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis.
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DOI：
10.1136/gutjnl-2017-314454
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发表时间：
2018-10
期刊：
影响因子：
24.5
通讯作者：
all members of the PanEuropean Working group on ACP
中科院分区：
文献类型：
--
作者：
Rosendahl J;Kirsten H;Hegyi E;Kovacs P;Weiss FU;Laumen H;Lichtner P;Ruffert C;Chen JM;Masson E;Beer S;Zimmer C;Seltsam K;Algül H;Bühler F;Bruno MJ;Bugert P;Burkhardt R;Cavestro GM;Cichoz-Lach H;Farré A;Frank J;Gambaro G;Gimpfl S;Grallert H;Griesmann H;Grützmann R;Hellerbrand C;Hegyi P;Hollenbach M;Iordache S;Jurkowska G;Keim V;Kiefer F;Krug S;Landt O;Leo MD;Lerch MM;Lévy P;Löffler M;Löhr M;Ludwig M;Macek M;Malats N;Malecka-Panas E;Malerba G;Mann K;Mayerle J;Mohr S;Te Morsche RHM;Motyka M;Mueller S;Müller T;Nöthen MM;Pedrazzoli S;Pereira SP;Peters A;Pfützer R;Real FX;Rebours V;Ridinger M;Rietschel M;Rösmann E;Saftoiu A;Schneider A;Schulz HU;Soranzo N;Soyka M;Simon P;Skipworth J;Stickel F;Strauch K;Stumvoll M;Testoni PA;Tönjes A;Werner L;Werner J;Wodarz N;Ziegler M;Masamune A;Mössner J;Férec C;Michl P;P H Drenth J;Witt H;Scholz M;Sahin-Tóth M;all members of the PanEuropean Working group on ACP
在胃肠道疾病中，酒精相关胰腺炎与不成比例的大量住院相关。尽管酒精性慢性胰腺炎（CP）具有重要的临床意义，但其遗传易感性尚不清楚。为了确定酒精性CP的风险基因，并评估其在非酒精性CP中的相关性，我们进行了一项全基因组关联研究和一个新的胰腺炎位点的功能表征。使用Illumina技术筛选来自KORA、LIFE和INCIPE研究的1959名欧洲酒精性CP患者和基于人群的对照（n=4708）以及来自GESGA联盟的慢性酒精中毒者（n=1332）。为了重复，使用了来自相同国家的三个欧洲队列，包括1650例非酒精性CP患者和6695例对照。我们复制了先前报道的酒精性CP患者的风险位点CLDN 2-MORC 4、CTRC、PRSS 1-PRSS 2和SPINK 1。我们确定CTRB 1-CTRB 2（胰凝乳蛋白酶B1和B2）是一个新的风险位点，其前导单核苷酸多态性（SNP）rs 8055167（OR 1.35，95%CI 1.23至1.6）。我们发现，CTRB 1-CTRB 2基因座中的16.6 kb倒位与CP相关的SNP连锁不平衡，并且最好由rs 8048956标记。这种关联在三个独立的欧洲非酒精性CP队列（1650例患者和6695例对照）中得到了复制（OR 1.62，95%CI 1.42 - 1.86）。这种倒位改变了CTRB 1和CTRB 2亚型的表达比例，从而影响保护性胰蛋白酶原降解，并最终影响胰腺炎风险。CTRB 1-CTRB 2基因座的倒位改变了酒精性和非酒精性CP的风险，表明这些炎症性疾病涉及共同的病理机制。
Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus. 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used. We replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk. An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
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影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
2.9
作者：
Paliwal, Sumit;Bhaskar, Seema;Chandak, Giriraj Ratan
通讯作者：
Chandak, Giriraj Ratan
影响因子：
5.4
作者：
Szabo, Andras;Sahin-Toth, Miklos
通讯作者：
Sahin-Toth, Miklos
影响因子：
3.5
作者：
de Bakker, Paul I. W.;Ferreira, Manuel A. R.;Voight, Benjamin F.
通讯作者：
Voight, Benjamin F.