Oracz Grzegorz, Zaród Michał, Ewers Maren, Laumen Helmut, Gambin Tomasz, Kamiński Paweł, Grabowska Iwona, Drożak Anna, Kwiatkowski Sebastian, Wertheim-Tysarowska Katarzyna, Kołodziejczyk Elwira, Domaszewicz Alicja, Dorożko Barbara, Kosińska Joanna, Głuszek Stanisław, Kozieł Dorota, Płoski Rafał, Rosendahl Jonas, Witt Heiko, Drożak Jakub, Rygiel Agnieszka Magdalena
Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland.
Department of Metabolic Regulation, Faculty of Biology, University of Warsaw, Warsaw, Poland.
Pancreatology. 2021 Dec;21(8):1434-1442. doi: 10.1016/j.pan.2021.09.005. Epub 2021 Sep 10.
Loss of function variants of the transient receptor potential cation channel, subfamily V, member 6 (TRPV6) have been recently associated with chronic pancreatitis (CP) in Japanese, German and French patients. Here, we investigated the association of TRPV6 variants with CP in independent European cohorts of early-onset CP patients from Poland and Germany.
We enrolled 152 pediatric CP patients (median age 8.6 yrs) with no history of alcohol/smoking abuse and 472 controls from Poland as well as 157 nonalcoholic young CP patients (median age 20 yrs) and 750 controls from Germany. Coding regions of TRPV6 were screened by Sanger and next generation sequencing. Selected, potentially pathogenic TRPV6 variants were expressed in HEK293T cells and TRPV6 activity was analyzed using ratiometric Ca measurements.
Overall, we identified 10 novel (3 nonsense and 7 missenses) TRPV6 variants in CP patients. TRPV6 p.V239SfsX53 nonsense variant and the variants showing significant decrease in intracellular Ca concentration in HEK293T cells (p.R174X, p.L576R, p.R342Q), were significantly overrepresented in Polish patients as compared to controls (6/152, 3.9% vs. 0/358, 0%; P = 0,0007). Nonsense TRPV6 variants predicted as loss of function (p.V239SfsX53 and p.R624X) were also significantly overrepresented in German patients (3/157; 2.0% vs 0/750; 0%, P = 0.005).
We showed that TRPV6 loss of function variants are associated with elevated CP risk in early-onset Polish and German patients confirming that TRPV6 is a novel CP susceptibility gene.
瞬时受体电位阳离子通道亚家族V成员6（TRPV6）的功能缺失变异最近在日本、德国和法国患者中与慢性胰腺炎（CP）相关。在此，我们在来自波兰和德国的早发性CP患者的独立欧洲队列中研究了TRPV6变异与CP的关联。
我们招募了152名无酗酒/吸烟史的儿科CP患者（中位年龄8.6岁）以及来自波兰的472名对照，还有157名非酒精性年轻CP患者（中位年龄20岁）和来自德国的750名对照。通过桑格测序和下一代测序对TRPV6的编码区进行筛选。选定的、潜在致病性的TRPV6变异在HEK293T细胞中表达，并使用比率钙测量分析TRPV6活性。
总体而言，我们在CP患者中鉴定出10种新的（3种无义突变和7种错义突变）TRPV6变异。与对照相比，TRPV6 p.V239SfsX53无义变异以及在HEK293T细胞中细胞内钙浓度显著降低的变异（p.R174X、p.L576R、p.R342Q）在波兰患者中显著富集（6/152，3.9%对0/358，0%；P = 0.0007）。预测为功能丧失的无义TRPV6变异（p.V239SfsX53和p.R624X）在德国患者中也显著富集（3/157；2.0%对0/750；0%，P = 0.005）。
我们表明TRPV6功能丧失变异与早发性波兰和德国患者中CP风险升高相关，证实TRPV
