TRPV6variants confer susceptibility to chronic pancreatitis in the Chinese population
TRPV6variants confer susceptibility to chronic pancreatitis in the Chinese population
复制标题
TRPV6变异导致中国人群对慢性胰腺炎易感性
DOI：
10.1002/humu.24032
复制
发表时间：
2020
期刊：
影响因子：
3.9
通讯作者：
Liao Zhuan
中科院分区：
文献类型：
--
作者：
Zou Wen-Bin;Wang Yuan-Chen;Ren Xin-Lu;Wang Lei;Deng Shun-Jiang;Mao Xiao-Tong;Li Zhao-Shen;Liao Zhuan
慢性胰腺炎（CP）是由遗传和环境因素引起的胰腺组织进行性纤维炎症综合征。以前报道的CP易感基因解释了不到一半的表观遗传力。为了揭示新的致病机制，我们首先对464名中国CP患者和504名对照进行了低覆盖率全基因组测序。瞬时受体电位阳离子通道，亚家族V，成员6（TRPV 6）基因被发现与CP显着相关后，负荷测试的聚集罕见的非同义变异与组合的注释依赖性消耗得分> 20（p= .020）。在复制阶段，我们用桑格测序法分析了205例CP患者和105例对照的TPRV 6基因的整个编码序列和外显子/内含子边界。整合这两个阶段的发现，鉴定出25种TRPV 6变异体：1种罕见的无义变异体，20种罕见的错义变异体和4种常见的错义变异体。与对照组相比，通过转染HEK 293 T细胞中的细胞内Ca 2+浓度确定的功能丧失变体在患者中的代表性显著过高（9/669 [1.35%] vs. 1/609 [0.16%];比值比= 8.29;p= 0.022）。本研究为TRPV 6是CP的一个新的易感基因提供了证据。
Chronic pancreatitis (CP) is a progressive fibroinflammatory syndrome of the pancreatic tissue caused by genetic and environmental factors. Previously reported susceptibility genes in CP explain less than half of the apparent heritability. To uncover novel pathogenic mechanisms, we initially performed low‐coverage whole‐genome sequencing on 464 Chinese CP patients and 504 controls. The transient receptor potential cation channel, Subfamily V, Member 6 (TRPV6) gene was found to be significantly associated with CP after a burden test of aggregated rare nonsynonymous variants with a combined annotation dependent depletion score > 20 (p= .020). In the replication stage, we analyzed the entire coding sequence and exon/intron boundaries of theTPRV6gene by Sanger sequencing in another 205 patients with CP and 105 controls. Integration of the findings from the two stages resulted in the identification of 25TRPV6variants: 1 rare nonsense variant, 20 rare missense variants, and 4 common missense variants. Loss‐of‐function variants, as determined by intracellular Ca2+concentration in transfected HEK293T cells, were significantly overrepresented in patients as compared to controls (9/669 [1.35%] vs. 1/609 [0.16%]; odds ratio = 8.29;p= .022). This study provides evidence suggesting thatTRPV6is a novel susceptibility gene for CP.