NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population.
NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population.
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DOI：
10.1038/s41598-018-26369-6
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发表时间：
2018-05-23
影响因子：
4.6
通讯作者：
Nakamura M
中科院分区：
文献类型：
--
作者：
Nishida N;Aiba Y;Hitomi Y;Kawashima M;Kojima K;Kawai Y;Ueno K;Nakamura H;Yamashiki N;Tanaka T;Tamura S;Mori A;Yagi S;Soejima Y;Yoshizumi T;Takatsuki M;Tanaka A;Harada K;Shimoda S;Komori A;Eguchi S;Maehara Y;Uemoto S;Kokudo N;Nagasaki M;Tokunaga K;Nakamura M
无论是否使用熊去氧胆酸和苯扎贝特治疗，约10 - 20%的原发性胆汁性胆管炎（PBC）患者进展至黄疸期。在这项研究中，我们进行了一项GWAS和一项复制研究，以确定与PBC黄疸期进展相关的遗传变异，共使用了日本人群中的1，375例患者（1，202例早期和173例黄疸期）。SNP rs13720位于组织蛋白酶Z（CTSZ）的3 ′ UTR，与GWAS进展至黄疸期的相关性最强（比值比[OR]= 2.15，P = 7.62 × 10 − 7）。CTSZ和负延伸因子复合体成员C/D（NELFCD）基因座位于一个强连锁不平衡（LD）区块内，其高密度关联图谱显示CTSZ的内含子SNP rs163800与黄疸期进展显著相关（OR = 2.16，P = 8.57 × 10 − 8）。此外，eQTL分析和计算机功能分析表明，rs163800的基因型或具有rs163800的强LD中的变体影响NELFCD和CTSZ mRNA的表达水平。目前的新发现将有助于剖析PBC进展的机制，并促进对目前治疗耐药的PBC患者的治疗方法的发展。
Approximately 10–20% of patients with primary biliary cholangitis (PBC) progress to jaundice stage regardless of treatment with ursodeoxycholic acid and bezafibrate. In this study, we performed a GWAS and a replication study to identify genetic variants associated with jaundice-stage progression in PBC using a total of 1,375 patients (1,202 early-stage and 173 jaundice-stage) in a Japanese population. SNP rs13720, which is located in the 3′UTR of cathepsin Z (CTSZ), showed the strongest association (odds ratio [OR] = 2.15, P = 7.62 × 10−7) with progression to jaundice stage in GWAS. High-density association mapping at the CTSZ and negative elongation factor complex member C/D (NELFCD) loci, which are located within a strong linkage disequilibrium (LD) block, revealed that an intronic SNP of CTSZ, rs163800, was significantly associated with jaundice-stage progression (OR = 2.16, P = 8.57 × 10−8). In addition, eQTL analysis and in silico functional analysis indicated that genotypes of rs163800 or variants in strong LD with rs163800 influence expression levels of both NELFCD and CTSZ mRNA. The present novel findings will contribute to dissect the mechanism of PBC progression and also to facilitate the development of therapies for PBC patients who are resistant to current therapies.
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影响因子：
13.5
作者：
Nakamura, Minoru;Kondo, Hisayoshi;Ishibashi, Hiromi
通讯作者：
Ishibashi, Hiromi
一项全基因组关联研究确定了原发性胆汁性胆管炎的六个新风险位点。
影响因子：
16.6
作者：
Qiu F;Tang R;Zuo X;Shi X;Wei Y;Zheng X;Dai Y;Gong Y;Wang L;Xu P;Zhu X;Wu J;Han C;Gao Y;Zhang K;Jiang Y;Zhou J;Shao Y;Hu Z;Tian Y;Zhang H;Dai N;Liu L;Wu X;Zhao W;Zhang X;Zang Z;Nie J;Sun W;Zhao Y;Mao Y;Jiang P;Ji H;Dong Q;Li J;Li Z;Bai X;Li L;Lin M;Dong M;Li J;Zhu P;Wang C;Zhang Y;Jiang P;Wang Y;Jawed R;Xu J;Zhang Y;Wang Q;Yang Y;Yang F;Lian M;Jiang X;Xiao X;Li Y;Fang J;Qiu D;Zhu Z;Qiu H;Zhang J;Tian W;Chen S;Jiang L;Ji B;Li P;Chen G;Wu T;Sun Y;Yu J;Tang H;He M;Xia M;Pei H;Huang L;Qing Z;Wu J;Huang Q;Han J;Xie W;Sun Z;Guo J;He G;Eric Gershwin M;Lian Z;Liu X;Seldin MF;Liu X;Chen W;Ma X
通讯作者：
Ma X
影响因子：
3.7
作者：
Nishida N;Mawatari Y;Sageshima M;Tokunaga K
通讯作者：
Tokunaga K
影响因子：
2.7
作者：
Baker, Allison R.;Zalwango, Sarah;Stein, Catherine M.
通讯作者：
Stein, Catherine M.
影响因子：
16.6
作者：
Cordell HJ;Han Y;Mells GF;Li Y;Hirschfield GM;Greene CS;Xie G;Juran BD;Zhu D;Qian DC;Floyd JA;Morley KI;Prati D;Lleo A;Cusi D;Canadian-US PBC Consortium;Italian PBC Genetics Study Group;UK-PBC Consortium;Gershwin ME;Anderson CA;Lazaridis KN;Invernizzi P;Seldin MF;Sandford RN;Amos CI;Siminovitch KA
通讯作者：
Siminovitch KA