Replication and meta-analysis of GWAS identified susceptibility loci in Kawasaki disease confirm the importance of B lymphoid tyrosine kinase (BLK) in disease susceptibility.
Replication and meta-analysis of GWAS identified susceptibility loci in Kawasaki disease confirm the importance of B lymphoid tyrosine kinase (BLK) in disease susceptibility.
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DOI：
10.1371/journal.pone.0072037
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lee YC
中科院分区：
文献类型：
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作者：
Chang CJ;Kuo HC;Chang JS;Lee JK;Tsai FJ;Khor CC;Chang LC;Chen SP;Ko TM;Liu YM;Chen YJ;Hong YM;Jang GY;Hibberd ML;Kuijpers T;Burgner D;Levin M;Burns JC;Davila S;International Kawasaki Disease Genetics Consortium;Korean Kawasaki Disease Genetics Consortium;Taiwan Kawasaki Disease Genetics Consortium;Chen YT;Chen CH;Wu JY;Lee YC
在两项全基因组关联研究（GWAS）中，BLK和CD40位点与川崎病（KD）有关，该研究在台湾汉族人群（台湾人）和日本人群中进行。在这里，我们通过对韩国和欧洲血统人群中BLK和CD40基因座的复制研究来建立这些发现。在两个人群中，BLK区域与KD易感性显著相关。在BLK基因中，位于rs2736340的连锁不平衡（LD）包括启动子和第一个内含子与KD密切相关，包括台湾、日本和韩国在内的亚洲人群（2539名KD患者和7021名对照）的综合研究结果提供了非常令人信服的关联证据（rs2736340, OR = 1.498, 1.354-1.657; P = 4.74×10−31）。我们测定了KD患者急性期和恢复期外周血单个核细胞（PBMC）中B细胞的百分比和外周血白细胞（白细胞）中BLK的表达。观察KD急性期患者PBMC中B细胞的百分比及白细胞中BLK的表达。在来自KD患者的B细胞系中，以及在急性期获得的KD患者纯化的B细胞中，具有rs2736340风险等位基因的B细胞表达的BLK水平显著降低。提示外周血B细胞在KD急性期起致病作用。外周血B细胞中BLK表达的降低可能改变B细胞功能，使个体易患KD。这些相关数据表明B细胞在急性KD中的作用。了解其功能意义可以促进B细胞介导的KD治疗的发展。
The BLK and CD40 loci have been associated with Kawasaki disease (KD) in two genome-wide association studies (GWAS) conducted in a Taiwanese population of Han Chinese ancestry (Taiwanese) and in Japanese cohorts. Here we build on these findings with replication studies of the BLK and CD40 loci in populations of Korean and European descent. The BLK region was significantly associated with KD susceptibility in both populations. Within the BLK gene the rs2736340-located linkage disequilibrium (LD ) comprising the promoter and first intron was strongly associated with KD, with the combined results of Asian studies including Taiwanese, Japanese, and Korean populations (2,539 KD patients and 7,021 controls) providing very compelling evidence of association (rs2736340, OR = 1.498, 1.354–1.657; P = 4.74×10−31). We determined the percentage of B cells present in the peripheral blood mononuclear cell (PBMC) population and the expression of BLK in the peripheral blood leukocytes (leukocytes) of KD patients during the acute and convalescent stages. The percentage of B cells in the PBMC population and the expression of BLK in leukocytes were induced in patients in the acute stage of KD. In B cell lines derived from KD patients, and in purified B cells from KD patients obtained during the acute stage, those with the risk allele of rs2736340 expressed significantly lower levels of BLK. These results suggest that peripheral B cells play a pathogenic role during the acute stage of KD. Decreased BLK expression in peripheral blood B cells may alter B cell function and predispose individuals to KD. These associative data suggest a role for B cells during acute KD. Understanding the functional implications may facilitate the development of B cell-mediated therapy for KD.
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影响因子：
30.8
作者：
Fairfax, Benjamin P.;Makino, Seiko;Radhakrishnan, Jayachandran;Plant, Katharine;Leslie, Stephen;Dilthey, Alexander;Ellis, Peter;Langford, Cordelia;Vannberg, Fredrik O.;Knight, Julian C.
通讯作者：
Knight, Julian C.
影响因子：
4.8
作者：
Jacob, A;Cooney, D;Coggeshall, KM
通讯作者：
Coggeshall, KM
影响因子：
5.3
作者：
Kim, Jae-Jung;Hong, Young Mi;Lee, Jong-Keuk
通讯作者：
Lee, Jong-Keuk
影响因子：
3
作者：
Holm K;Melum E;Franke A;Karlsen TH
通讯作者：
Karlsen TH
人类基因表达的群体基因组学。
影响因子：
30.8
作者：
通讯作者：
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