title: Replication and meta-analysis of GWAS identified susceptibility loci in Kawasaki disease confirm the importance of B lymphoid tyrosine kinase (BLK) in disease susceptibility.
abstract: 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.
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan ; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Chia-Jung
authors.initials: CJ
authors.lastname: Chang
authors.forename: Ho-Chang
authors.initials: HC
authors.lastname: Kuo
authors.forename: Jeng-Sheng
authors.initials: JS
authors.lastname: Chang
authors.forename: Jong-Keuk
authors.initials: JK
authors.lastname: Lee
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.forename: Chiea Chuen
authors.initials: CC
authors.lastname: Khor
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Chang
authors.forename: Shih-Ping
authors.initials: SP
authors.lastname: Chen
authors.forename: Tai-Ming
authors.initials: TM
authors.lastname: Ko
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Liu
authors.forename: Ying-Ju
authors.initials: YJ
authors.lastname: Chen
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Hong
authors.forename: Gi Young
authors.initials: GY
authors.lastname: Jang
authors.forename: Martin L
authors.initials: ML
authors.lastname: Hibberd
authors.forename: Taco
authors.initials: T
authors.lastname: Kuijpers
authors.forename: David
authors.initials: D
authors.lastname: Burgner
authors.forename: Michael
authors.initials: M
authors.lastname: Levin
authors.forename: Jane C
authors.initials: JC
authors.lastname: Burns
authors.forename: Sonia
authors.initials: S
authors.lastname: Davila
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
authors.forename: Chien-Hsiun
authors.initials: CH
authors.lastname: Chen
authors.forename: Jer-Yuarn
authors.initials: JY
authors.lastname: Wu
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Lee
mesh_terms: D044466:Asian People / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D015331:Cohort Studies; D015971:Gene Expression Regulation, Enzymologic; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D009080:Mucocutaneous Lymph Node Syndrome / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D015203:Reproducibility of Results; D056910:Republic of Korea; D013624:Taiwan; D044465:White People / Q000235:genetics; D019061:src-Family Kinases / Q000235:genetics*
chemical_list: C082599:protein-tyrosine kinase p55(blk); D019061:src-Family Kinases
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