Replication and Meta-Analysis of GWAS Identified Susceptibility Loci in Kawasaki Disease Confirm the Importance of B Lymphoid Tyrosine Kinase (BLK) in Disease Susceptibility

Chia Jung Chang, Ho Chang Kuo, Jeng Sheng Chang, Jong Keuk Lee, Fuu Jen Tsai, Chiea Chuen Khor, Li Ching Chang, Shih Ping Chen, Tai Ming Ko, Yi Min Liu, Ying Ju Chen, Young Mi Hong, Gi Young Jang, Martin L. Hibberd, Taco W. Kuijpers, David Burgner, Michael E Levin, Jane C. Burns, Sonia Davila, Yuan Tsong ChenChien Hsiun Chen, Jer Yuarn Wu, Yi Ching Lee

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41 Citations (Scopus)

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.

Original languageEnglish
Article numbere72037
Number of pages8
JournalPLoS ONE
Volume8
Issue number8
DOIs
Publication statusPublished - 30 Aug 2013
Externally publishedYes

Keywords

  • B cells
  • genome-wide association studies
  • Europe
  • meta-analysis
  • white blood cells
  • B cell receptors
  • variant genotypes
  • Han Chinese people

Cite this

Chang, C. J., Kuo, H. C., Chang, J. S., Lee, J. K., Tsai, F. J., Khor, C. C., Chang, L. C., Chen, S. P., Ko, T. M., Liu, Y. M., Chen, Y. J., Hong, Y. M., Jang, G. Y., Hibberd, M. L., Kuijpers, T. W., Burgner, D., Levin, M. E., Burns, J. C., Davila, S., ... Lee, Y. C. (2013). Replication and Meta-Analysis of GWAS Identified Susceptibility Loci in Kawasaki Disease Confirm the Importance of B Lymphoid Tyrosine Kinase (BLK) in Disease Susceptibility. PLoS ONE, 8(8), [e72037]. https://doi.org/10.1371/journal.pone.0072037