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

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

doi:10.1371/journal.pone.0072037

Cited by 59 publications

(58 citation statements)

References 19 publications

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“…Following this study, Japanese and Taiwanese studies also confirmed this genetic association while at the same time characterizing CD40 and BLK , respectively, as being associated with KD, as confirmed for BLK in Caucasian KD patients in a subsequent meta-analysis [12, 72, 94]. CD40 is a protein expressed on antigen-presenting cells, such as dendritic cells, macrophages, and B cells, and interacts with CD40L which is primarily expressed by activated T cells and platelets [49].…”

Section: Geneticssupporting

confidence: 53%

Dissecting Kawasaki disease: a state-of-the-art review

et al. 2017

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Kawasaki disease (KD) is a pediatric vasculitis with coronary artery aneurysms (CAA) as its main complication. The diagnosis is based on the presence of persistent fever and clinical features including exanthema, lymphadenopathy, conjunctival injection, and changes to the mucosae and extremities. Although the etiology remains unknown, the current consensus is that it is likely caused by an (infectious) trigger initiating an abnormal immune response in genetically predisposed children. Treatment consists of high dose intravenous immunoglobulin (IVIG) and is directed at preventing the development of CAA. Unfortunately, 10–20% of all patients fail to respond to IVIG and these children need additional anti-inflammatory treatment. Coronary artery lesions are diagnosed by echocardiography in the acute and subacute phases. Both absolute arterial diameters and z-scores, adjusted for height and weight, are used as criteria for CAA. Close monitoring of CAA is important as ischemic symptoms or myocardial infarction due to thrombosis or stenosis can occur. These complications are most likely to arise in the largest, so-called giant CAA. Apart from the presence of CAA, it is unclear whether KD causes an increased cardiovascular risk due to the vasculitis itself. Conclusion: Many aspects of KD remain unknown, although there is growing knowledge on the etiology, treatment, and development and classification of CAA. Since children with previous KD are entering adulthood, long-term follow-up is increasingly important. What is known: • Kawasaki disease (KD) is a pediatric vasculitis with coronary artery damage as its main complication. • Although KD approaches its 50th birthday since its first description, many aspects of the disease remain poorly understood. What is new: • In recent years, multiple genetic candidate pathways involved in KD have been identified, with recently promising information about the ITPKC pathway. • As increasing numbers of KD patients are reaching adulthood, increasing information is available about the long-term consequences of coronary artery damage and broader cardiovascular risk.

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Section: Geneticssupporting

confidence: 53%

Dissecting Kawasaki disease: a state-of-the-art review

et al. 2017

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“…Recent GWAS studies have discovered that several genetic polymorphisms (SNPs) are associated with increased risk for KD and CAA 58, 59 . Among these SNPs that are associated with increased risk for KD as well as risk for CAA, one that has attracted a major interest is found in the inositol 1,4,5,-triphosphate 3 kinase (ITPKC) gene 4, 60–62 .…”

Section: Discussionmentioning

confidence: 99%

IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model

Lee

Wakita

Dagvadorj

et al. 2015

ATVB

104

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Objective Kawasaki disease (KD) is the most common cause of acute vasculitis and acquired cardiac disease among US children. We have previously shown that both TLR2/MyD88 and IL-1β signaling are required for the Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis mouse model. The objectives of this study were to investigate the cellular origins of IL-1 production, the role of CD11c+ Dendritic Cells (DCs) and macrophages and the relative contribution of hematopoietic and stromal cells for IL-1 responsive cells, as well the MyD88 signaling in LCWE-induced KD mouse model of vasculitis. Approach and Results Using mouse knockout models as well as antibody depletion, we found that both IL-1α and IL-1β were required for LCWE-induced KD. Both DCs and macrophages were necessary and we found that MyD88 signaling was required in both hematopoietic and stromal cells. However, IL-1 response and signaling was critically required in non-endothelial stromal cells, but not hematopoietic cells. Conclusions Our results suggest that IL-1α and IL-1β as well as CD11c+ DCs and macrophages are essential for the development of KD vasculitis and coronary arteritis in this mouse model. Bone marrow chimera experiments suggest that MyD88 signaling is important in both hematopoietic and stromal cells, while IL-1 signaling and response is required only in stromal cells, but not in endothelial cells. Determining the role IL-1α and IL-1β and of specific cell types in the KD vasculitis mouse model may have important implications for the design of more targeted therapies and understanding of the molecular mechanisms of KD immunopathologies.

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“…In 2013, the International Kawasaki Disease Genetics Consortium performed a replication study in populations of Korean and European descent and confirmed the genetic contribution to KD pathogenesis by finding an association between B‐lymphoid tyrosine kinase ( BLK ) gene with KD . BLK is a Src family tyrosine kinase expressed primarily in the B‐cell lineage.…”

Section: Kawasaki Disease Featuresmentioning

confidence: 99%

Pathogenetic determinants in Kawasaki disease: the haematological point of view

Principe

Pietraforte

Gambardella

et al. 2017

J Cellular Molecular Medi

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Kawasaki disease is a multisystemic vasculitis that can result in coronary artery lesions. It predominantly affects young children and is characterized by prolonged fever, diffuse mucosal inflammation, indurative oedema of the hands and feet, a polymorphous skin rash and non‐suppurative lymphadenopathy. Coronary artery involvement is the most important complication of Kawasaki disease and may cause significant coronary stenosis resulting in ischemic heart disease. The introduction of intravenous immunoglobulin decreases the incidence of coronary artery lesions to less than 5%. The etiopathogenesis of this disease remains unclear. Several lines of evidence suggest that an interplay between a microbial infection and a genetic predisposition could take place in the development of the disease. In this review, we summarize the state of the art of pathogenetic mechanisms of Kawasaki disease underscoring the relevance of haematological features as a novel field of investigation.

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

Cited by 59 publications

References 19 publications

Dissecting Kawasaki disease: a state-of-the-art review

Dissecting Kawasaki disease: a state-of-the-art review

IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model

Pathogenetic determinants in Kawasaki disease: the haematological point of view

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