Genetics of Kawasaki Disease

Onouchi, Yoshihiro

doi:10.1253/circj.cj-12-0568

Cited by 111 publications

(64 citation statements)

References 68 publications

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“…Genetics are considered to contribute to susceptibility to KD, and probably to CAA and response to treatment [91, 132]. A number of genome-wide association studies (GWAS) have been performed [7, 63, 69, 72, 92, 94, 126].…”

Section: Geneticsmentioning

confidence: 99%

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: Geneticsmentioning

confidence: 99%

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

et al. 2017

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“…It is expressed on the surface of immune cells like, dendritic cells, macrophages, monocytes and neutrophils and transduces activation signals into cells on binding with immune complexes [27]. The A to G substitution of the SNP in FGR2A (rs1801274) alters the translation of the 131 st amino acid from histidine (H) to arginine (R) [33]. This polymorphic form now has lower binding affinity to IgG2, that could be related to more immune activation during the acute phase of KD [33].…”

Section: Etiopathogenesismentioning

confidence: 99%

“…The A to G substitution of the SNP in FGR2A (rs1801274) alters the translation of the 131 st amino acid from histidine (H) to arginine (R) [33]. This polymorphic form now has lower binding affinity to IgG2, that could be related to more immune activation during the acute phase of KD [33]. …”

Section: Etiopathogenesismentioning

confidence: 99%

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Kawasaki disease: etiopathogenesis and novel treatment strategies

Agarwal

Agrawal

2016

Expert Review of Clinical Immunology

164

113

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Introduction-Kawasaki disease is an acute febrile systemic vasculitis that predominantly occurs in children below five years of age. Its etiopathogenesis is still not clear, but it is thought to be a complex interplay of genetic factors, infections and immunity.Areas covered-This review article discusses in detail Kawasaki disease, with particular emphasis on the recent updates on its pathogenesis and upcoming alternate treatment options. Though self-limiting in many cases, it can lead to severe complications like coronary artery aneurysms and thrombo-embolic occlusions, and hence requires early diagnosis and urgent attention to avoid them. Intravenous immunoglobulin (IVIG) with or without aspirin has remained the sole treatment option for these cases, but 10-15% cases develop resistance to this treatment.Expert Commentary-There is a need to develop additional treatment strategies for children with Kawasaki disease. Targeting different steps of pathogenesis could provide us with alternate therapeutic options.

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“…Although KS is not contagious, more than 50% of these siblings develop KS within 10 days of the first sibling. As outlined by Onouchi,6) this can subsequently "... give the impression that KD is a type of endemic disease or a disease related to a lifestyle commonly found among the East Asian populations". While this no doubt reflects the shared genetic components conferring susceptibility, the role of exposure to specific environmental agents influenced by varying cultural habits, health practices, and economic or industrial development should not be overlooked.…”

Section: Introductionmentioning

confidence: 99%

Mercury Promotes Catecholamines Which Potentiate Mercurial Autoimmunity and Vasodilation: Implications for Inositol 1,4,5-Triphosphate 3-Kinase C Susceptibility in Kawasaki Syndrome

Yeter¹,

Deth

Kuo

2013

Korean Circ J

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Previously, we reviewed biological evidence that mercury could induce autoimmunity and coronary arterial wall relaxation as observed in Kawasaki syndrome (KS) through its effects on calcium signaling, and that inositol 1,4,5-triphosphate 3-kinase C (ITPKC) susceptibility in KS would predispose patients to mercury by increasing Ca2+ release. Hg2+ sensitizes inositol 1,4,5-triphosphate (IP3) receptors at low doses, which release Ca2+ from intracellular stores in the sarcoplasmic reticulum, resulting in delayed, repetitive calcium influx. ITPKC prevents IP3 from triggering IP3 receptors to release calcium by converting IP3 to inositol 1,3,4,5-tetrakisphosphate. Defective IP3 phosphorylation resulting from reduced genetic expressions of ITPKC in KS would promote IP3, which increases Ca2+ release. Hg2+ increases catecholamine levels through the inhibition of S-adenosylmethionine and subsequently catechol-O-methyltransferase (COMT), while a single nucleotide polymorphism of the COMT gene (rs769224) was recently found to be significantly associated with the development of coronary artery lesions in KS. Accumulation of norepinephrine or epinephrine would potentiate Hg2+-induced calcium influx by increasing IP3 production and increasing the permeability of cardiac sarcolemma to Ca2+. Norepinephrine and epinephrine also promote the secretion of atrial natriuretic peptide, a potent vasodilator that suppresses the release of vasoconstrictors. Elevated catecholamine levels can induce hypertension and tachycardia, while increased arterial pressure and a rapid heart rate would promote arterial vasodilation and subsequent fatal thromboses, particularly in tandem. Genetic risk factors may explain why only a susceptible subset of children develops KS although mercury exposure from methylmercury in fish or thimerosal in pediatric vaccines is nearly ubiquitous. During the infantile acrodynia epidemic, only 1 in 500 children developed acrodynia whereas mercury exposure was very common due to the use of teething powders. This hypothesis mirrors the leading theory for KS in which a widespread infection only induces KS in susceptible children. Acrodynia can mimic the clinical picture of KS, leading to its inclusion in the differential diagnosis for KS. Catecholamine levels are often elevated in acrodynia and may also play a role in KS. We conclude that KS may be the acute febrile form of acrodynia.

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Genetics of Kawasaki Disease

Cited by 111 publications

References 68 publications

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

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

Kawasaki disease: etiopathogenesis and novel treatment strategies

Mercury Promotes Catecholamines Which Potentiate Mercurial Autoimmunity and Vasodilation: Implications for Inositol 1,4,5-Triphosphate 3-Kinase C Susceptibility in Kawasaki Syndrome

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