High-density genotyping of immune loci in Kawasaki disease and IVIG treatment response in European-American case–parent trio study

Shendre, Aditi; Wiener, Howard W.; Zhi, Degui; Vázquez, Ana I.; Portman, Michael A.; Shrestha, Sadeep

doi:10.1038/gene.2014.47

Cited by 24 publications

(22 citation statements)

References 52 publications

(65 reference statements)

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“…It is likely that host genetic factors, such as polymorphisms in the Fc gamma receptors, play a role in both the response and resistance to IVIG. 61,202,203 Risk Scores for Predicting Nonresponse to IVIG Approximately 10% to 20% of patients with KD have persistent or recurrent fever after primary therapy with IVIG plus ASA. 204,205 Many studies have shown that patients who are resistant to initial IVIG are at increased risk of developing coronary artery abnormalities.…”

Section: Ivig Resistancementioning

confidence: 99%

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association

McCrindle¹,

Rowley²,

Newburger³

et al. 2017

Circulation

2,738

4,124

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BACKGROUND:Kawasaki disease is an acute vasculitis of childhood that leads to coronary artery aneurysms in ≈25% of untreated cases. It has been reported worldwide and is the leading cause of acquired heart disease in children in developed countries. METHODS AND RESULTS:To revise the previous American Heart Association guidelines, a multidisciplinary writing group of experts was convened to review and appraise available evidence and practice-based opinion, as well as to provide updated recommendations for diagnosis, treatment of the acute illness, and long-term management. Although the cause remains unknown, discussion sections highlight new insights into the epidemiology, genetics, pathogenesis, pathology, natural history, and longterm outcomes. Prompt diagnosis is essential, and an updated algorithm defines supplemental information to be used to assist the diagnosis when classic clinical criteria are incomplete. Although intravenous immune globulin is the mainstay of initial treatment, the role for additional primary therapy in selected patients is discussed. Approximately 10% to 20% of patients do not respond to initial intravenous immune globulin, and recommendations for additional therapies are provided. Careful initial management of evolving coronary artery abnormalities is essential, necessitating an increased frequency of assessments and escalation of thromboprophylaxis. Risk stratification for long-term management is based primarily on maximal coronary artery luminal dimensions, normalized as Z scores, and is calibrated to both past and current involvement. Patients with aneurysms require life-long and uninterrupted cardiology follow-up. CONCLUSIONS:These recommendations provide updated and best evidence-based guidance to healthcare providers who diagnose and manage Kawasaki disease, but clinical decision making should be individualized to specific patient circumstances. K awasaki disease (KD) is an acute, self-limited febrile illness of unknown cause that predominantly affects children <5 years of age. When initially described, the potential for coronary artery complications was not appreciated. KD is now the most common cause of acquired heart disease in children in developed countries. In the absence of pathognomonic tests, the diagnosis continues to rest on the identification of principal clinical findings and the exclusion of other clinically similar entities with known causes. Timely initiation of treatment with intravenous immunoglobulin (IVIG) has reduced the incidence of coronary artery aneurysms defined from absolute luminal dimensions from 25% to ≈4%. Ongoing studies with additional therapies have not substantially reduced this residual risk. The long-term prognosis is determined by the initial and current level of coronary artery involvement. Certain subsets of patients are at risk for myocardial ischemia from coronary artery thrombosis and stenoses. Medical management of such patients hinges on judicious use of thromboprophylaxis and vigilance to identify evolving stenoses. Invasive revascul...

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Section: Ivig Resistancementioning

confidence: 99%

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association

McCrindle¹,

Rowley²,

Newburger³

et al. 2017

Circulation

2,738

4,124

View full text Add to dashboard Cite

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“…Recently, in a large genome-wide association study, KD susceptibility in Japanese children was associated with a polymorphism near the HLA-DQA2 locus on 6p21.3 [47]. The association of polymorphisms in HLA/DQB2 and HLD/DOB were recently validated in a study of KD trios of European descent, thus broadening the suspected importance of HLA in KD susceptibility [17]. The role of the HLA in the Fc-specific Treg response is currently under study by our laboratory.…”

Section: Minimal Fc Epitopes For Treg Recognitionmentioning

confidence: 99%

“…There were significantly fewer patients with coronary artery abnormalities in the group receiving prednisolone plus IVIG (3% vs. 23%, CI 0.12–0.28, p<0.001). Caveats to the adoption of this protocol for other countries is that the scoring system has been shown to have poor predictive value in mixed ethnic populations and patients with coronary artery abnormalities on their first echocardiogram at diagnosis were excluded[17, 18]. In a U.S. population, of the patients who go on to develop aneurysms, 81% had an abnormal first echocardiogram and would have been excluded from the RAISE study[19].…”

Section: Ivig Resistancementioning

confidence: 99%

“…However, thus far, the small, unreplicated genetic association studies of IVIG resistance in KD patients have not uncovered determinants affecting sialylation[23]. The largest genetic case:control study to date of IVIG responsive versus resistant subjects of European descent identified loci in intergenic regions of several genes that have also been associated with immune pathways and autoimmune diseases[17]. These results will need to be validated in additional studies, although small sample size will always be a limiting factor.…”

Section: Ivig Resistancementioning

confidence: 99%

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The immunomodulatory effects of intravenous immunoglobulin therapy in Kawasaki disease

Burns

Franco

2015

Expert Review of Clinical Immunology

111

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Summary The introduction of intravenous immunoglobulin (IVIG) for modulation of inflammation in acute Kawasaki disease (KD) was a great therapeutic triumph. However, three decades later, the mechanisms underlying immune regulation by IVIG are only beginning to be revealed. Stimulation of an immature myeloid population of dendritic cells (DC) that secretes IL-10 and the elucidation of Fc-specific, HLA-restricted natural regulatory T cells (Treg) provide insights into mechanisms of IVIG. Other potential mechanisms include provision of agent-specific neutralizing antibody, anti-idiotype and anti-cytokine antibodies, blockade of activating Fcγ receptors, and stimulation of the inhibitory FcγRIIb receptor. New initiatives must seek to understand the mechanisms of IVIG in order to one day replace it with more affordable and more targeted therapies.

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“…Parents of KD patients in Japan have two-fold higher prevalence than general populations (Uehara et al , 2003). Additionally, multiple genome-wide association (GWA) and candidate gene studies, including our own, have consistently identified the Fc gamma receptors (FcGRs) as major players in the pathogenesis and treatment response for KD (Khor et al , 2011; Makowsky et al , 2013; Onouchi et al , 2012; Shendre et al , 2014; Shrestha et al , 2012; Shrestha et al , 2011). However, there are reports of other genes that have not been adequately studied, including the human leukocyte antigen (HLA) genes in the major histocompatibility complex (MHC) region.…”

Section: Introductionmentioning

confidence: 99%

Imputation of class I and II HLA loci using high‐density SNPs from ImmunoChip and their associations with Kawasaki disease in family‐based study

Shrestha

Wiener

Aissani

et al. 2015

Int J Immunogenetics

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Summary Kawasaki disease (KD) is the leading cause of acquired heart disease in children in most developed countries including the United States. The etiology of KD is not known; however, epidemiological and immunological data suggest infectious or immune-related factors in the manifestation of the disease. Further, KD has several hereditary features that strongly suggest a genetic component to disease pathogenesis. Human leukocyte antigen (HLA) loci have also been reported to be associated with KD but results have been inconsistent, in part, because of small study samples and varying linkage disequilibrium (LD) patterns observed across different ethnic groups. To maximize the informativeness of single nucleotide polymorphism (SNP) genotypes in the major histocompatibility (MHC) region, we imputed classical HLA I (A, B, C) and HLA II (DRB1, DQA1, DQB1) alleles using SNP2HLA method from genotypes of 6700 SNPs within the extended MHC region contained in the ImmunoChip among 112 white KD patients and their biological parents from North America and tested their association with KD susceptibility using the transmission disequilibrium test. Mendelian consistency in the trios suggested high accuracy and reliability of the imputed alleles (class I=97.5%, class II=96.6%). While several SNPs in the MHC region were individually associated with KD susceptibility, we report over-transmission of HLA-C*15 (z=+2.19, P=0.03) and under-transmission of HLA-B*44 (z=−2.49, P=0.01) alleles from parents to KD patients. HLA-B*44 has been associated with KD in other smaller studies and both HLA-C*15 and HLA-B*44 have biological mechanisms that could potentially be involved in KD pathogenesis. Overall, inferring HLA loci within the same ethnic group, using family based information is a powerful approach. However, larger families are warranted to evaluate the correlations of the strength and directions between the SNPs in MHC region and the imputed HLA alleles with KD.

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High-density genotyping of immune loci in Kawasaki disease and IVIG treatment response in European-American case–parent trio study

Cited by 24 publications

References 52 publications

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association

The immunomodulatory effects of intravenous immunoglobulin therapy in Kawasaki disease

Imputation of class I and II HLA loci using high‐density SNPs from ImmunoChip and their associations with Kawasaki disease in family‐based study

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