Original ResearchSoy isoflavone intake is associated with risk of Kawasaki disease
Introduction
Kawasaki disease (KD) is the leading cause of acquired heart disease in children in most developed countries including the United States [1]. Peak age incidence of KD occurs in children younger than 5 years, but cases can occur even in adolescence. In the United States alone, approximately 5500 cases were estimated in 2009 with only passive surveillance [2], and based on system dynamics modeling simulations, there will be an average of 6200 new patients each year with an acute KD [3]. Kawasaki disease is a life-threatening acute vasculitis that diffusely involves multiple organ systems in children but has a predilection for involvement of the coronary arteries [4]. Acute inflammation within the coronaries can result in arterial dilation and aneurysm formation with subsequent development of stenosis during a chronic convalescent phase. Thus, KD leads to significant morbidity in a relatively young population.
Even after 50 years of research, the etiology for this disease remains elusive, and the risk factors still need to be defined. Many consider KD an autoimmune phenomenon, and thus, anti-inflammatory high-dose intravenous immunoglobulin provides the mainstay therapy. The prevailing theories for causation include antigen presentation followed by an autoimmune response in genetically susceptible individuals [5]. Asian ethnicity is the primary risk factor. Kawasaki disease incidence in Japan exceeds 220 per 100 000 children, greater than 10 times the rate in the United States [6]. Eastern Asian countries including Korea and Taiwan [7] also show remarkably high KD incidence compared to nations with populations of predominantly European descent [8]. The high incidence rate persists in Japanese descendant children living in the United States [9]. Hypotheses implicating genetic differences among populations as the defining factors for ethnic variation in incidence predominate [7]. Genetic studies have identified ethnic differences in HLA and CD40 loci in KD populations. However, these differences do not account for the extreme variation in KD incidence [10]. Environmental agents or toxins have historically been considered as potential KD triggers or risk factors [11]. More recent theories suggest that environmental factors borne by tropospheric wind currents emanating from central Asia and extending over Japan, Hawaii, and then the US Pacific Coast play an important role for in the pathogenesis [12].
We recently proposed a hypothesis that isoflavones in soy alter immune response in young children and cultural differences in diet therefore may explain in part the ethnic differences in KD incidence [13]. The hypothesis is supported by mechanistic data on effects of the soy isoflavone genistein [14], [15], [16] and by epidemiological studies conducted in Hawaii, which show ethnic group–based associations between soy consumption and KD incidence [9], [17], [13]. However, the epidemiologic analysis did not directly consider soy consumption in KD patients but extrapolated data from the general population. Accordingly, we tested the hypothesis that soy isoflavone consumption is associated with risk of KD in a US-based cohort by performing nutritional assessments in children with KD. We also extended the hypothesis to include maternal soy consumption during pregnancy and lactation as risk factors for KD.
Section snippets
Study design and subjects
We conducted a case-control study in the Seattle Children's Hospital (SCH) Kawasaki cohort, which included all patients diagnosed and seen in clinic between January 2000 and July 2014 and treated and/or followed at the SCH and their mothers. This study was conducted according to the guidelines laid down in the Declaration of Helsinki, and all procedures involving human subjects/patients were approved by the SCH Institutional Review Board number 11897. Written informed consent was obtained from
Results
Characteristics of KD cases and controls by category of isoflavone intake are given in Table 1. Race is recorded from self-report on the survey. Overall, age of KD case at reference date was slightly younger (4.0 ± 3.7 vs 5.2 ± 4.2; P< .01), and cases were more likely to be male (61% vs 51%; P= .03). Both cases and controls tended to be predominantly white (65% and 77% for cases and controls, respectively) with slightly more cases tending to be of Asian descent (17% vs 11%), although cases and
Discussion
We report for the first time an association between soy isoflavone intake and KD in a case-control study. Thus, we accept our original hypothesis. When compared to soy nonconsumers, the odds of KD were 2 to 2½ times greater among children in the highest category of total isoflavone and genistein intakes. The odds were 7 to 8 times greater among children of Asian descent in the highest category of total isoflavone and genistein intakes, which were higher than among whites.
Kawasaki disease likely
Financial disclosure
None.
Conflict of interest
None.
Acknowledgment
The authors thank Lauren Hunter for help with data entry and Margarita Santiago for her assistance with the figure. This work was support in part by Fred Hutchinson Cancer Research Center and National Institutes of Health/National Cancer Institute award P30 CA015704. SL Navarro was supported by NIH/NCI training grant T32CA09168.
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