Kawasaki disease (KD) is a pediatric vasculitis that damages the coronary arteries in 25% of untreated and approximately 5% of treated children. Epidemiologic data suggest that KD is triggered by unidentified infection(s) in genetically susceptible children. To investigate genetic determinants of KD susceptibility, we performed a genome-wide association study (GWAS) in 119 Caucasian KD cases and 135 matched controls with stringent correction for possible admixture, followed by replication in an independent cohort and subsequent fine-mapping, for a total of 893 KD cases plus population and family controls. Significant associations of 40 SNPs and six haplotypes, identifying 31 genes, were replicated in an independent cohort of 583 predominantly Caucasian KD families, with NAALADL2 (rs17531088, p_combined = 1.13×10⁻⁶) and ZFHX3 (rs7199343, p_combined = 2.37×10⁻⁶) most significantly associated. Sixteen associated variants with a minor allele frequency of >0.05 that lay within or close to known genes were fine-mapped with HapMap tagging SNPs in 781 KD cases, including 590 from the discovery and replication stages. Original or tagging SNPs in eight of these genes replicated the original findings, with seven genes having further significant markers in adjacent regions. In four genes (ZFHX3, NAALADL2, PPP1R14C, and TCP1), the neighboring markers were more significantly associated than the originally associated variants. Investigation of functional relationships between the eight fine-mapped genes using Ingenuity Pathway Analysis identified a single functional network (p = 10⁻¹³) containing five fine-mapped genes—LNX1, CAMK2D, ZFHX3, CSMD1, and TCP1—with functional relationships potentially related to inflammation, apoptosis, and cardiovascular pathology. Pair-wise blood transcript levels were measured during acute and convalescent KD for all fine-mapped genes, revealing a consistent trend of significantly reduced transcript levels prior to treatment. This is one of the first GWAS in an infectious disease. We have identified novel, plausible, and functionally related variants associated with KD susceptibility that may also be relevant to other cardiovascular diseases. Kawasaki disease is an inflammatory pediatric condition that damages the coronary arteries in a quarter of untreated patients and is the commonest cause of childhood acquired heart disease in developed countries. While the infectious trigger(s) remain unknown, epidemiologic evidence suggests that human genetic variation underlies the susceptibility. In order to identify novel mechanisms that may predispose to this disease, we undertook a genome-wide association study, which investigates genetic determinants without prior supposition regarding the loci of interest. This was amongst the first complex infectious diseases to be studied in this way and one of the largest genetic studies of Kawasaki disease with 893 cases. We identified and confirmed 40 SNPs and six haplotypes, identifying 31 genes, in an international cohort of Caucasian patients. We followed up 16 SNPs where the associated genetic variant was more common and was situated within a gene, confirming eight SNPs by fine-mapping across the entire gene. Of these eight genes, seven were expressed in blood and five showed significantly different gene expression in paired patient samples taken during acute and convalescent Kawasaki disease. Five of the eight genes also appear to be involved in a single putative functional network of interacting genes. These novel genes and pathways may ultimately lead to novel diagnostics and treatment for Kawasaki disease.

Kawasaki disease (KD) is an acute self-limiting inflammatory disorder, associated with vasculitis, affecting predominantly medium-sized arteries, particularly the coronary arteries. In developed countries KD is the commonest cause of acquired heart disease in childhood. The aetiology of KD remains unknown, and it is currently believed that one or more as yet unidentified infectious agents induce an intense inflammatory host response in genetically susceptible individuals. Genetic studies have identified several susceptibility genes for KD and its sequelae in different ethnic populations, including FCGR2A, CD40, ITPKC, FAM167A-BLK and CASP3, as well as genes influencing response to intravenous immunoglobulin (IVIG) and aneurysm formation such as FCGR3B, and transforming growth factor (TGF) β pathway genes. IVIG and aspirin are effective therapeutically, but recent clinical trials and meta-analyses have demonstrated that the addition of corticosteroids to IVIG is beneficial for the prevention of coronary artery aneurysms (CAA) in severe cases with highest risk of IVIG resistance. Outside of Japan, however, clinical scores to predict IVIG resistance perform suboptimally. Furthermore, the evidence base does not provide clear guidance on which corticosteroid regimen is most effective. Other therapies, including anti-TNFα, could also have a role for IVIG-resistant KD. Irrespective of these caveats, it is clear that therapy that reduces inflammation in acute KD, improves outcome. This paper summarises recent advances in the understanding of KD pathogenesis and therapeutics, and provides an approach for managing KD patients in the UK in the light of these advances.

Background— Pulmonary arterial hypertension (PAH) is a potentially fatal vasculopathy that can develop at any age. Adult-onset disease has previously been associated with mutations in BMPR2 and ALK-1 . Presentation in early life may be associated with congenital heart disease but frequently is idiopathic. Methods and Results— We performed mutation analysis in genes encoding receptor members of the transforming growth factor-β cell-signaling pathway in 18 children (age at presentation <6 years) with PAH. Sixteen children were initially diagnosed with idiopathic PAH and 2 with PAH in association with congenital heart defects. Germ-line mutations were observed in 4 patients (22%) (age at disease onset, 1 month to 6 years), all of whom presented with idiopathic PAH. The BMPR2 mutations (n=2, 11%) included a partial gene deletion and a nonsense mutation, both arising de novo in the proband. Importantly, a missense mutation of ALK-1 and a branch-site mutation of endoglin were also detected. Presenting clinical features or progression of pulmonary hypertension did not distinguish between patients with mutations in the different genes or between those without mutations. Conclusions— The cause of PAH presenting in childhood is heterogeneous in nature, with genetic defects of transforming growth factor-β receptors playing a critical role.

Background: In recent large paediatric cardiomyopathy population studies from North America and Australia, vitamin D deficiency was not identified as a cause of infant heart failure. However, rickets is resurgent in developed countries. Objective: To review the prevalence of this cardiomyopathy in paediatric cardiology units of southeast England and determine the prognosis. Methods and results: A retrospective review from 2000 to 2006 in southeast England. Sixteen infants (6 Indian subcontinent, 10 black ethnicity) were identified: median (range) age at presentation was 5.3 months (3 weeks–8 months). All had been breast fed. Ten presented at the end of the British winter (February–May). Median shortening fraction was 10% (range 5–18%) and median left ventricular end diastolic dimension z score was 4.1 (range 3.1–7.0). Six had a cardiac arrest; three infants died. Eight were ventilated, two required mechanical circulatory support and 12 required intravenous inotropic support. Two were referred for cardiac transplantation. Median (range) of biochemical values on admission was: total calcium 1.5 (1.07–1.74) mmol/l; alkaline phosphatase 646 (340–1057) IU/l; 25-hydroxyvitamin D 18.5 (0–46) nmol/l (normal range >35) and parathyroid hormone 34.3 (8.9–102) pmol/l (normal range <6.1). The clinical markers and echocardiographic indices of all survivors have improved. The mean time from diagnosis to achieve normal fractional shortening was 12.4 months. Conclusions: Vitamin D deficiency and consequent hypocalcaemia are seen in association with severe and life-threatening infant heart failure. That no infant or mother was receiving the recommended vitamin supplementation highlights the need for adequate provision of vitamin D to ethnic minority populations.

Understanding global seasonal patterns of Kawasaki disease (KD) may provide insight into the etiology of this vasculitis that is now the most common cause of acquired heart disease in children in developed countries worldwide. Data from 1970-2012 from 25 countries distributed over the globe were analyzed for seasonality. The number of KD cases from each location was normalized to minimize the influence of greater numbers from certain locations. The presence of seasonal variation of KD at the individual locations was evaluated using three different tests: time series modeling, spectral analysis, and a Monte Carlo technique. A defined seasonal structure emerged demonstrating broad coherence in fluctuations in KD cases across the Northern Hemisphere extra-tropical latitudes. In the extra-tropical latitudes of the Northern Hemisphere, KD case numbers were highest in January through March and approximately 40% higher than in the months of lowest case numbers from August through October. Datasets were much sparser in the tropics and the Southern Hemisphere extra-tropics and statistical significance of the seasonality tests was weak, but suggested a maximum in May through June, with approximately 30% higher number of cases than in the least active months of February, March and October. The seasonal pattern in the Northern Hemisphere extra-tropics was consistent across the first and second halves of the sample period. Using the first global KD time series, analysis of sites located in the Northern Hemisphere extra-tropics revealed statistically significant and consistent seasonal fluctuations in KD case numbers with high numbers in winter and low numbers in late summer and fall. Neither the tropics nor the Southern Hemisphere extra-tropics registered a statistically significant aggregate seasonal cycle. These data suggest a seasonal exposure to a KD agent that operates over large geographic regions and is concentrated during winter months in the Northern Hemisphere extra-tropics.