Common variants in CASP3 confer susceptibility to Kawasaki disease.

Kawasaki disease (KD; OMIM 611775) is an acute vasculitis syndrome which predominantly affects small- and medium-sized arteries of infants and children. Epidemiological data suggest that host genetics underlie the disease pathogenesis. Here we report that multiple variants in the caspase-3 gene (CASP3) that are in linkage disequilibrium confer susceptibility to KD in both Japanese and US subjects of European ancestry. We found that a G to A substitution of one commonly associated SNP located in the 5' untranslated region of CASP3 (rs72689236; P = 4.2 x 10(-8) in the Japanese and P = 3.7 x 10(-3) in the European Americans) abolished binding of nuclear factor of activated T cells to the DNA sequence surrounding the SNP. Our findings suggest that altered CASP3 expression in immune effecter cells influences susceptibility to KD.

[Criteria for differential diagnosis of epilepsy and long QT syndrome presenting with seizures and EEG abnormalities].

We report a 13-year-old girl with congenital long QT syndrome (LQTS) who developed a cluster of generalized tonic clonic seizures with post-ictal EEG abnormality. The provisional diagnosis was epilepsy. However, ECG monitoring showed torsade de pointes, and thus the final diagnosis was LQTS. Although LQTS can be potentially misdiagnosed as epilepsy when it presents with seizures, it is important to differentiate LQTS from epilepsy because patients with LQTS are at risk of sudden death. We reviewed 11 previously reported cases with LQTS and EEG abnormalities who were initially diagnosed as epilepsy. We emphasized the importance of the following five criteria in the differentiation of LQTS from epilepsy: 1) awareness that LQT2 and LQT3 can cause life-threatening arrhythmia at rest or during sleep, 2) examination of arterial pulse during seizures, 3) monitoring ECG during EEG recording, 4) careful establishment of the correct diagnosis taking into consideration the interictal EEG findings, and 5) reconsidering the possibility of cardiac origin when the attacks cannot be controlled even by therapeutic levels of antiepileptic drugs in the blood.

[Sympathetic skin response in patients with severe motor and intellectual disabilities].

To elucidate autonomic function in individuals with severe motor and intellectual disabilities, we evaluated sympathetic skin response in 14 patients with severe motor and intellectual disabilities. The results of sympathetic skin response were compared with those of patients with mild or moderate motor and intellectual disabilities who could walk and had an intelligence quotient > or = 35 (7 cases) and neuromuscular diseases (3 cases). No sympathetic skin response was recorded in patients with severe motor and intellectual disabilities, whereas all patients with mild or moderate motor and intellectual disabilities defined above and neuromuscular diseases showed sympathetic skin response. The results suggested that all patients with severe motor and intellectual disabilities had autonomic dysfunction, and sympathetic skin response can be a useful test that can evaluate autonomic function in patients with severe motor and intellectual disabilities.

Variations in ORAI1 Gene Associated with Kawasaki Disease.

Kawasaki disease (KD; MIM#61175) is a systemic vasculitis syndrome with unknown etiology which predominantly affects infants and children. Recent findings of susceptibility genes for KD suggest possible involvement of the Ca(2+)/NFAT pathway in the pathogenesis of KD. ORAI1 is a Ca(2+) release activated Ca(2+) (CRAC) channel mediating store-operated Ca(2+) entry (SOCE) on the plasma membrane. The gene for ORAI1 is located in chromosome 12q24 where a positive linkage signal was observed in our previous affected sib-pair study of KD. A common non-synonymous single nucleotide polymorphism located within exon 2 of ORAI1 (rs3741596) was significantly associated with KD (P = 0.028 in the discovery sample set (729 KD cases and 1,315 controls), P = 0.0056 in the replication sample set (1,813 KD cases vs. 1,097 controls) and P = 0.00041 in a meta-analysis by the Mantel-Haenszel method). Interestingly, frequency of the risk allele of rs3741596 is more than 20 times higher in Japanese compared to Europeans. We also found a rare 6 base-pair in-frame insertion variant associated with KD (rs141919534; 2,544 KD cases vs. 2,414 controls, P = 0.012). These data indicate that ORAI1 gene variations are associated with KD and may suggest the potential importance of the Ca(2+)/NFAT pathway in the pathogenesis of this disorder.

CD40 ligand gene and Kawasaki disease.

Kawasaki disease (KD) is an acute systemic vasculitis syndrome of infants and young children. Although its etiology is largely unknown, epidemiological findings suggest that genetic factors play a role in the pathogenesis of KD. To identify genetic factors, affected sib-pair analysis has been performed. One of the identified peaks was located on the Xq26 region. A recent report of elevated expression of CD40 ligand (CD40L), which maps to Xq26, during the acute-phase KD, and its relationship to the development of coronary artery lesions (CAL) prompted us to screen for polymorphism of CD40L and to study the association of the gene to KD. A newly identified SNP in intron 4 (IVS4+121 A>G) is marginally over-represented in KD patients as compared to controls (109/602, 18.1 vs 111/737, 15.1%). When male KD patients with CAL were analyzed as a patient group, the SNP was significantly more frequent than in controls (15/58, 25.9%, vs 111/737, 15.1%, OR=2.0, 95% CI=1.07-3.66; P=0.030). Interestingly, this variation was extremely rare in a control Caucasian population (1/145, 0.7%). Our results suggest a role of CD40L in the pathogenesis of CAL and might explain the excess of males affected with KD.

Effect of aging on autonomic function in individuals with severe motor and intellectual disabilities.

Autonomic nervous function is often abnormally regulated in individuals with severe motor and intellectual disabilities (SMID). In this study, we assessed autonomic nervous function of patients with SMID and determined how it was influenced by age. The study included 21 individuals with SMID and 15 healthy adolescents (control). To determine the effect of aging, the patients with SMID were divided into an older age group (Old) and younger age group (Young). Autonomic nervous function was assessed using power spectral analysis of heart rate variability (HRV) for 24-h Holter electrocardiogram recordings. The low- and high-frequency components (LH and HF) of HRV were calculated. The ratio between LF and HF (LF/HF) was used as an indicator of sympathetic modulation, while HF alone was used as an indicator of parasympathetic modulation. The LH/HF in the control group was higher in the daytime than at nighttime, while HF had an opposite pattern of change. Therefore, circadian rhythms were observed in the control group for both sympathetic and parasympathetic nervous activities. In contrast, the LF/HF in patients with SMID had no circadian rhythm. The HF was higher in the Old SMID group than in the Young group, and it exhibited a circadian rhythm in eight patients in the Old SMID group versus none of the patients in the Young group. These findings suggest that the sympathetic nervous system is suppressed in both old and young patients with SMID. However, while the parasympathetic nervous system is suppressed in younger patients with SMID, it is activated with increasing age.

A genome-wide association study identifies three new risk loci for Kawasaki disease.

We performed a genome-wide association study (GWAS) of Kawasaki disease in Japanese subjects using data from 428 individuals with Kawasaki disease (cases) and 3,379 controls genotyped at 473,803 SNPs. We validated the association results in two independent replication panels totaling 754 cases and 947 controls. We observed significant associations in the FAM167A-BLK region at 8p22-23 (rs2254546, P = 8.2 × 10(-21)), in the human leukocyte antigen (HLA) region at 6p21.3 (rs2857151, P = 4.6 × 10(-11)) and in the CD40 region at 20q13 (rs4813003, P = 4.8 × 10(-8)). We also replicated the association of a functional SNP of FCGR2A (rs1801274, P = 1.6 × 10(-6)) identified in a recently reported GWAS of Kawasaki disease. Our findings provide new insights into the pathogenesis and pathophysiology of Kawasaki disease.

ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms.

Kawasaki disease is a pediatric systemic vasculitis of unknown etiology for which a genetic influence is suspected. We identified a functional SNP (itpkc_3) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 that is significantly associated with Kawasaki disease susceptibility and also with an increased risk of coronary artery lesions in both Japanese and US children. Transfection experiments showed that the C allele of itpkc_3 reduces splicing efficiency of the ITPKC mRNA. ITPKC acts as a negative regulator of T-cell activation through the Ca2+/NFAT signaling pathway, and the C allele may contribute to immune hyper-reactivity in Kawasaki disease. This finding provides new insights into the mechanisms of immune activation in Kawasaki disease and emphasizes the importance of activated T cells in the pathogenesis of this vasculitis.

Possible synergic effect of angiotensin-I converting enzyme gene insertion/deletion polymorphism and angiotensin-II type-1 receptor 1166A/C gene polymorphism on ischemic heart disease in patients with Kawasaki disease.

ACE I/D and AT1R 1166A/C polymorphisms are considered to comprise individual risk factors for the development of coronary disease. We sought to demonstrate that the ACE I/D and AT1R 1166A/C polymorphisms affect coronary artery stenosis in patients with Kawasaki disease (KD). We examined 147 healthy controls and 281 Japanese children with KD. The patients were further divided into group N (n = 246, no ischemia) and group I (n = 35, severe coronary artery stenosis with myocardial ischemia), and we studied the genotype of ACE I/D and AT1R 1166A/C polymorphisms. We also examined ACE activity in patients with acute KD. We did not detect any prevalent genotypes of the ACE and AT1R polymorphisms between controls and KD patients. However, the prevalence of the D allele in the ACE polymorphism and of the C allele in the AT1R polymorphism tended to be higher in group I than in group N (odds ratios, 2.00 and 2.32, respectively). In addition, the presence of the D and/or C alleles significantly increased the relative risk of developing myocardial ischemia (odds ratio, 2.71; p = 0.038). During the convalescent phase of KD, ACE activity was increased despite significant attenuation during the acute phase. These results suggested that the renin-angiotensin system is associated with the formation of severe coronary artery stenosis and myocardial ischemia.