Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10(-11), odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10(-9), OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10(-12), OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings(1). The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.

Abstract-Angiotensin II (Ang II) and nitric oxide (NO) signaling pathways mutually regulate each other by multiple mechanisms. Ang II regulates the expression of NO synthase and NO production, whereas NO downregulates the Ang II type I (AT1) receptor. A ngiotensin II (Ang II), the primary effector of the renin-angiotensin system (RAS), is a multifunctional hormone that plays an important role in vascular function. The local RAS, acting in both autocrine and paracrine fashions, is also functionally operative and important in the vasculature. 1,2 The role of the RAS, particularly of Ang II, is of great interest in cardiovascular physiology and pathology because of the beneficial effects of Ang II-converting enzyme (ACE) inhibitors and Ang II receptor blockers in cardiovascular diseases (hypertension, atherosclerosis, heart failure, and stroke). [3][4][5][6] Nitric oxide (NO) as an endogenous endothelium-derived relaxing factor has also been extensively studied. NO plays critical roles in the maintenance of vascular homeostasis. Reduction of NO production due to endothelial dysfunction is the result of many cardiovascular risk factors.In the vasculature, Ang II and NO interact with each other (albeit indirectly) to influence each other's functions. The interaction between Ang II and NO occurs in both the endothelial cell (EC) and vascular smooth muscle cell (VSMC). Vascular smooth muscle constricts in response to Ang II and dilates in response to NO. In addition to vascular tone, these 2 molecules antagonize each other in many vascular functions, such as cell growth, apoptosis, and inflammation. Ang II Signaling PathwaysThe actions of Ang II are primarily mediated by 2 receptors, Ang II type 1 (AT1) and type 2 (AT2). The AT1 receptor is widely present in many organs, such as the heart, kidneys, adrenal glands, and brain. The vast majority of well-known physiological and pathophysiological effects of Ang II have been shown to occur via the AT1 receptor. In the vasculature, the AT1 receptor is mainly expressed in VSMCs, where it mediates the vasoconstrictor, proliferative, and inflammatory actions of Ang II. There are AT1 receptors in the endothelium and in monocytes/macrophages as well, 7,8 which are pathophysiologically important because Ang II induces the oxidized LDL receptor in the endothelium and stimulates macrophages to express tumor necrosis factor-␣. 8,9 The AT2 receptor is highly and ubiquitously expressed in fetal tissue, and its expression is dramatically reduced after birth. 10,11 The fact that AT2 receptor expression is much higher in fetal compared with normal adult tissues has led to speculation as to its possible role in cell growth, development, and differentiation. AT2 receptor-mediated signaling pathways and function are not very well understood but in general appear to antagonize the effects of the AT1 receptor.Functions of the AT1 receptor, a G protein-coupled receptor, have been best characterized in VSMCs. The AT1 receptor coupled to Gq leads to phospholipase C (PLC) activation and, in turn, ...

OBJECTIVES: Prophylactic vaccination of youngwomen aged 16 to 26 years with the 9-valent (6/11/16/18/31/33/45/52/58) human papillomavirus (HPV) virus-like particle (9vHPV) vaccine prevents infection and disease. We conducted a noninferiority immunogenicity study to bridge the findings in young women to girls and boys aged 9 to 15 years.METHODS: Subjects (N = 3066) received a 3-dose regimen of 9vHPV vaccine administered at day 1, month 2, and month 6. Anti-HPV serologic assays were performed at day 1 and month 7. Noninferiority required that the lower bound of 2-sided 95% confidence intervals of geometric mean titer ratios (boys:young women or girls:young women) be .0.67 for each HPV type. Systemic and injection-site adverse experiences (AEs) and serious AEs were monitored.RESULTS: At 4 weeks after dose 3, .99% of girls, boys, and young women seroconverted for each vaccine HPV type. Increases in geometric mean titers to HPV types 6/11/16/18/ 31/33/45/52/58 were elicited in all vaccine groups. Responses in girls and boys were noninferior to those of young women. Persistence of anti-HPV responses was demonstrated through 2.5 years after dose 3. Administration of the 9vHPV vaccine was generally well tolerated. A lower proportion of girls (81.9%) and boys (72.8%) than young women (85.4%) reported injection-site AEs, most of which were mild to moderate in intensity.CONCLUSIONS: These data support bridging the efficacy findings with 9vHPV vaccine in young women 16 to 26 years of age to girls and boys 9 to 15 years of age and implementing genderneutral HPV vaccination programs in preadolescents and adolescents.WHAT'S KNOWN ON THIS SUBJECT: Prophylactic vaccination of young women 16 to 26 years of age with the 9-valent human papillomavirus (HPV)-like particle (9vHPV) vaccine prevents infection and disease with vaccine HPV types.WHAT THIS STUDY ADDS: These data support bridging the efficacy findings with 9vHPV vaccine in young women 16 to 26 years of age to girls and boys 9 to 15 years of age and implementation of gender-neutral HPV vaccination programs in preadolescents and adolescents.