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.

Pancreatic islet autoimmunity leading to type 1 diabetes could be triggered by viruses in genetically susceptible individuals. Rotavirus (RV), the most common cause of childhood gastroenteritis, contains peptide sequences highly similar to T-cell epitopes in the islet autoantigens GAD and tyrosine phosphatase IA-2 (IA-2), suggesting T-cells to RV could trigger islet autoimmunity by molecular mimicry. We therefore sought an association between RV infection and islet autoantibody markers in children at risk for diabetes who were followed from birth. There was a specific and highly significant association between RV seroconversion and increases in any of these antibodies: 86% of antibodies to IA-2, 62% to insulin, and 50% to GAD first appeared or increased with increases in RV IgG or IgA. RV infection may therefore trigger or exacerbate islet autoimmunity in genetically susceptible children. Diabetes 49:1319-1324, 2000 T ype 1 diabetes is an autoimmune disease that results from the destruction of pancreatic islet ␤-cells in genetically predisposed individuals. A large proportion of the lifetime risk of type 1 diabetes is attributed to environmental agents (1,2), but the only virus shown unequivocally to be responsible for clinical disease is rubella following infection in utero of infants bearing the HLA haplotype B8-(DR3-DQ2) (3). Circulating insulin autoantibodies (IAA), GAD65 antibodies (GADAb), and tyrosine phosphatase IA-2 autoantibodies (IA-2Ab) are markers of islet autoimmunity that predict the T-cell-mediated destruction of ␤-cells (4-6). Peptides in these islet autoantigens that are recognized by T-cells may provide clues to environmental agents that trigger or exacerbate islet autoimmunity through the mechanism of molecular mimicry (7,8).Recently, we identified T-cell epitope peptides in tyrosine phosphatase IA-2 (IA-2) restricted by HLA-DR4 in individuals at risk for type 1 diabetes (9,10). The dominant epitope (amino acid [aa] 805-820) contains a core 9-aa sequence in which 5 aa are identical and 4 aa are homologous with a 9-aa sequence (aa 41-49) within virus protein (VP)7 of rotavirus (RV) serotype G3 and to a lesser extent in the G1 and G2 serotypes. Because the T-cell contact residues in these similar IA-2 and RV VP7 sequences appear to be identical (9), the potential exists for molecular mimicry. Furthermore, just NH 2 -terminal of this region in VP7 is a 12-aa sequence (11) strongly similar to a sequence in GAD65 (aa 117-128) (9) that is a T-cell epitope in HLA-DR4 transgenic mice (12) and DR4-DQ8 homozygous at-risk humans (13). All human RV serotypes in the GenBank database contain the GAD-related sequence. VP7, the major outer capsid protein of RV, is an important determinant of virulence and induces virus-neutralizing antibodies (14). However, elimination of RV infection is predominantly due to T-cells (15). The CD4 T-cell epitopes in VP7 are unknown, but in C57/Bl 6 and BALB/c mice, CD8 T-cell epitopes (15,16) map adjacent to the IA-2-and GAD-like sequences, confirming that this signal sequenc...

II.