EGAGenomicsIllumina Infinium HumanCoreExome BeadchipOtherhttps://ega-archive.org/studies/EGAS00001002678EGAEGA study EGAS00001002678Illumina_HumanCoreExomeEGArestrictedDisease, Bouillauds Disease, Antigenic Mimicry, wide/broad, determination, Mimicry, familial, Bouillaud's, Rheumatic Heart Diseases, Heart Diseases, Factor, broad, Risk Factor Score, Risk Factor Scores, Rheumatic, Rheumatic Heart, Antigenic Mimicries, Risk Factors, DNA Mimicry, chemical analysis, Heart Disease, Diseases, Antigen, Score, Molecular., rheumatic heart, rheumatic heart disease, Risk Factor, DNA Mimicries, Correlates, Bouillaud Disease, Populations at Risk, Factors, Social Risk Factors, Risk, rheumatic, Genomes, Molecular, RHD, Risk Score, Antigenic, heart disease, whole genome, Population at Risk, Bouillaud, Antigen Mimicries, Risk Scores, rheumatic carditis, genetic, Social, Rheumatic carditis, Social Risk, disease, wide, Health, Antigen Mimicry, Bouillaud's Disease, Health Correlates, Social Risk Factor, Rheumatic Heart Disease, inherited genetic, assay, DNA, Molecular Mimicries, constitutitional genetic, hereditary, MimicriesHeart, Antigenic Determinants, Antigenic Mimicry, Rh polypeptide 2, BamF, determination, methionine aminopeptidase activity, BamC, AP-2, Mimicry, alpha-Spe, positive regulation by symbiont of host non-apoptotic programmed cell death, Infestations and Infections, DELTA AND GAMMA, Risk Factor Score, betaTub1, CG31654, alpha-Spc, Relative, Actin Activated, Techniques, l(3)04276, Rheumatic Heart, B1t, Risk Factors, epitope function, Method, Associations, Heart Disease, Antigen, pathogenesis, 2, alpha-adaptin, germacrene A synthase activity, RH, DmelCG10422, Cardiac Valve, DNA Mimicries, Rhl1, peptidase M activity, alpha-spec, Correlates, adenomas, rabGAPLP, L-methionine aminopeptidase activity, Man (Taxonomy), kus, rheumatic, CG4260, beta1tub, stimulation by symbiont of host programmed cell death, Genomes, antigenic determinant, CG9277, Molecular, Myosin ATPase, RabGAP-5, T, beta-particle, Rh, procedures, PMNC, group A streptococcus, rhesus D antigen, alpha-spectrin, genetic, Social, PA1, CD, 1t, geographical area, e, Adenosinetriphosphatase, Methodological Studies, e-, Bouillaud's Disease, beta1Tub, Health Correlates, RUSC3, C16orf53, MHC16, Infections and Infestations, Nucleotide, Streptococcus sp. (group A), epitope role, Mimicries, group A streptococci, (+)-germacrene A synthase activity, Epitope, heart valve, BETA 56D, wide/broad, RHCED, Modern, NMHC-II-C, familial, MYH-associated polyposis, autosomal recessive familial adenomatous polyposis, Actin Activated ATPase, Maps, ham, Rhced, PMN cell, Procedure, results, Haplotype, Rh4, ada, Rheumatic, alphaSpec, D-Ada, l(1)G0108, Relative Risks, Diseases, cg4260, modulation by symbiont of host system process, Corpuscles, NMHC II-C, Score, DQ-A1, FLOWERING TIME CONTROL PROTEIN FCA ALPHA, dAP-2a, GAS, 6-trans-farnesyl-diphosphate diphosphate-lyase (germacrene-A-forming) activity, spectrin, nucleotides, autosomal recessive, Antigenic Determinant, DFNA4, CELIAC1, l(2)06694, MENE (2L)-A, RUTBC3, Blood Cell, beta-tub, Factors, positional polypeptide feature, Beta <eudicots>, Social Risk Factors, Risk, RHD, Myosin Adenosine Triphosphatase, FCAALL.331, Infection and Infestation, valvule, Methodological, whole genome, alpha, GSE, AP-2alpha, beta56D, White Blood Corpuscles, DmelCG9277, Methodological Study, human, Bouillaud, Antigen Mimicries, DmelCG4260, RABGAP5, White Blood Cells, beta1-tub, beta(-), DTB2, disease, white blood cell, Corpuscle, beta-Tub, Social Risk, wide, Health, RhPI, i6, DL4180C, activation by symbiont of host programmed cell death, multiple colorectal, White, inherited genetic, Blood Corpuscles, DNA, beta-Tub56D, betaTub, Specbeta, polymorphonuclear cell, beta1-Tubulin, alpha-Ada, anon-EST:fe2E2, human being, l(3)alpha-Spec, Procedures, RHXIII, DFNA4A, Myosin Adenosinetriphosphatase, region or site annotation, regulation by symbiont of host system process, alpha-Spect, Bouillaud's, e(-), 2-trans, Gene, Heart Diseases, broad, electron, Antigenic Specificity, White Blood Corpuscle, l(2)SH2 0460, Human, fs(3)neo61, CG10422, MYH17, alpha-ada, Cardiac, Determinant, myosin 1, Actin-Activated ATPase, Homo sapiens, B-spec, RHDVA(TT), DNA Mimicry, induction by organism of non-apoptotic programmed cell death in other organism during symbiotic interaction, betaspec, klo, Gene Products, Studies, causality., alpha-Sp, rheumatic heart, RH30, rheumatic heart disease, CG1977, Blood Corpuscle, Man, Technique, familial adenomatous polyposis, Risk Factor, MAP, Bouillaud Disease, stomodaeal valve, positional, betatub(56D), Populations at Risk, Valves, familial adenomatous polyposis 2, ligand, Elektron, RHDel, beta[[1]] tubulin, dre3, beta1t, Antigenic, Risk Score, causes, Alpha-Adaptin, HLA-DQA, Population at Risk, autosomal recessive multiple colorectal adenomas, anon-EST:fe1B3, Study, blood group RhD polypeptide, Infestation and Infection, ATPase, Antigen Mimicry, myosin, SPEC8, RhDCw, Social Risk Factor, CG5870, constitutitional genetic, DIIIc, l(3)dre3, beta-tubulin56D, Spec-beta, Disease, Dmbeta1, Bouillauds Disease, Leukocyte, alpha-Spectrin, activation by organism of non-apoptotic programmed cell death in other organism, MUTYH-Associated Polyposis, immune cell, Actomyosin Adenosinetriphosphatase, hemolysin activity, 3A9, DmelCG1977, 6-trans-farnesyl-diphosphate diphosphate-lyase [(+)-germacrene-A-forming] activity, Proteins, Rheumatic Heart Diseases, Tubulin, heart valves, Myosin, Factor, Valve, i168, (+)-(10R)-germacrene A synthase activity, Risk Factor Scores, CD240D, Cell, Heart Valve, Antigenic Mimicries, Protein, chemical analysis, Infection, sequence, MENE(2L)-A, betaSpec, background, techniques, Determinants, alphaSp, b-Spec, Relative Risk, Blood Cells, DmelCG5870, PNMHH, l(1)G0074, MYOSIN, leucocyte, Adenosine Triphosphatase, l(1)G0198, D-alphaAda, mating_type_alpha, negatron, beta[[1]]-tubulin, RhII, Risks, Specificity, FCP-B, b spectrin, beta1, heart disease, Actomyosin ATPase, MYH-Associated Polyposis, primary structure of sequence macromolecule, introduction, beta, rheumatic carditis, RHPII, Risk Scores, Rheumatic carditis, Protein Gene Products, Tub, Gene Proteins, AP2, Actomyosin, l(3)62Bd, beta-spec, RhK562-II, Bam-C, Modern Man, RhPII, White Blood, BAM, Bam, alpha mating type (yeast), BETA, l(2)SH0460, alfa-Spec, Rheumatic Heart Disease, MAP syndrome, assay, Molecular Mimicries, hereditary, White Blood Cell, Spec, FAP2, Cardiac Valves, methodology, Actin-Activated, colorectal adenomatous polyposisfalseGenome-wide analysis of genetic risk factors for rheumatic heart disease in Aboriginal Australians provides support for pathogenic molecular mimicryBackground. Rheumatic heart disease (RHD) following Group A Streptococcus (GAS) infections is heritable and prevalent in Indigenous populations. Molecular mimicry between human and GAS proteins triggers pro-inflammatory cardiac valve-reactive T-cells. Methods. Genome-wide genetic analysis was undertaken in 1263 Aboriginal Australians (398 RHD cases; 865 controls). Single nucleotide polymorphisms (SNPs) were genotyped using Illumina HumanCoreExome BeadChips. Direct typing and imputation was used to fine-map the human leukocyte antigen (HLA) region. Epitope binding affinities were mapped for human cross-reactive GAS proteins, including M5 and M6. Results. The strongest genetic association was intronic to HLA-DQA1 (rs9272622; P=1.86x10-7). Conditional analyses showed rs9272622 and/or DQA1*AA16 account for the HLA signal. HLA-DQA1*0101_DQB1*0503 (OR 1.44, 95%CI 1.09-1.90, P=9.56x10-3) and HLA-DQA1*0103_DQB1*0601 (OR 1.27, 95%CI 1.07-1.52, P=7.15x10-3) were risk haplotypes; HLA_DQA1*0301-DQB1*0402 (OR 0.30, 95%CI 0.14-0.65, P=2.36x10-3) was protective. Human myosin cross-reactive N-terminal and B repeat epitopes of GAS M5/M6 bind with higher affinity to DQA1/DQB1 alpha/beta dimers for the two risk haplotypes than the protective haplotype. Conclusions. Variation at HLA_DQA1-DQB1 is the major genetic risk factor for RHD in Aboriginal Australians studied here. Cross-reactive epitopes bind with higher affinity to alpha/beta dimers formed by risk haplotypes, supporting molecular mimicry as the key mechanism of RHD pathogenesis.2017-11-30 17:50:53EGAS000010026789606EGAD00010001410EGAC00001000261