Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2021
Common and Rare Genetic Variants That Could Contribute to Severe Otitis Media in an Australian Aboriginal Population.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Jamieson Sarra E, Fakiola Michaela, Tang Dave, Scaman Elizabeth, Syn Genevieve, Francis Richard W, Coates Harvey L, Anderson Denise, Lassmann Timo, Cordell Heather J, Blackwell Jenefer M
Аннотация
BACKGROUND: Our goal was to identify genetic risk factors for severe otitis media (OM) in Aboriginal Australians.
METHODS: Illumina® Omni2.5 BeadChip and imputed data were compared between 21 children with severe OM (multiple episodes chronic suppurative OM and/or perforations or tympanic sclerosis) and 370 individuals without this phenotype, followed by FUnctional Mapping and Annotation (FUMA). Exome data filtered for common (EXaC_all ≥ 0.1) putative deleterious variants influencing protein coding (CADD-scaled scores ≥15] were used to compare 15 severe OM cases with 9 mild cases (single episode of acute OM recorded over ≥3 consecutive years). Rare (ExAC_all ≤ 0.01) such variants were filtered for those present only in severe OM. Enrichr was used to determine enrichment of genes contributing to pathways/processes relevant to OM.
RESULTS: FUMA analysis identified 2 plausible genetic risk loci for severe OM: NR3C1 (Pimputed_1000G = 3.62 × 10-6) encoding the glucocorticoid receptor, and NREP (Pimputed_1000G = 3.67 × 10-6) encoding neuronal regeneration-related protein. Exome analysis showed: (i) association of severe OM with variants influencing protein coding (CADD-scaled ≥ 15) in a gene-set (GRXCR1, CDH23, LRP2, FAT4, ARSA, EYA4) enriched for Mammalian Phenotype Level 4 abnormal hair cell stereociliary bundle morphology and related phenotypes; (ii) rare variants influencing protein coding only seen in severe OM provided gene-sets enriched for "abnormal ear" (LMNA, CDH23, LRP2, MYO7A, FGFR1), integrin interactions, transforming growth factor signaling, and cell projection phenotypes including hair cell stereociliary bundles and cilium assembly.
CONCLUSIONS: This study highlights interacting genes and pathways related to cilium structure and function that may contribute to extreme susceptibility to OM in Aboriginal Australian children.
METHODS: Illumina® Omni2.5 BeadChip and imputed data were compared between 21 children with severe OM (multiple episodes chronic suppurative OM and/or perforations or tympanic sclerosis) and 370 individuals without this phenotype, followed by FUnctional Mapping and Annotation (FUMA). Exome data filtered for common (EXaC_all ≥ 0.1) putative deleterious variants influencing protein coding (CADD-scaled scores ≥15] were used to compare 15 severe OM cases with 9 mild cases (single episode of acute OM recorded over ≥3 consecutive years). Rare (ExAC_all ≤ 0.01) such variants were filtered for those present only in severe OM. Enrichr was used to determine enrichment of genes contributing to pathways/processes relevant to OM.
RESULTS: FUMA analysis identified 2 plausible genetic risk loci for severe OM: NR3C1 (Pimputed_1000G = 3.62 × 10-6) encoding the glucocorticoid receptor, and NREP (Pimputed_1000G = 3.67 × 10-6) encoding neuronal regeneration-related protein. Exome analysis showed: (i) association of severe OM with variants influencing protein coding (CADD-scaled ≥ 15) in a gene-set (GRXCR1, CDH23, LRP2, FAT4, ARSA, EYA4) enriched for Mammalian Phenotype Level 4 abnormal hair cell stereociliary bundle morphology and related phenotypes; (ii) rare variants influencing protein coding only seen in severe OM provided gene-sets enriched for "abnormal ear" (LMNA, CDH23, LRP2, MYO7A, FGFR1), integrin interactions, transforming growth factor signaling, and cell projection phenotypes including hair cell stereociliary bundles and cilium assembly.
CONCLUSIONS: This study highlights interacting genes and pathways related to cilium structure and function that may contribute to extreme susceptibility to OM in Aboriginal Australian children.