Common and Rare Genetic Variants That Could Contribute to Severe Otitis Media in an Australian Aboriginal Population.

Autor:	Jamieson SE; Telethon Kids Institute, The University of Western Australia, Perth, Western Australia., Fakiola M; FIRC Institute of Molecular Oncology (IFOM), Milan, Italy., Tang D; Telethon Kids Institute, The University of Western Australia, Perth, Western Australia., Scaman E; Telethon Kids Institute, The University of Western Australia, Perth, Western Australia., Syn G; Telethon Kids Institute, The University of Western Australia, Perth, Western Australia., Francis RW; Telethon Kids Institute, The University of Western Australia, Perth, Western Australia., Coates HL; Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Western Australia., Anderson D; Telethon Kids Institute, The University of Western Australia, Perth, Western Australia., Lassmann T; Telethon Kids Institute, The University of Western Australia, Perth, Western Australia., Cordell HJ; Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK., Blackwell JM; Telethon Kids Institute, The University of Western Australia, Perth, Western Australia.
Jazyk:	angličtina
Zdroj:	Clinical infectious diseases : an official publication of the Infectious Diseases Society of America [Clin Infect Dis] 2021 Nov 16; Vol. 73 (10), pp. 1860-1870.
DOI:	10.1093/cid/ciab216
Abstrakt:	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. (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)
Databáze:	MEDLINE
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