FUT2 Variants Confer Susceptibility to Familial Otitis Media

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UWCMG 2018 , ' FUT2 Variants Confer Susceptibility to Familial Otitis Media ' , American Journal of Human Genetics , vol. 103 , no. 5 , pp. 679-690 . https://doi.org/10.1016/j.ajhg.2018.09.010

Title: FUT2 Variants Confer Susceptibility to Familial Otitis Media
Author: UWCMG
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Date: 2018-11-01
Language: eng
Number of pages: 12
Belongs to series: American Journal of Human Genetics
ISSN: 0002-9297
DOI: https://doi.org/10.1016/j.ajhg.2018.09.010
URI: http://hdl.handle.net/10138/306619
Abstract: Non-secretor status due tohomozygosity for the commonFUT2 variant c. 461G> A(p. Trp154*) is associated witheither risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjectswith otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c. 604C> T (p. Arg202*) variant co-segregates with otitismedia in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c. 412C> T (p. Arg138Cys), is associated with recurrent/ chronic otitismedia in European-American children (p = 1.2310(-5)) and US trios (TDT p = 0.01). The c. 461G> A (p. Trp154*) variant was also overtransmitted in US trios (TDT p = 0.01) and was associated with shifts inmiddle ear microbiota composition (PERMANOVA p <10(-7)) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios withCADD> 20 were combined, FUT2 variantswere over-transmitted in trios (TDTp = 0.001). Fut2 is transiently upregulated inmouse middle ear after inoculation withnon-typeable Haemophilus influenzae. Four FUT2 variants-namely p. Ala104Val, p. Arg138Cys, p. Trp154*, and p. Arg202*-reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our familiesdemonstratemarked intra-familial genetic heterogeneity, suggesting thatmultiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.
3125 Otorhinolaryngology, ophthalmology

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