Dataset Information

FUT2 Variants Confer Susceptibility to Familial Otitis Media.

ABSTRACT: Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154?) is associated with either 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 subjects with 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 otitis media in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p = 1.2 × 10-5) and US trios (TDT p = 0.01). The c.461G>A (p.Trp154?) variant was also over-transmitted in US trios (TDT p = 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p < 10-7) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios with CADD > 20 were combined, FUT2 variants were over-transmitted in trios (TDT p = 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-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 families demonstrate marked intra-familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.

SUBMITTER: Santos-Cortez RLP

PROVIDER: S-EPMC6217759 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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FUT2 Variants Confer Susceptibility to Familial Otitis Media.

Santos-Cortez Regie Lyn P RLP Chiong Charlotte M CM Frank Daniel N DN Ryan Allen F AF Giese Arnaud P J APJ Bootpetch Roberts Tori T Daly Kathleen A KA Steritz Matthew J MJ Szeremeta Wasyl W Pedro Melquiadesa M Pine Harold H Yarza Talitha Karisse L TKL Scholes Melissa A MA Llanes Erasmo Gonzalo D V EGDV Yousaf Saira S Friedman Norman N Tantoco Ma Leah C MLC Wine Todd M TM Labra Patrick John PJ Benoit Jeanne J Ruiz Amanda G AG de la Cruz Rhodieleen Anne R RAR Greenlee Christopher C Yousaf Ayesha A Cardwell Jonathan J Nonato Rachelle Marie A RMA Ray Dylan D Ong Kimberly Mae C KMC So Edward E Robertson Charles E CE Dinwiddie Jordyn J Lagrana-Villagracia Sheryl Mae SM Gubbels Samuel P SP Shaikh Rehan S RS Cass Stephen P SP Einarsdottir Elisabet E Lee Nanette R NR Schwartz David A DA Gloria-Cruz Teresa Luisa I TLI Bamshad Michael J MJ Yang Ivana V IV Kere Juha J Abes Generoso T GT Prager Jeremy D JD Riazuddin Saima S Chan Abner L AL Yoon Patricia J PJ Nickerson Deborah A DA Cutiongco-de la Paz Eva Maria EM Streubel Sven-Olrik SO Reyes-Quintos Maria Rina T MRT Jenkins Herman A HA Mattila Petri P Chan Kenny H KH Mohlke Karen L KL Leal Suzanne M SM Hafrén Lena L Chonmaitree Tasnee T Sale Michele M MM Ahmed Zubair M ZM

American journal of human genetics 20181025 5

Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154<sup>∗</sup>) is associated with either 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 subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common F ...[more]

PMID: 30401457

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Project description:Otitis media (OM) is common in young children and can cause hearing loss and speech, language, and developmental delays. OM has high heritability; however, little is known about OM-related molecular and genetic processes. CDHR3 was previously identified as a locus for OM susceptibility, but to date, studies have focused on how the CDHR3 p.Cys529Tyr variant increases epithelial binding of rhinovirus-C and risk for lung or sinus pathology. In order to further delineate a role for CDHR3 in OM, we performed the following: exome sequencing using DNA samples from OM-affected individuals from 257 multi-ethnic families; Sanger sequencing, logistic regression and transmission disequilibrium tests for 407 US trios or probands with OM; 16S rRNA sequencing and analysis for middle ear and nasopharyngeal samples; and single-cell RNA sequencing and differential expression analyses for mouse middle ear. From exome sequence data, we identified a novel pathogenic CDHR3 splice variant that co-segregates with OM in US and Finnish families. Additionally, a frameshift and six missense rare or low-frequency variants were identified in Finnish probands. In US probands, the CDHR3 p.Cys529Tyr variant was associated with the absence of middle ear fluid at surgery and also with increased relative abundance of Lysobacter in the nasopharynx and Streptomyces in the middle ear. Consistent with published data on airway epithelial cells and our RNA-sequence data from human middle ear tissues, Cdhr3 expression is restricted to ciliated epithelial cells of the middle ear and is downregulated after acute OM. Overall, these findings suggest a critical role for CDHR3 in OM susceptibility. KEY MESSAGES: • Novel rare or low-frequency CDHR3 variants putatively confer risk for otitis media. • Pathogenic variant CDHR3 c.1653 + 3G > A was found in nine families with otitis media. • CDHR3 p.Cys529Tyr was associated with lack of effusion and bacterial otopathogens. • Cdhr3 expression was limited to ciliated epithelial cells in mouse middle ear. • Cdhr3 was downregulated 3 h after infection of mouse middle ear.

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FUT2 Variants Confer Susceptibility to Familial Otitis Media.

Publications

FUT2 Variants Confer Susceptibility to Familial Otitis Media.

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