| Literature DB >> 30401457 |
Regie Lyn P Santos-Cortez1, Charlotte M Chiong2, Daniel N Frank3, Allen F Ryan4, Arnaud P J Giese5, Tori Bootpetch Roberts6, Kathleen A Daly7, Matthew J Steritz6, Wasyl Szeremeta8, Melquiadesa Pedro9, Harold Pine8, Talitha Karisse L Yarza10, Melissa A Scholes11, Erasmo Gonzalo D V Llanes12, Saira Yousaf5, Norman Friedman11, Ma Leah C Tantoco12, Todd M Wine11, Patrick John Labra13, Jeanne Benoit3, Amanda G Ruiz11, Rhodieleen Anne R de la Cruz13, Christopher Greenlee11, Ayesha Yousaf14, Jonathan Cardwell15, Rachelle Marie A Nonato13, Dylan Ray6, Kimberly Mae C Ong13, Edward So5, Charles E Robertson3, Jordyn Dinwiddie11, Sheryl Mae Lagrana-Villagracia9, Samuel P Gubbels6, Rehan S Shaikh14, Stephen P Cass6, Elisabet Einarsdottir16, Nanette R Lee17, David A Schwartz15, Teresa Luisa I Gloria-Cruz12, Michael J Bamshad18, Ivana V Yang15, Juha Kere19, Generoso T Abes12, Jeremy D Prager11, Saima Riazuddin5, Abner L Chan12, Patricia J Yoon11, Deborah A Nickerson18, Eva Maria Cutiongco-de la Paz20, Sven-Olrik Streubel11, Maria Rina T Reyes-Quintos21, Herman A Jenkins6, Petri Mattila22, Kenny H Chan11, Karen L Mohlke23, Suzanne M Leal24, Lena Hafrén22, Tasnee Chonmaitree25, Michele M Sale26, Zubair M Ahmed5.
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.Entities:
Keywords: 16S rRNA sequencing; A antigen; FUT2; TDT; fucosyltransferase; microbiome; middle ear infection; otitis media; transient expression; transmission disequilibrium test
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Year: 2018 PMID： 30401457 PMCID： PMC6217759 DOI： 10.1016/j.ajhg.2018.09.010
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.025