FUT2 Variants Confer Susceptibility to Familial Otitis Media.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Santos-Cortez Regie Lyn P, Chiong Charlotte M, Frank Daniel N, Ryan Allen F, Giese Arnaud P J, Bootpetch Roberts Tori, Daly Kathleen A, Steritz Matthew J, Szeremeta Wasyl, Pedro Melquiadesa, Pine Harold, Yarza Talitha Karisse L, Scholes Melissa A, Llanes Erasmo Gonzalo D V, Yousaf Saira, Friedman Norman, Tantoco Ma Leah C, Wine Todd M, Labra Patrick John, Benoit Jeanne, Ruiz Amanda G, de la Cruz Rhodieleen Anne R, Greenlee Christopher, Yousaf Ayesha, Cardwell Jonathan, Nonato Rachelle Marie A, Ray Dylan, Ong Kimberly Mae C, So Edward, Robertson Charles E, Dinwiddie Jordyn, Lagrana-Villagracia Sheryl Mae, University of Washington Center for Mendelian Genomics (UWCMG), Gubbels Samuel P, Shaikh Rehan S, Cass Stephen P, Einarsdottir Elisabet, Lee Nanette R, Schwartz David A, Gloria-Cruz Teresa Luisa I, Bamshad Michael J, Yang Ivana V, Kere Juha, Abes Generoso T, Prager Jeremy D, Riazuddin Saima, Chan Abner L, Yoon Patricia J, Nickerson Deborah A, Cutiongco-de la Paz Eva Maria, Streubel Sven-Olrik, Reyes-Quintos Maria Rina T, Jenkins Herman A, Mattila Petri, Chan Kenny H, Mohlke Karen L, Leal Suzanne M, Hafrén Lena, Chonmaitree Tasnee, Sale Michele M, Ahmed Zubair M
Аннотация
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.