Regie Lyn P. Santos-Cortez, Charlotte M. Chiong, Daniel N. Frank, Allen F. Ryan, Arnaud P.J. Giese, Tori Bootpetch Roberts, Kathleen A. Daly, Matthew J. Steritz, Wasyl Szeremeta, Melquiadesa Pedro, Harold Pine, Talitha Karisse L. Yarza, Melissa A. Scholes, Erasmo Gonzalo d.V. Llanes, Saira Yousaf, Norman Friedman, Ma. Leah C. Tantoco, Todd M. Wine, Patrick John Labra, Jeanne Benoit, Amanda G. Ruiz, Rhodieleen Anne R. de la Cruz, Christopher Greenlee, Ayesha Yousaf, Jonathan Cardwell, Rachelle Marie A. Nonato, Dylan Ray, Kimberly Mae C. Ong, Edward So, Charles E. Robertson, Jordyn Dinwiddie, Sheryl Mae Lagrana-Villagracia, Samuel P. Gubbels, Rehan S. Shaikh, Stephen P. Cass, Elisabet Einarsdottir, Nanette R. Lee, David A. Schwartz, Teresa Luisa I. Gloria-Cruz, Michael J. Bamshad, Ivana V. Yang, Juha Kere, Generoso T. Abes, Jeremy D. Prager, Saima Riazuddin, Abner L. Chan, Patricia J. Yoon, Deborah A. Nickerson, Eva Maria Cutiongco-de la Paz, Sven-Olrik Streubel, Maria Rina T. Reyes-Quintos, Herman A. Jenkins, Petri Mattila, Kenny H. Chan, Karen L. Mohlke, Suzanne M. Leal, Lena Hafrén, Tasnee Chonmaitree, Michele M. Sale, Zubair M. Ahmed
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. © 2018 American Society of Human Genetics
Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, 80045, CO, United States; Center for Children's Surgery, Children's Hospital Colorado (CHCO), Aurora, 80045, CO, United States; Philippine National Ear Institute, University of the Philippines (UP) Manila – National Institutes of Health (NIH), Manila, 1000, Philippines; National Hearing Screening Reference Center, UP Manila-NIH, Manila, 1000, Philippines; Department of Otorhinolaryngology, UP Manila College of Medicine – Philippine General Hospital, Manila, 1000, Philippines; Division of Infectious Diseases, Department of Medicine, CUSOM, Aurora, 80045, CO, United States; Division of Otolaryngology, Department of Surgery, University of California San Diego School of Medicine, La Jolla, 92093, CA, United States; Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, 21201, MD, United States; Department of Otolaryngology, Head and Neck Surgery, University of Minnesota, Minneapolis, 55455, MN, United States; Department of Otolaryngology, University of Texas Medical Branch (UTMB), Galveston, 77555, TX, United States; Department of Pediatric Otolaryngology, CHCO, Aurora, 80045, CO, United States; Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Punjab, Pakistan; Department of Medicine, CUSOM, Aurora, 80045, CO, United States; Folkhälsan Institute of Genetics and Molecular Neurology Research Program, University of Helsinki, Helsinki, 00014, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, 141 83, Sweden; USC-Office of Population Studies Foundation and Department of Anthropology, Sociology and History, University of San Carlos, Cebu City, 6000, Philippines; Department of Genome Sciences, University of Washington, Seattle, 98195, WA, United States; Department of Medical and Molecular Genetics, King's College London, London, SE1 9RT, United Kingdom; UP Manila – NIH, Manila, 1000, Philippines; Philippine Genome Center, UP, Quezon City, 1101, Philippines; Department of Otorhinolaryngology, Head & Neck Surgery, University of Helsinki and Helsinki University Hospital, HUS, 00029, Finland; Department of Genetics, University of North Carolina, Chapel Hill, 27599, NC, United States; Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 77030, TX, United States; Department of Pediatrics, Division of Infectious Diseases, UTMB, Galveston, 77555, TX, United States; Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville, 22908, VA, United States; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, 22908, VA, United States; Department of Public Health Sciences, University of Virginia, Charlottesville, 22908, VA, United States
