부산대학교 도서관

University of Washington Center for Mendelian Genomics (UWCMG) Keywords FUT2; fucosyltransferase; otitis media; middle ear infection; transmission disequilibrium test; TDT; microbiome; 16S rRNA sequencing; transient expression; A antigen Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154.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 FUT2 c.604C>T (p.Arg202.sup.*) 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 x 10.sup.-5) and US trios (TDT p = 0.01). The c.461G>A (p.Trp154.sup.*) variant was also over-transmitted in US trios (TDT p = 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p 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.sup.*, and p.Arg202.sup.*--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. Author Affiliation: (1) Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA (2) Center for Children's Surgery, Children's Hospital Colorado (CHCO), Aurora, CO 80045, USA (3) Philippine National Ear Institute, University of the Philippines (UP) Manila -- National Institutes of Health (NIH), Manila 1000, Philippines (4) National Hearing Screening Reference Center, UP Manila-NIH, Manila 1000, Philippines (5) Department of Otorhinolaryngology, UP Manila College of Medicine -- Philippine General Hospital, Manila 1000, Philippines (6) Division of Infectious Diseases, Department of Medicine, CUSOM, Aurora, CO 80045, USA (7) Division of Otolaryngology, Department of Surgery, University of California San Diego School of Medicine, La Jolla, CA 92093, USA (8) Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA (9) Department of Otolaryngology, Head and Neck Surgery, University of Minnesota, Minneapolis, MN 55455, USA (10) Department of Otolaryngology, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA (11) Department of Pediatric Otolaryngology, CHCO, Aurora, CO 80045, USA (12) Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Punjab, Pakistan (13) Department of Medicine, CUSOM, Aurora, CO 80045, USA (14) Folkhalsan Institute of Genetics and Molecular Neurology Research Program, University of Helsinki, Helsinki 00014, Finland (15) Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge 141 83, Sweden (16) USC-Office of Population Studies Foundation and Department of Anthropology, Sociology and History, University of San Carlos, Cebu City 6000, Philippines (17) Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA (18) Department of Medical and Molecular Genetics, King's College London, London SE1 9RT, UK (19) UP Manila -- NIH, Manila 1000, Philippines (20) Philippine Genome Center, UP, Quezon City 1101, Philippines (21) Department of Otorhinolaryngology, Head & Neck Surgery, University of Helsinki and Helsinki University Hospital, 00029 HUS, Finland (22) Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA (23) Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA (24) Department of Pediatrics, Division of Infectious Diseases, UTMB, Galveston, TX 77555, USA (25) Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA (26) Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA (27) Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA * Corresponding author Article History: Received 25 July 2018; Accepted 19 September 2018 (miscellaneous) Published: October 25, 2018 Byline: Regie Lyn P. Santos-Cortez [regie.santos-cortez@ucdenver.edu] (1,2,3,*), Charlotte M. Chiong (3,4,5), Daniel N. Frank (6), Allen F. Ryan (7), Arnaud P.J. Giese (8), Tori Bootpetch Roberts (1), Kathleen A. Daly (9), Matthew J. Steritz (1), Wasyl Szeremeta (10), Melquiadesa Pedro (3), Harold Pine (10), Talitha Karisse L. Yarza (3,4), Melissa A. Scholes (1,11), Erasmo Gonzalo d.V. Llanes (3,5), Saira Yousaf (8), Norman Friedman (1,11), Ma. Leah C. Tantoco (3,5), Todd M. Wine (1,11), Patrick John Labra (5), Jeanne Benoit (6), Amanda G. Ruiz (1,11), Rhodieleen Anne R. de la Cruz (5), Christopher Greenlee (1,11), Ayesha Yousaf (12), Jonathan Cardwell (13), Rachelle Marie A. Nonato (5), Dylan Ray (1), Kimberly Mae C. Ong (5), Edward So (8), Charles E. Robertson (6), Jordyn Dinwiddie (1,11), Sheryl Mae Lagrana-Villagracia (3), Samuel P. Gubbels (1), Rehan S. Shaikh (12), Stephen P. Cass (1), Elisabet Einarsdottir (14,15), Nanette R. Lee (16), David A. Schwartz (13), Teresa Luisa I. Gloria-Cruz (3,5), Michael J. Bamshad (17), Ivana V. Yang (13), Juha Kere (14,15,18), Generoso T. Abes (3,5), Jeremy D. Prager (1,11), Saima Riazuddin (8), Abner L. Chan (3,5), Patricia J. Yoon (1,11), Deborah A. Nickerson (17), Eva Maria Cutiongco-de la Paz (19,20), Sven-Olrik Streubel (1,11), Maria Rina T. Reyes-Quintos (3,4,5,19), Herman A. Jenkins (1), Petri Mattila (21), Kenny H. Chan (1,11), Karen L. Mohlke (22), Suzanne M. Leal (23), Lena Hafren (21), Tasnee Chonmaitree (24), Michele M. Sale (25,26,27), Zubair M. Ahmed (8)