FUT2 Variants Confer Susceptibility to Familial Otitis Media.

Autor:	Santos-Cortez RLP; Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA; Center for Children's Surgery, Children's Hospital Colorado (CHCO), Aurora, CO 80045, USA; Philippine National Ear Institute, University of the Philippines (UP) Manila - National Institutes of Health (NIH), Manila 1000, Philippines. Electronic address: regie.santos-cortez@ucdenver.edu., Chiong CM; 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., Frank DN; Division of Infectious Diseases, Department of Medicine, CUSOM, Aurora, CO 80045, USA., Ryan AF; Division of Otolaryngology, Department of Surgery, University of California San Diego School of Medicine, La Jolla, CA 92093, USA., Giese APJ; Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA., Bootpetch Roberts T; Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA., Daly KA; Department of Otolaryngology, Head and Neck Surgery, University of Minnesota, Minneapolis, MN 55455, USA., Steritz MJ; Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA., Szeremeta W; Department of Otolaryngology, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA., Pedro M; Philippine National Ear Institute, University of the Philippines (UP) Manila - National Institutes of Health (NIH), Manila 1000, Philippines., Pine H; Department of Otolaryngology, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA., Yarza TKL; 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., Scholes MA; Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA; Department of Pediatric Otolaryngology, CHCO, Aurora, CO 80045, USA., Llanes EGDV; Philippine National Ear Institute, University of the Philippines (UP) Manila - National Institutes of Health (NIH), Manila 1000, Philippines; Department of Otorhinolaryngology, UP Manila College of Medicine - Philippine General Hospital, Manila 1000, Philippines., Yousaf S; Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA., Friedman N; Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA; Department of Pediatric Otolaryngology, CHCO, Aurora, CO 80045, USA., Tantoco MLC; Philippine National Ear Institute, University of the Philippines (UP) Manila - National Institutes of Health (NIH), Manila 1000, Philippines; Department of Otorhinolaryngology, UP Manila College of Medicine - Philippine General Hospital, Manila 1000, Philippines., Wine TM; Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA; Department of Pediatric Otolaryngology, CHCO, Aurora, CO 80045, USA., Labra PJ; Department of Otorhinolaryngology, UP Manila College of Medicine - Philippine General Hospital, Manila 1000, Philippines., Benoit J; Division of Infectious Diseases, Department of Medicine, CUSOM, Aurora, CO 80045, USA., Ruiz AG; Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA; Department of Pediatric Otolaryngology, CHCO, Aurora, CO 80045, USA., de la Cruz RAR; Department of Otorhinolaryngology, UP Manila College of Medicine - Philippine General Hospital, Manila 1000, Philippines., Greenlee C; Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA; Department of Pediatric Otolaryngology, CHCO, Aurora, CO 80045, USA., Yousaf A; Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Punjab, Pakistan., Cardwell J; Department of Medicine, CUSOM, Aurora, CO 80045, USA., Nonato RMA; Department of Otorhinolaryngology, UP Manila College of Medicine - Philippine General Hospital, Manila 1000, Philippines., Ray D; Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA., Ong KMC; Department of Otorhinolaryngology, UP Manila College of Medicine - Philippine General Hospital, Manila 1000, Philippines., So E; Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA., Robertson CE; Division of Infectious Diseases, Department of Medicine, CUSOM, Aurora, CO 80045, USA., Dinwiddie J; Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA; Department of Pediatric Otolaryngology, CHCO, Aurora, CO 80045, USA., Lagrana-Villagracia SM; Philippine National Ear Institute, University of the Philippines (UP) Manila - National Institutes of Health (NIH), Manila 1000, Philippines., Gubbels SP; Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA., Shaikh RS; Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Punjab, Pakistan., Cass SP; Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA., Einarsdottir E; 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., Lee NR; USC-Office of Population Studies Foundation and Department of Anthropology, Sociology and History, University of San Carlos, Cebu City 6000, Philippines., Schwartz DA; Department of Medicine, CUSOM, Aurora, CO 80045, USA., Gloria-Cruz TLI; Philippine National Ear Institute, University of the Philippines (UP) Manila - National Institutes of Health (NIH), Manila 1000, Philippines; Department of Otorhinolaryngology, UP Manila College of Medicine - Philippine General Hospital, Manila 1000, Philippines., Bamshad MJ; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA., Yang IV; Department of Medicine, CUSOM, Aurora, CO 80045, USA., Kere J; 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; Department of Medical and Molecular Genetics, King's College London, London SE1 9RT, UK., Abes GT; Philippine National Ear Institute, University of the Philippines (UP) Manila - National Institutes of Health (NIH), Manila 1000, Philippines; Department of Otorhinolaryngology, UP Manila College of Medicine - Philippine General Hospital, Manila 1000, Philippines., Prager JD; Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA; Department of Pediatric Otolaryngology, CHCO, Aurora, CO 80045, USA., Riazuddin S; Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA., Chan AL; Philippine National Ear Institute, University of the Philippines (UP) Manila - National Institutes of Health (NIH), Manila 1000, Philippines; Department of Otorhinolaryngology, UP Manila College of Medicine - Philippine General Hospital, Manila 1000, Philippines., Yoon PJ; Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA; Department of Pediatric Otolaryngology, CHCO, Aurora, CO 80045, USA., Nickerson DA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA., Cutiongco-de la Paz EM; UP Manila - NIH, Manila 1000, Philippines; Philippine Genome Center, UP, Quezon City 1101, Philippines., Streubel SO; Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA; Department of Pediatric Otolaryngology, CHCO, Aurora, CO 80045, USA., Reyes-Quintos MRT; 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; UP Manila - NIH, Manila 1000, Philippines., Jenkins HA; Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA., Mattila P; Department of Otorhinolaryngology, Head & Neck Surgery, University of Helsinki and Helsinki University Hospital, 00029 HUS, Finland., Chan KH; Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA; Department of Pediatric Otolaryngology, CHCO, Aurora, CO 80045, USA., Mohlke KL; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA., Leal SM; Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Hafrén L; Department of Otorhinolaryngology, Head & Neck Surgery, University of Helsinki and Helsinki University Hospital, 00029 HUS, Finland., Chonmaitree T; Department of Pediatrics, Division of Infectious Diseases, UTMB, Galveston, TX 77555, USA., Sale MM; Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA; Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA., Ahmed ZM; Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2018 Nov 01; Vol. 103 (5), pp. 679-690. Date of Electronic Publication: 2018 Oct 25.
DOI:	10.1016/j.ajhg.2018.09.010
Abstrakt:	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. (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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