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Am J Hum Genet. 2018 Nov 1;103(5):679-690. doi: 10.1016/j.ajhg.2018.09.010. Epub 2018 Oct 25.

FUT2 Variants Confer Susceptibility to Familial Otitis Media.

Author information

1
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.
2
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.
3
Division of Infectious Diseases, Department of Medicine, CUSOM, Aurora, CO 80045, USA.
4
Division of Otolaryngology, Department of Surgery, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
5
Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
6
Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA.
7
Department of Otolaryngology, Head and Neck Surgery, University of Minnesota, Minneapolis, MN 55455, USA.
8
Department of Otolaryngology, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA.
9
Philippine National Ear Institute, University of the Philippines (UP) Manila - National Institutes of Health (NIH), Manila 1000, Philippines.
10
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.
11
Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, CO 80045, USA; Department of Pediatric Otolaryngology, CHCO, Aurora, CO 80045, USA.
12
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.
13
Department of Otorhinolaryngology, UP Manila College of Medicine - Philippine General Hospital, Manila 1000, Philippines.
14
Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Punjab, Pakistan.
15
Department of Medicine, CUSOM, Aurora, CO 80045, USA.
16
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.
17
USC-Office of Population Studies Foundation and Department of Anthropology, Sociology and History, University of San Carlos, Cebu City 6000, Philippines.
18
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
19
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.
20
UP Manila - NIH, Manila 1000, Philippines; Philippine Genome Center, UP, Quezon City 1101, Philippines.
21
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.
22
Department of Otorhinolaryngology, Head & Neck Surgery, University of Helsinki and Helsinki University Hospital, 00029 HUS, Finland.
23
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
24
Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
25
Department of Pediatrics, Division of Infectious Diseases, UTMB, Galveston, TX 77555, USA.
26
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.

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.

KEYWORDS:

16S rRNA sequencing; A antigen; FUT2; TDT; fucosyltransferase; microbiome; middle ear infection; otitis media; transient expression; transmission disequilibrium test

PMID:
30401457
PMCID:
PMC6217759
[Available on 2019-05-01]
DOI:
10.1016/j.ajhg.2018.09.010

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