FUT2 Variants Confer Susceptibility to Familial Otitis Media

University of Washington Center for Mendelian Genomics (UWCMG)

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)679-690
Number of pages12
JournalAmerican Journal of Human Genetics
Volume103
Issue number5
DOIs
StatePublished - Nov 1 2018

Fingerprint

Otitis Media
Middle Ear
Microbiota
Exome
Antigens
Genetic Heterogeneity
COS Cells
Haemophilus influenzae
Pedigree
Autoimmune Diseases
Diarrhea
Epithelial Cells
HIV
Phenotype
DNA
Proteins

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

University of Washington Center for Mendelian Genomics (UWCMG) (2018). FUT2 Variants Confer Susceptibility to Familial Otitis Media. American Journal of Human Genetics, 103(5), 679-690. https://doi.org/10.1016/j.ajhg.2018.09.010

FUT2 Variants Confer Susceptibility to Familial Otitis Media. / University of Washington Center for Mendelian Genomics (UWCMG).

In: American Journal of Human Genetics, Vol. 103, No. 5, 01.11.2018, p. 679-690.

Research output: Contribution to journalArticle

University of Washington Center for Mendelian Genomics (UWCMG) 2018, 'FUT2 Variants Confer Susceptibility to Familial Otitis Media', American Journal of Human Genetics, vol. 103, no. 5, pp. 679-690. https://doi.org/10.1016/j.ajhg.2018.09.010
University of Washington Center for Mendelian Genomics (UWCMG). FUT2 Variants Confer Susceptibility to Familial Otitis Media. American Journal of Human Genetics. 2018 Nov 1;103(5):679-690. https://doi.org/10.1016/j.ajhg.2018.09.010
University of Washington Center for Mendelian Genomics (UWCMG). / FUT2 Variants Confer Susceptibility to Familial Otitis Media. In: American Journal of Human Genetics. 2018 ; Vol. 103, No. 5. pp. 679-690.
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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.",
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AU - University of Washington Center for Mendelian Genomics (UWCMG)

AU - Santos-Cortez, Regie Lyn P.

AU - Chiong, Charlotte M.

AU - Frank, Daniel N.

AU - Ryan, Allen F.

AU - Giese, Arnaud P.J.

AU - Bootpetch Roberts, Tori

AU - Daly, Kathleen A.

AU - Steritz, Matthew J.

AU - Szeremeta, Wasyl

AU - Pedro, Melquiadesa

AU - Pine, Harold

AU - Yarza, Talitha Karisse L.

AU - Scholes, Melissa A.

AU - Llanes, Erasmo Gonzalo d.V.

AU - Yousaf, Saira

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AU - Wine, Todd M.

AU - Labra, Patrick John

AU - Benoit, Jeanne

AU - Ruiz, Amanda G.

AU - de la Cruz, Rhodieleen Anne R.

AU - Greenlee, Christopher

AU - Yousaf, Ayesha

AU - Cardwell, Jonathan

AU - Nonato, Rachelle Marie A.

AU - Ray, Dylan

AU - Ong, Kimberly Mae C.

AU - So, Edward

AU - Robertson, Charles E.

AU - Dinwiddie, Jordyn

AU - Lagrana-Villagracia, Sheryl Mae

AU - Gubbels, Samuel P.

AU - Shaikh, Rehan S.

AU - Cass, Stephen P.

AU - Einarsdottir, Elisabet

AU - Lee, Nanette R.

AU - Schwartz, David A.

AU - Gloria-Cruz, Teresa Luisa I.

AU - Bamshad, Michael J.

AU - Yang, Ivana V.

AU - Kere, Juha

AU - Abes, Generoso T.

AU - Prager, Jeremy D.

AU - Riazuddin, Saima

AU - Chan, Abner L.

AU - Yoon, Patricia J.

AU - Nickerson, Deborah A.

AU - Cutiongco-de la Paz, Eva Maria

AU - Streubel, Sven Olrik

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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.

AB - 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.

KW - 16S rRNA sequencing

KW - A antigen

KW - fucosyltransferase

KW - FUT2

KW - microbiome

KW - middle ear infection

KW - otitis media

KW - TDT

KW - transient expression

KW - transmission disequilibrium test

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