The role of CDHR3 in susceptibility to otitis media

• Abstract: Otitis media (OM) is common in young children and can cause hearing loss and speech, language, and developmental delays. OM has high heritability; however, little is known about OM-related molecular and genetic processes. CDHR3 was previously identified as a locus for OM susceptibility, but to date, studies have focused on how the CDHR3 p.Cys529Tyr variant increases epithelial binding of rhinovirus-C and risk for lung or sinus pathology. In order to further delineate a role for CDHR3 in OM, we performed the following: exome sequencing using DNA samples from OM-affected individuals from 257 multi-ethnic families; Sanger sequencing, logistic regression and transmission disequilibrium tests for 407 US trios or probands with OM; 16S rRNA sequencing and analysis for middle ear and nasopharyngeal samples; and single-cell RNA sequencing and differential expression analyses for mouse middle ear. From exome sequence data, we identified a novel pathogenic CDHR3 splice variant that co-segregates with OM in US and Finnish families. Additionally, a frameshift and six missense rare or low-frequency variants were identified in Finnish probands. In US probands, the CDHR3 p.Cys529Tyr variant was associated with the absence of middle ear fluid at surgery and also with increased relative abundance of Lysobacter in the nasopharynx and Streptomyces in the middle ear. Consistent with published data on airway epithelial cells and our RNA-sequence data from human middle ear tissues, Cdhr3 expression is restricted to ciliated epithelial cells of the middle ear and is downregulated after acute OM. Overall, these findings suggest a critical role for CDHR3 in OM susceptibility. Key messages: • Novel rare or low-frequency CDHR3 variants putatively confer risk for otitis media. • Pathogenic variant CDHR3 c.1653 + 3G > A was found in nine families with otitis media. • CDHR3 p.Cys529Tyr was associated with lack of effusion and bacterial otopathogens. • Cdhr3 expression was limited to ciliated epithelial cells in mouse middle ear. • Cdhr3 was downregulated 3 h after infection of mouse middle ear.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

Nyckelord

CDHR3

Expression

Microbiome

Middle ear

Otitis media

rs6967330

antibiotic agent

messenger RNA

RNA 16S

cadherin related protein

CDHR3 protein

human

membrane protein

transcriptome

acute otitis media

airway epithelium cell

allergic rhinitis

Article

bacterial microbiome

Caucasian

cdhr3 gene

child

cohort analysis

Colorado

differential expression analysis

DNA sequencing

ear tissue

ethnicity

exome

female

Finland

gene

gene frequency

gene function

gene identification

gene linkage disequilibrium

genetic susceptibility

genetic variability

genotype

Hispanic

human

human tissue

loss of function mutation

Lysobacter

major clinical study

male

Minnesota

nasopharynx

nontypeable Haemophilus influenzae

otoscopy

Pakistani

pathogenesis

population abundance

preschool child

recurrent disease

RNA sequencing

Sanger sequencing

single cell RNA seq

single nucleotide polymorphism

Streptomyces

Texas

tympanometry

whole exome sequencing

animal

C57BL mouse

genetic predisposition

genetics

infant

microbiology

microflora

mutation

Animals

Cadherin Related Proteins

Child

Preschool

Genetic Predisposition to Disease

Humans

Membrane Proteins

Mice

Inbred C57BL

Microbiota

RNA

Ribosomal

16S

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)