Genetic and functional evidence for a role for SLC11A1 in susceptibility to otitis media in early childhood in a Western Australian population |
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| Affiliation: | 1. Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Subiaco, Western Australia, Australia;2. School of Paediatrics and Child Health, University of Western Australia, Perth, Australia;3. Department of Otolaryngology, Head and Neck Surgery, Princess Margaret Hospital for Children, Perth, Australia;4. Department of Otolaryngology, Head and Neck Surgery, University of Western Australia, Western Australia, Australia;1. Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom;2. Pathophysiology Department, School of Medicine, University of Athens, Greece;1. Division of Child Health, Menzies School of Health Research, Charles Darwin University, NT, Australia;2. Queensland Lung Transplant Service, The Prince Charles Hospital, QLD, Australia;3. School of Medicine, The University of Queensland, QLD, Australia;4. Department of Respiratory Medicine, Princess Alexandra Hospital, QLD, Australia;5. Telethon Kids Institute, The University of Western Australia, WA, Australia;6. Department of Respiratory Medicine, Queensland Children''s Medical Research Institute, Royal Children''s Hospital, QLD, Australia;1. Federal State Institution of Science Saratov Scientific Center Russian Academy of Sciences, St. Rabochaya 24, Saratov, 410028, Russia;2. Yuri Gagarin State Technical University of Saratov, St. Politechnicheskaya 77, Saratov, 410054, Russia;1. Basic Science Research Group, School of Graduate Studies, CES University, Medellín, Colombia;2. School of Medicine, CES University, Medellín, Colombia;3. Colombian Tropical Medicine Institute (ICMT), Medellín, Colombia |
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| Abstract: | Otitis media (OM) is a common disease in early childhood characterised by inflammation of the middle ear. Susceptibility to recurrent acute OM (rAOM; ⩾3 episodes AOM in 6 months) and chronic OM with effusion (COME; middle ear effusion ⩾3 months) is 40–70% heritable. Three bacterial pathogens commonly associated with OM, Streptococcus pneumoniae (Sp), non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mc), have been observed within adenoids and as facultative intracellular pathogens that invade and survive in mononuclear cells. Case/pseudo-control conditional logistic regression analysis of variants in the SLC11A1 gene, initially identified for its role in resistance to intra-macrophage pathogens in mice, revealed association with OM at four polymorphisms (Pbest = 0.025) in 531 families (660 affected children) from the Western Australian Family Study of Otitis Media. This included association at the functional promoter GTn polymorphism (rs34448891) with alleles that regulate high (allele 3; odds ratio = 1.2, 95% CI 1.00–1.44, P = 0.04) versus low (allele 2; odds ratio = 0.83, 95% CI 0.69–0.99, P = 0.04) SLC11A1 expression. Haplotype and stepwise conditional logistic regression analyses support a single genetic effect in the proximal region of SLC11A1, with the haplotype 3_C_C_G across rs34448891_rs2276631_rs3731865_rs2695343 significantly (P = 0.008) over-transmitted to affected offspring. Stratified analysis showed no association with OM in children who had undergone adenoidectomy (296 children), whereas children with adenoids intact (364 children) showed improved significance at the GTn polymorphism (allele 3: odds ratio = 1.38, 95% CI = 1.10–1.75, P = 0.006). Quantitative RT/PCR demonstrated high expression of SLC11A1 in mononuclear cells isolated from adenoid tissue, with a trend for decreased expression with increasing copies of GTn allele 2. Expression of SLC11A1 was enhanced at 12 (P = 1.2 × 10−3) and 24 h (P < 1.0 × 10−4) after infection of Mono-Mac-6 cells with NTHi. This study identifies SLC11A1 as a novel candidate for OM susceptibility, particularly in children with adenoids intact. Further analysis in other cohorts is required to validate these observations. |
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| Keywords: | SLC11A1 Acute otitis media Otitis media with effusion Genetic polymorphisms Association Qrt-PCR expression analysis |
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