Dataset Information

Predisposition to Childhood Otitis Media and Genetic Polymorphisms within the Toll-Like Receptor 4 (TLR4) Locus.

ABSTRACT: Predisposition to childhood otitis media (OM) has a strong genetic component, with polymorphisms in innate immunity genes suspected to contribute to risk. Studies on several genes have been conducted, but most associations have failed to replicate in independent cohorts.We investigated 53 gene polymorphisms in a Finnish cohort of 624 cases and 778 controls. A positive association signal was followed up in a tagging approach and tested in an independent Finnish cohort of 205 cases, in a British cohort of 1269 trios, as well as in two cohorts from the United States (US); one with 403 families and the other with 100 cases and 104 controls.In the initial Finnish cohort, the SNP rs5030717 in the TLR4 gene region showed significant association (OR 1.33, P = .003) to OM. Tagging SNP analysis of the gene found rs1329060 (OR 1.33, P = .002) and rs1329057 (OR 1.29, P = .003) also to be associated. In the more severe phenotype the association was stronger. This finding was supported by an independent Finnish case cohort, but the associations failed to replicate in the British and US cohorts. In studies on TLR4 signaling in 20 study subjects, the three-marker risk haplotype correlated with a decreased TNF? secretion in myeloid dendritic cells.The TLR4 gene locus, regulating the innate immune response, influences the genetic predisposition to childhood OM in a subpopulation of patients. Environmental factors likely modulate the genetic components contributing to the risk of OM.

SUBMITTER: Hafren L

PROVIDER: S-EPMC4503307 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Predisposition to Childhood Otitis Media and Genetic Polymorphisms within the Toll-Like Receptor 4 (TLR4) Locus.

Hafrén Lena L Einarsdottir Elisabet E Kentala Erna E Hammarén-Malmi Sari S Bhutta Mahmood F MF MacArthur Carol J CJ Wilmot Beth B Casselbrant Margaretha M Conley Yvette P YP Weeks Daniel E DE Mandel Ellen M EM Vaarala Outi O Kallio Anna A Melin Merit M Nieminen Janne K JK Leinonen Eira E Kere Juha J Mattila Petri S PS

PloS one 20150715 7

<h4>Background</h4>Predisposition to childhood otitis media (OM) has a strong genetic component, with polymorphisms in innate immunity genes suspected to contribute to risk. Studies on several genes have been conducted, but most associations have failed to replicate in independent cohorts.<h4>Methods</h4>We investigated 53 gene polymorphisms in a Finnish cohort of 624 cases and 778 controls. A positive association signal was followed up in a tagging approach and tested in an independent Finnish ...[more]

PMID: 26177520

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Project description:BACKGROUND: Otitis media (OM) is a common childhood disease characterised by middle ear effusion and inflammation. Susceptibility to recurrent acute OM and chronic OM with effusion is 40-70% heritable. Linkage studies provide evidence for multiple putative OM susceptibility loci. This study attempts to replicate these linkages in a Western Australian (WA) population, and to identify the etiological gene(s) in a replicated region. METHODS: Microsatellites were genotyped in 468 individuals from 101 multicase families (208 OM cases) from the WA Family Study of OM (WAFSOM) and non-parametric linkage analysis carried out in ALLEGRO. Association mapping utilized dense single nucleotide polymorphism (SNP) data extracted from Illumina 660 W-Quad analysis of 256 OM cases and 575 controls from the WA Pregnancy Cohort (Raine) Study. Logistic regression analysis was undertaken in ProbABEL. RT-PCR was used to compare gene expression in paired adenoid and tonsil samples, and in epithelial and macrophage cell lines. Comparative genomics methods were used to identify putative regulatory elements and transcription factor binding sites potentially affected by associated SNPs. RESULTS: Evidence for linkage was observed at 10q26.3 (Zlr = 2.69; P = 0.0036; D10S1770) with borderline evidence for linkage at 10q22.3 (Zlr = 1.64; P = 0.05; D10S206). No evidence for linkage was seen at 3p25.3, 17q12, or 19q13.43. Peak association at 10q26.3 was in the intergenic region between TCERG1L and PPP2R2D (rs7922424; P = 9.47 × 10-6), immediately under the peak of linkage. Independent associations were observed at DOCK1 (rs9418832; P = 7.48 × 10-5) and ADAM12 (rs7902734; P = 8.04 × 10-4). RT-PCR analysis confirmed expression of all 4 genes in adenoid samples. ADAM12, DOCK1 and PPP2R2D, but not TCERG1L, were expressed in respiratory epithelial and macrophage cell lines. A significantly associated polymorphism (rs7087384) in strong LD with the top SNP (rs7922424; r2 = 0.97) alters a transcription factor binding site (CREB/CREBP) in the intergenic region between TCERG1L and PPP2R2D. CONCLUSIONS: OM linkage was replicated at 10q26.3. Whilst multiple genes could contribute to this linkage, the weight of evidence supports PPP2R2D, a TGF-?/Activin/Nodal pathway modulator, as the more likely functional candidate lying immediately under the linkage peak for OM susceptibility at chromosome 10q26.3.

Project description:A comprehensive understanding about the pathogenesis of otitis media (OM), one of the most common pediatric diseases, has the potential to alleviate a substantial disease burden across the globe. Advancements in genetic and bioinformatic detection methods, as well as a growing interest in the microbiome, has enhanced the capability of researchers to investigate the interplay between host genes, host microbiome, invading bacteria, and resulting OM susceptibility. Early studies deciphering the role of genetics in OM susceptibility assessed the heritability of the phenotype in twin and triplet studies, followed by linkage studies, candidate gene approaches, and genome-wide association studies that have helped in the identification of specific loci. With the advancements in techniques, various chromosomal regions and genes such as FBXO11, TGIF1, FUT2, FNDC1, and others have been implicated in predisposition to OM, yet questions still remain as to whether these implicated genes truly play a causative role in OM and to what extent. Meanwhile, 16S ribosomal RNA (rRNA) sequencing, microbial quantitative trait loci (mbQTL), and microbial genome-wide association studies (mGWAS) have mapped the microbiome of upper airways sites and therefore helped in enabling a more detailed study of interactions between host polymorphisms and host microbiome composition. Variants of specific genes conferring increased OM susceptibility, such as A2ML1, have also been shown to influence the microbial composition of the outer and middle ear in patients with OM, suggesting their role as mediators of disease. These interactions appear to impact the colonization of known otopathogens (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis), as well as Neisseria, Gemella, Porphyromonas, Alloprevotella, and Fusobacterium populations that have also been implicated in OM pathogenesis. Meanwhile, studies demonstrating an increased abundance of Dolosigranulum and Corynebacterium in healthy patients compared to those with OM suggest a protective role for these bacteria, thereby introducing potential avenues for future probiotic treatment. Incorporating insights from these genetic, microbiome, and host-pathogen studies will allow for a more robust, comprehensive understanding of OM pathogenesis that can ultimately facilitate in the development of exciting new treatment modalities.

Project description:BACKGROUND: Otitis media (OM) is a common childhood disease characterised by middle ear inflammation and effusion. Susceptibility to recurrent acute OM (rAOM; ? 3 episodes of AOM in 6 months) and chronic OM with effusion (COME; MEE ? 3 months) is 40-70% heritable. Few underlying genes have been identified to date, and no genome-wide association study (GWAS) of OM has been reported. METHODS AND FINDINGS: Data for 2,524,817 single nucleotide polymorphisms (SNPs; 535,544 quality-controlled SNPs genotyped by Illumina 660W-Quad; 1,989,273 by imputation) were analysed for association with OM in 416 cases and 1,075 controls from the Western Australian Pregnancy Cohort (Raine) Study. Logistic regression analyses under an additive model undertaken in GenABEL/ProbABEL adjusting for population substructure using principal components identified SNPs at CAPN14 (rs6755194: OR = 1.90; 95%CI 1.47-2.45; P(adj-PCA) = 8.3 × 10(-7)) on chromosome 2p23.1 as the top hit, with independent effects (rs1862981: OR = 1.60; 95%CI 1.29-1.99; P(adj-PCA) = 2.2 × 10(-5)) observed at the adjacent GALNT14 gene. In a gene-based analysis in VEGAS, BPIFA3 (P(Gene) = 2 × 10(-5)) and BPIFA1 (P(Gene) = 1.07 × 10(-4)) in the BPIFA gene cluster on chromosome 20q11.21 were the top hits. In all, 32 genomic regions show evidence of association (P(adj-PCA)<10(-5)) in this GWAS, with pathway analysis showing a connection between top candidates and the TGF? pathway. However, top and tag-SNP analysis for seven selected candidate genes in this pathway did not replicate in 645 families (793 affected individuals) from the Western Australian Family Study of Otitis Media (WAFSOM). Lack of replication may be explained by sample size, difference in OM disease severity between primary and replication cohorts or due to type I error in the primary GWAS. CONCLUSIONS: This first discovery GWAS for an OM phenotype has identified CAPN14 and GALNT14 on chromosome 2p23.1 and the BPIFA gene cluster on chromosome 20q11.21 as novel candidate genes which warrant further analysis in cohorts matched more precisely for clinical phenotypes.

Dataset Information

Predisposition to Childhood Otitis Media and Genetic Polymorphisms within the Toll-Like Receptor 4 (TLR4) Locus.

Publications

Predisposition to Childhood Otitis Media and Genetic Polymorphisms within the Toll-Like Receptor 4 (TLR4) Locus.

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