Genetic and functional evidence for a locus controlling otitis media at chromosome 10q26.3

BMC Medical Genetics

Sarra E Jamieson¹  Jenefer M Blackwell¹  Craig E Pennell³  Richard W Francis¹  Harvey L Coates⁴  Shyan Vijayasekaran⁴  Ruth B Thornton²  Elizabeth SH Scaman¹  Marie S Rye¹ 

[1] Telethon Institute for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia;School of Paediatrics and Child Health, University of Western Australia, Perth, Australia;School of Women’s and Infants’ Health, University of Western Australia, Perth, Australia;Department of Otolaryngology, Head and Neck Surgery, University of Western Australia, Perth, Western Australia, Australia

关键词: Australia;    WAFSOM;    Raine study;    Association;    Linkage;    Genetic polymorphisms;    Otitis media with effusion;    Acute otitis media;   

Others  :  1122514
DOI  :  10.1186/1471-2350-15-18

 received in 2012-10-18, accepted in 2014-01-21,  发布年份 2014

【 摘 要 】

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 (Z_lr = 2.69; P = 0.0036; D10S1770) with borderline evidence for linkage at 10q22.3 (Z_lr = 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-β/Activin/Nodal pathway modulator, as the more likely functional candidate lying immediately under the linkage peak for OM susceptibility at chromosome 10q26.3.

【 授权许可】

   
2014 Rye et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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