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Transcriptomic analysis identifies phosphatases as novel targets for adenotonsillar hypertrophy of pediatric obstructive sleep apnea.

ABSTRACT: Obstructive sleep apnea (OSA) is a highly prevalent disorder in children, in which enlarged adenotonsillar tissues (AT) play a major pathophysiologic role. Mechanisms leading to the proliferation and hypertrophy of AT in children who subsequently develop OSA remain unknown, and surgical extirpation of AT is associated with potential morbidity and mortality.We hypothesized that a computationally based analysis of gene expression in tonsils from children with OSA and children with recurrent tonsillitis without OSA can identify putative mechanistic pathways associated with tonsillar proliferation and hypertrophy in OSA.Palatine tonsils from children with either polysomnographically documented OSA or recurrent infectious tonsillitis were subjected to whole-genome microarray and functional enrichment analyses followed by significance score ranking based on gene interaction networks. The latter enabled identification and confirmation of a candidate list of tonsil-proliferative genes in OSA.In vitro studies using a mixed tonsil cell culture system targeting one of these candidates, phosphoserine phosphatase, revealed that it was more abundantly expressed in tonsils of children with OSA, and that pharmacological inhibition of phosphoserine phosphatase led to marked reductions in T- and B-lymphocyte cell proliferation and increased apoptosis.A systems biology approach revealed a restricted set of candidate genes potentially underlying the heightened proliferative properties of AT in children with OSA. Furthermore, functional studies confirm a novel role for protein phosphatases in AT hypertrophy, and may provide a promising strategy for discovery of novel, nonsurgical therapeutic targets in pediatric OSA.

SUBMITTER: Khalyfa A

PROVIDER: S-EPMC2874453 | biostudies-other | 2010 May

REPOSITORIES: biostudies-other

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Transcriptomic analysis identifies phosphatases as novel targets for adenotonsillar hypertrophy of pediatric obstructive sleep apnea.

Khalyfa Abdelnaby A Gharib Sina A SA Kim Jinkwan J Dayyat Ehab E Snow Ayelet B AB Bhattacharjee Rakesh R Kheirandish-Gozal Leila L Goldman Julie L JL Gozal David D

American journal of respiratory and critical care medicine 20100121 10

<h4>Rationale</h4>Obstructive sleep apnea (OSA) is a highly prevalent disorder in children, in which enlarged adenotonsillar tissues (AT) play a major pathophysiologic role. Mechanisms leading to the proliferation and hypertrophy of AT in children who subsequently develop OSA remain unknown, and surgical extirpation of AT is associated with potential morbidity and mortality.<h4>Objectives</h4>We hypothesized that a computationally based analysis of gene expression in tonsils from children with O ...[more]

PMID: 20093640

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Project description:IntroductionDiagnosis and treatment of obstructive sleep apnea (OSA) in children is often delayed due to the high prevalence and limited physician and sleep testing resources. As a result, children may be referred to multiple specialties, such as pediatric sleep medicine and pediatric otolaryngology, resulting in long waitlists.MethodWe used data from our pediatric OSA clinic to identify predictors of tonsillectomy and/or adenoidectomy (AT). Before being seen in the clinic, parents completed the Pediatric Sleep Questionnaire (PSQ) and screening questionnaires for restless leg syndrome (RLS), nasal rhinitis, and gastroesophageal reflux disease (GERD). Tonsil size data were obtained from patient charts and graded using the Brodsky-five grade scale. Children completed an overnight oximetry study before being seen in the clinic, and a McGill oximetry score (MOS) was assigned based on the number and depth of oxygen desaturations. Logistic regression, controlling for otolaryngology physician, was used to identify significant predictors of AT. Three triage algorithms were subsequently generated based on the univariate and multivariate results to predict AT.ResultsFrom the OSA cohort, there were 469 eligible children (47% female, mean age = 8.19 years, SD = 3.59), with 89% of children reported snoring. Significant predictors of AT in univariate analysis included tonsil size and four PSQ questions, (1) struggles to breathe at night, (2) apneas, (3) daytime mouth breathing, and (4) AM dry mouth. The first triage algorithm, only using the four PSQ questions, had an odds ratio (OR) of 4.02 for predicting AT (sensitivity = 0.28, specificity = 0.91). Using only tonsil size, the second algorithm had an OR to predict AT of 9.11 (sensitivity = 0.72, specificity = 0.78). The third algorithm, where MOS was used to stratify risk for AT among those children with 2+ tonsils, had the same OR, sensitivity, and specificity as the tonsil-only algorithm.ConclusionTonsil size was the strongest predictor of AT, while oximetry helped stratify individual risk for AT. We recommend that referral letters for snoring children include graded tonsil size to aid in the triage based on our findings. Children with 2+ tonsil sizes should be triaged to otolaryngology, while the remainder should be referred to a pediatric sleep specialist.

Project description:Study objectivesObstructive sleep apnea is associated with neurobehavioral dysfunction, but the relationship between disease severity as measured by the apnea-hypopnea index and neurobehavioral morbidity is unclear. The objective of our study is to compare the neurobehavioral morbidity of mild sleep-disordered breathing versus obstructive sleep apnea.MethodsChildren 3-12 years old recruited for mild sleep-disordered breathing (snoring with obstructive apnea-hypopnea index < 3) into the Pediatric Adenotonsillectomy Trial for Snoring were compared to children 5-9 years old recruited for obstructive sleep apnea (obstructive apnea-hypopnea 2-30) into the Childhood Adenotonsillectomy Trial. Baseline demographic, polysomnographic, and neurobehavioral outcomes were compared using univariable and multivariable analysis.ResultsThe sample included 453 participants with obstructive sleep apnea (median obstructive apnea-hypopnea index 5.7) and 459 participants with mild sleep-disordered breathing (median obstructive apnea-hypopnea index 0.5). By polysomnography, participants with obstructive sleep apnea had poorer sleep efficiency and more arousals. Children with mild sleep-disordered breathing had more abnormal executive function scores (adjusted odds ratio 1.96, 95% CI 1.30-2.94) compared to children with obstructive sleep apnea. There were also elevated Conners scores for inattention (adjusted odds ratio 3.16, CI 1.98-5.02) and hyperactivity (adjusted odds ratio 2.82, CI 1.83-4.34) in children recruited for mild sleep-disordered breathing.ConclusionsAbnormal executive function, inattention, and hyperactivity were more common in symptomatic children recruited into a trial for mild sleep-disordered breathing compared to children recruited into a trial for obstructive sleep apnea. Young, snoring children with only minimally elevated apnea-hypopnea levels may still be at risk for deficits in executive function and attention.Trial registrationPediatric Adenotonsillectomy for Snoring (PATS), NCT02562040; Childhood Adenotonsillectomy Trial (CHAT), NCT00560859.

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Transcriptomic analysis identifies phosphatases as novel targets for adenotonsillar hypertrophy of pediatric obstructive sleep apnea.

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Transcriptomic analysis identifies phosphatases as novel targets for adenotonsillar hypertrophy of pediatric obstructive sleep apnea.

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