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


OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Khalyfa
Abdelnaby
A
Department of Pediatrics, University of Chicago, 5721 S. Maryland Avenue, Chicago, IL 60637, USA.
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
D000234:Adenoids / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D017209:Apoptosis; D016022:Case-Control Studies; D048708:Cell Growth Processes / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D016503:Drug Delivery Systems / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D006984:Hypertrophy / Q000235:genetics / Q000473:pathology; D008297:Male; D014066:Palatine Tonsil / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D012313:RNA / Q000032:analysis; D020181:Sleep Apnea, Obstructive / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D046888:Tissue Array Analysis; D014069:Tonsillitis / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
D004791:Enzyme Inhibitors; D012313:RNA; D010749:Phosphoprotein Phosphatases