Asthma Research Today is a free monthly online journal that collates and summarizes the latest research about Asthma, including details on symptoms, diagnosis, treatment, causes, medications. | ||||||||
|
A genetic variation in inositol polyphosphate 4 phosphatase a enhances susceptibility to asthma.Sharma M, Batra J, Mabalirajan U, Sharma S, Nagarkatti R, Aich J, Sharma SK, Niphadkar PV, Ghosh B Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007, India. RATIONALE: Microarray data from mouse studies have identified a number of genes to be differentially expressed in allergen-sensitized mice lungs. OBJECTIVES: Taking leads from these datasets, we attempted to identify novel genes associated with atopic asthma in humans. METHODS: We performed family-based genetic association analysis on selected markers within or in proximity of 21 human homologs of genes short-listed from ovalbumin-sensitized mouse studies in the Gene Expression Omnibus database of the National Center for Biotechnology Information. Family-based and case-control studies were undertaken for fine mapping and functional variation analysis of INPP4A (inositol polyphosphate 4 phosphatase type I). Western blot analysis was performed to analyze INPP4A protein stability from human platelets. MEASUREMENTS AND MAIN RESULTS: Our genetic association studies of 21 human genes in 171 trios led to the identification of a biallelic repeat (rs3217304) in INPP4A, associated with atopic asthma (P = 0.009). Further studies using additional three single nucleotide polymorphisms (SNPs), +92031A/T, +92344C/T, and +131237C/T, and two microsatellite markers, D2S2311 and D2S2187, revealed significant genetic associations with loci +92031A/T (P = 0.0012) and +92344C/T (P = 0.004). A nonsynonymous SNP, +110832A/G (Thr/Ala), present within a sequence enriched with proline, glutamic acid, serine, and threonine (PEST), in proximity of these two loci, showed a significant association with atopic asthma (P = 0.0006). The association results were also replicated in an independent cohort of 288 patients and 293 control subjects (P = 0.004). PEST score and Western blot analyses indicated a functional role of this SNP in regulating INPP4A protein stability. CONCLUSIONS: In our study, INPP4A was identified as a novel asthma candidate gene, whereby the +110832A/G (Thr/Ala) variant affected its stability and was significantly associated with asthma. Published 25 March 2008 in Am J Respir Crit Care Med, 177(7): 712-9.
© 2004-2008 Asthma Research Today. All Rights Reserved. |
| ||||||
