This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200705-781OCv1 177/7/712    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sharma, M. Articles by Ghosh, B. Search for Related Content PubMed PubMed Citation Articles by Sharma, M. Articles by Ghosh, B.

A Genetic Variation in Inositol Polyphosphate 4 Phosphatase A Enhances Susceptibility to Asthma

¹ Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative Biology, Delhi, India; ² Division of Pulmonary and Critical Care Medicine, Department of Medicine, All India Institute of Medical Sciences, Delhi, India; and ³ Asthma and Allergy Centre, Mumbai, India

Correspondence and requests for reprints should be addressed to Dr. Balaram Ghosh, Ph.D., Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007, India. E-mail: bghosh{at}igib.res.in

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.

Key Words: asthma • gene • INPP4A • single nucleotide polymorphism

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Signaling cascades involving PI3K–Akt pathway genes SHIP and PTEN have been found to be associated with asthma. However, no study involving the terminal enzyme in the pathway, INPP4A, has been undertaken in asthma and allergic disorders. What This Study Adds to the Field Using a genomewide candidate gene approach, we demonstrate the association of INPP4A with atopic asthma.