A genetic variation in inositol polyphosphate 4 phosphatase a enhances susceptibility to asthma.
BACKGROUND
Microarray data from mouse studies have identified a number of genes to be differentially expressed in allergen-sensitized mice lungs.


OBJECTIVE
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.


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.
Sharma
Mamta
M
Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007, India.
Batra
Jyotsna
J
Mabalirajan
Ulaganathan
U
Sharma
Shilpy
S
Nagarkatti
Rana
R
Aich
Jyotirmoi
J
Sharma
Surendra K
SK
Niphadkar
Pramod V
PV
Ghosh
Balaram
B
D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics*; D001249:Asthma / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D018946:Chemokine CCL5 / Q000097:blood; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007194:India / Q000453:epidemiology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
D018946:Chemokine CCL5; D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase