A haplotype in the inducible T-cell tyrosine kinase is a risk factor for seasonal allergic rhinitis.
BACKGROUND
Identification of disease-associated single nucleotide polymorphisms (SNPs) in seasonal allergic rhinitis (SAR) may be facilitated by focusing on genes in a disease-associated pathway.


OBJECTIVE
To search for SNPs in genes that belong to the T-cell receptor (TCR) pathway and that change in expression in allergen-challenged CD4+ cells from patients with SAR.


METHODS
CD4+ cells from patients with SAR were analysed with gene expression microarrays. Allele, genotype and haplotype frequencies were compared in 251 patients and 386 healthy controls.


RESULTS
Gene expression microarray analysis of allergen-challenged CD4+ cells from patients with SAR showed that 25 of 38 TCR pathway genes were differentially expressed. A total of 62 SNPs were analysed in eight of the 25 genes; ICOS, IL4, IL5, IL13, CSF2, CTLA4, the inducible T-cell tyrosine kinase (ITK) and CD3D. Significant chi-squared values were identified for several markers in the ITK kinase gene region. A total of five SNPs were nominally significant at the 5% level. Haplotype analysis of the five significant SNPs showed increased frequency of a haplotype that covered most of the coding part of ITK. The functional relevance of ITK was supported by analysis of an independent material, which showed increased expression of ITK in allergen-challenged CD4+ cells from patients, but not from controls.


CONCLUSIONS
Analysis of SNPs in TCR pathway genes revealed that a haplotype that covers a major part of the coding sequence of ITK is a risk factor for SAR.
Benson
M
M
Department of Pediatrics, Queen Silvia Children's Hospital, Gothenburg, Sweden.
Mobini
R
R
Barrenäs
F
F
Halldén
C
C
Naluai
A T
AT
Säll
T
T
Cardell
L O
LO
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000485:Allergens / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D005091:Exons / Q000235:genetics / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics / Q000276:immunology; D006801:Humans; D007438:Introns / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011058:Pollen / Q000276:immunology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000276:immunology; D006255:Rhinitis, Allergic, Seasonal / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
D000485:Allergens; D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase