Association of atopy and eczema with polymorphisms in T-cell immunoglobulin domain and mucin domain—IL-2–inducible T-cell kinase gene cluster in chromosome 5q33

Background

The T-cell immunoglobulin domain and mucin domain (TIM) gene family and the gene for IL-2–inducible T-cell kinase (ITK), located in chromosome 5q33 and potentially involved in the T-cell proliferation and differentiation, are good candidate genes for allergic diseases.

Objective

We assessed the role of polymorphisms in the TIM family genes and ITK in atopy, eczema, and asthma.

Methods

Twenty-one polymorphisms in the TIM-ITK gene cluster were genotyped in 564 children enrolled in the Tucson Children's Respiratory Study. Skin prick tests to common allergens were performed at age 6.1 years (n=508), age 10.8 years (n=539), and age 16.6 years (n=424). Asthma and eczema were assessed by questionnaire at these 3 points. Averaged relative risks were estimated.

Results

One 15-bp insertion/deletion in exon 4 of TIM1 was significantly related to atopy and eczema (relative risk associated with carrying at least 1 rare allele=1.24 [1.07-1.45], P=.005; and 1.43 [1.01-2.01], P=.004, respectively). The 3 tested single nucleotide polymorphisms (SNPs) in TIM3 were significantly related to atopy and eczema. One of them, at position +4259 calculated from the translation start site, predicts a putative change in the amino acid sequence of the protein, and was the most strongly related to atopy (relative risk=1.28 [1.12-1.47]; P=.0003). SNPs in the 5′ genomic region in ITK, which show moderate linkage disequilibrium with those in TIM3, had an independent effect on atopy. None of the polymorphisms studied was related to asthma.

Conclusion

Our findings support a potential role for SNPs in TIM1, TIM3, and ITK, independent of each other, in allergic diseases.

Key words: Atopy, asthma, eczema, TIM, ITK, polymorphisms

Abbreviations used: CRSP9, cofactor required for Sp1 transcriptional activation, subunit 9, HAV, Hepatitis A virus, ITK, IL-2–inducible T-cell kinase, LD, Linkage disequilibrium, RR, Relative risk, SNP, Single nucleotide polymorphism, SPT, Skin prick test, TIM, T-cell immunoglobulin domain and mucin domain