A common intronic variant ofCXCR3is functionally associated with gene expression levels and the polymorphic immune cell responses to stimuli

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Abstract

Background

CXCR3 is a chemokine receptor that plays important roles in mediating chemotactic signals and modulating the activation of lymphocytes. We have previously conducted a case-control study by using a candidate gene approach to investigate the association ofCXCR3polymorphisms with the risk of asthma. Results from the epidemiologic study showed that a common nucleotide variant in theCXCR3intron(rs2280964G>A)was associated with disease susceptibility (1006 cases and 384 control subjects; odds ratio, 0.81; 95% CI, 0.69-0.94;P= .007).

Objective

The aim of our study was to evaluate the epidemiologic study and provide functional evidence for the association ofrs2280964G>Awith asthma by investigating the effects of intronic variant on chemokine-mediated phenotypes of human-derived T cells.

Methods

We used cell line-basedin vitroand human primary T cell-basedex vivostudies to examine the functional consequences of the intronic polymorphism, focusing on the regulation of gene expression, splicing, and immune responsiveness toward activating signals.

Results

We present functional evidence indicating that thers2280964Aallele significantly correlates with decreasedCXCR3gene expression, which would lead to variation in immune cell responses to chemokine-cytokine signalsin vitroandex vivothat includes a decrease in chemotactic activity.

Conclusion

These findings, in conjunction with those of our previous epidemiologic studies, might implicate a functional link between a common nucleotide variant of a chemokine receptor gene,CXCR3, and a cause for a complex-trait disease, asthma.

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