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A Common Intronic Variant of CXCR3 is Functionally Associated with Gene Expression Levels and the Polymorphic Immune Cell Responses to Stimuli

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Date 2008 Oct 31
PMID 18962861
Citations 15
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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 of CXCR3 polymorphisms with the risk of asthma. Results from the epidemiologic study showed that a common nucleotide variant in the CXCR3 intron (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 of rs2280964G>A with asthma by investigating the effects of intronic variant on chemokine-mediated phenotypes of human-derived T cells.

Methods: We used cell line-based in vitro and human primary T cell-based ex vivo studies 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 the rs2280964A allele significantly correlates with decreased CXCR3 gene expression, which would lead to variation in immune cell responses to chemokine-cytokine signals in vitro and ex vivo that 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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