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.
Bibliographical noteFunding Information:
Supported by the National Institute of Health (National Budget Code 347-2910-212-207-00) and the Ministry of Health and Welfare, Republic of Korea (01-PJ10-PG6-01GN14-0003). M. H. was funded by the Brain Korea 21 fellowship.
- case-control association study
- Chemokine receptor
- functional study
- single nucleotide polymorphism