A common intronic variant of CXCR3 is functionally associated with gene expression levels and the polymorphic immune cell responses to stimuli.
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.


CONCLUSIONS
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.
Choi
Jung-Won
JW
Center for Genome Science, the National Institute of Health, Seoul, South Korea.
Park
Choon-Sik
CS
Hwang
Minyoung
M
Nam
Hye-Young
HY
Chang
Hun Soo
HS
Park
Seong Gyu
SG
Han
Bok-Ghee
BG
Kimm
Kuchan
K
Kim
Hyung Lae
HL
Oh
Bermseok
B
Kim
Yeonjung
Y
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001249:Asthma / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D002461:Cell Line, Transformed; D018925:Chemokines / Q000276:immunology; D002633:Chemotaxis / Q000235:genetics / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics* / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns / Q000235:genetics* / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics / Q000276:immunology; D054367:Receptors, CXCR3 / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
C515187:CXCR3 protein, human; D018925:Chemokines; D054367:Receptors, CXCR3