Variant eotaxin: its effects on the asthma phenotype.
BACKGROUND
Eotaxin, a CC chemokine expressed in the asthmatic lung, has been associated with impaired lung function. The role of its variant form is unknown.


OBJECTIVE
The purpose of this study was to detect the population frequency and effects of a known single-nucleotide polymorphism in the eotaxin gene in which a threonine residue (THR(23)) is substituted for the wild-type alanine (ALA(23)) at the 23rd amino acid at the terminus of the peptide leader sequence.


METHODS
We measured eotaxin protein secretion in 293 cells transfected with expression vectors and in PBMCs obtained from individuals bearing the alternative forms of the gene. A case-control study of plasma eotaxin levels and eosinophil counts, a comparison of baseline lung function by genotype in a population of 806 subjects with asthma, and a comparison of the allele frequency with a nonasthmatic population were performed.


RESULTS
Human 293 cells and PBMCs with THR(23) variant eotaxin secreted significantly less eotaxin protein than did ALA(23)-bearing cells. In the case-control study, THR(23)-THR(23) individuals had lower plasma levels of eotaxin (310 [240-350] vs 420 [270-700] pg/mL; P < .05) and eosinophil counts (120 [5-220] vs 190 [110-470] cells/microL; P < .05) than ALA(23)-ALA(23) subjects; heterozygous subjects had intermediate levels. Higher levels of lung function were associated with THR(23) eotaxin (percent of predicted FEV(1), 65% +/- 3.5% [THR(23)-THR(23)] vs 58% +/- 0.9% [THR(23)-ALA(23)] and 56% +/- 0.5% [ALA(23)-ALA(23)]; P < .05).


CONCLUSIONS
The THR(23) variant is associated with both decreased eosinophil counts and higher levels of lung function in subjects with asthma.
Nakamura
H
H
Combined Program in Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Luster
A D
AD
Nakamura
T
T
In
K H
KH
Sonna
L A
LA
Deykin
A
A
Israel
E
E
Drazen
J M
JM
Lilly
C M
CM
D000328:Adult; D001249:Asthma / Q000235:genetics*; D016022:Case-Control Studies; D002478:Cells, Cultured; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000235:genetics*; D003001:Cloning, Molecular; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational
C515456:CCL11 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC