Association of asthma severity and bronchial hyperresponsiveness with a polymorphism in the cytotoxic T-lymphocyte antigen-4 gene.
OBJECTIVE
Cytotoxic T-lymphocyte antigen (CTLA)-4 is a homolog of CD28, which is expressed only on activated T cells. It binds to accessory molecule B7 and mediates T-cell-dependent immune response. Signaling through CTLA-4 may down-regulate type 1 T-helper cell proliferation; moreover, some studies suggest that CTLA-4 might also deliver a positive signal to type 2 T-helper cell activation. Disruption of this delicate balance of immune regulation may lead to autoimmune diseases or atopic diseases. To evaluate the possible role of CTLA-4 polymorphisms in bronchial asthma, we investigated the association between polymorphisms (exon 1 +49 A/G, promoter -318 C/T) and atopy, asthma severity, and bronchial hyperresponsiveness in bronchial asthma patients and a group of healthy control subjects.


METHODS
Eighty-eight asthmatic patients and 88 healthy control subjects were studied.


RESULTS
Asthma severity assessment, methacholine challenge, allergy skinprick test, and serum total IgE measurements were performed. The genotypes of the CTLA-4 promoter (-318 C/T) and exon 1 (+49 A/G) in all subjects were determined using the polymerase chain reaction and restriction fragment length polymorphism. The CTLA-4 promoter (-318 C/T) polymorphism was shown to be associated with asthma severity, but not with asthma, atopy, or bronchial hyperresponsiveness. A significant association was found between severe asthma and the T allele (p = 0.037). The CTLA-4 exon 1 (+49 A/G) polymorphism was shown to be associated with bronchial hyperresponsiveness, but not with asthma, atopy, or asthma severity. Asthmatic patients of the GG genotype had more hyperresponsive airways than those with the AG or AA genotype (p = 0.019).


CONCLUSIONS
The CTLA-4 promoter (-318 C/T) T allele may serve as a clinically useful marker of severe asthma. The CTLA-4 exon 1 (+49 A/G) polymorphism may have a disease-modifying effect in asthmatic airways.
Division of Pulmonology, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea.
Sang Yeub
SY
Lee
Young Ho
YH
Lee
Chol
C
Shin
Jae Jeong
JJ
Shim
Kyung Ho
KH
Kang
Se Hwa
SH
Yoo
Kwang Ho
KH
In
D000069594:Abatacept; D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D001249:Asthma / Q000145:classification / Q000235:genetics / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000235:genetics*; D001985:Bronchial Provocation Tests; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D006801:Humans; D018796:Immunoconjugates; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D012720:Severity of Illness Index
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D000069594:Abatacept