A functional CD86 polymorphism associated with asthma and related allergic disorders.
BACKGROUND
Several studies have documented a substantial genetic component in the aetiology of allergic diseases and a number of atopy susceptibility loci have been suggested. One of these loci is 3q21, at which linkage to multiple atopy phenotypes has been reported. This region harbours the CD86 gene encoding the costimulatory B7.2 protein. The costimulatory system, consisting of receptor proteins, cytokines and associated factors, activates T cells and regulates the immune response upon allergen challenge.


METHODS
We sequenced the CD86 gene in patients with atopy from 10 families that showed evidence of linkage to 3q21. Identified polymorphisms were analysed in a subsequent family-based association study of two independent Danish samples, respectively comprising 135 and 100 trios of children with atopy and their parents. Functional analysis of the costimulatory effect on cytokine production was performed in an autologous cell-based system based on cells expressing CD86 variants.


RESULTS
Two polymorphisms were identified, encoding the amino acid changes Ile179Val and Ala304Thr, respectively. Significant associations were observed between the Ile179Val polymorphism and allergy phenotypes in both samples (eg, asthma, p = 4 x 10(-3) in the two samples combined). The undertransmitted (protective) Val179 allele was found to induce higher production of both Th1 and Th2 cytokines than the overtransmitted (risk) Ile179 allele, suggesting a functional impact of the polymorphism.


CONCLUSIONS
The CD86 gene, and specifically the Ile179Val polymorphism, may be a novel aetiological factor in the development of asthma and related allergic disorders.
Corydon
Thomas Juhl
TJ
Institute of Human Genetics, the Bartholin Building, University of Aarhus, DK-8000 Aarhus C, Denmark.
Haagerup
Annette
A
Jensen
Thomas Gryesten
TG
Binderup
Helle Glud
HG
Petersen
Mikkel Steen
MS
Kaltoft
Keld
K
Vestbo
Jørgen
J
Kruse
Torben Arvid
TA
Børglum
Anders Dupont
AD
D019943:Amino Acid Substitution; D015703:Antigens, CD / Q000235:genetics; D001249:Asthma / Q000235:genetics*; D051940:B7-2 Antigen / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D002893:Chromosomes, Human, Pair 3; D003001:Cloning, Molecular; D005260:Female; D008040:Genetic Linkage; D014644:Genetic Variation; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics*; D008297:Male; D008545:Melanoma; D011110:Polymorphism, Genetic; D035781:Siblings; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; D051940:B7-2 Antigen