Fine mapping of an IgE-controlling gene on chromosome 2q: Analysis of CTLA4 and CD28.
BACKGROUND
Several genomic regions have been identified that might contain genes contributing to the development of asthma and atopy. These include chromosome 2q33, where we have observed evidence for linkage for variation in total serum IgE levels in a Dutch asthma population. Two candidate genes, CTLA4 and CD28, important homeostatic regulators of T-cell activation and subsequent IgE production, map within this candidate region.


OBJECTIVE
We sought to fine-map the chromosome 2q33 region and evaluate CTLA4 and CD28 as candidate genes for the regulation of total serum IgE levels and related phenotypes.


METHODS
The coding regions of CTLA4 and CD28 were resequenced in 96 individuals; 4 novel SNPs in CTLA4 and 10 in CD28 were identified. Polymorphisms in both genes were analyzed in 200 asthmatic probands and their spouses (n = 201).


RESULTS
Subsequent fine- mapping in this region has resulted in an increased log of the odds (lod) score (1.96 to 3.16) for total serum IgE levels. For CTLA4, the +49 A/G single nucleotide polymorphism (SNP) in exon 1 and the 3 ' untranslated region microsatellite were significantly associated with total serum IgE levels (P =.0005 and.006, respectively). For the combined +49 A/G and 3 'untranslated region genotypes, individuals homozygous for the risk allele for both polymorphisms (AA and 86/86) had the highest total serum IgE values (87.1 IU/mL), whereas those individuals with the GG and XX/XX genotypes (anything but the 86-bp allele) had the lowest IgE values (29.3 IU/mL). Significant association was also observed for the CTLA4 -1147 C/T SNP with bronchial hyperresponsiveness (BHR) and asthma (P =.008 and.012, respectively), but not for allergy-related phenotypes. Promoter luciferase assays examining the -1147 polymorphism suggested that the T allele, which was associated with increased BHR susceptibility, was expressed at half the level of the C allele. Individuals with the risk genotypes for both BHR (-1147 CT or TT) and elevated IgE levels (+49 AA) were 4.5 times more likely to have asthma than individuals with both nonrisk genotypes (P =.0009). No significant associations were observed for SNPs in CD28.


CONCLUSIONS
These data suggest that the costimulatory pathway, specifically CTLA4, is important in the development of atopy and asthma.
Howard
Timothy D
TD
Center for Human Genomics, Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Postma
Dirkje S
DS
Hawkins
Gregory A
GA
Koppelman
Gerard H
GH
Zheng
Siqun L
SL
Wysong
Alicia K S
AK
Xu
Jianfeng
J
Meyers
Deborah A
DA
Bleecker
Eugene R
ER
D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D001249:Asthma / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000175:diagnosis; D018106:CD28 Antigens / Q000235:genetics*; D060908:CTLA-4 Antigen; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D018796:Immunoconjugates; D007073:Immunoglobulin E / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007073:Immunoglobulin E; D000069594:Abatacept