Association of a STAT 6 haplotype with elevated serum IgE levels in a population based cohort of white adults.

BACKGROUND: Several studies have shown linkage of chromosome 12q 13-24 with atopy related phenotypes. Among candidate genes in this region is STAT6 (signal transducer and activator of transcription), which is essential for Th2 cell differentiation, recruitment, and effector function. METHODS: We evaluated six polymorphisms of STAT6 for evidence of associations with serum IgE levels and atopic diseases in a population based cross sectional cohort of 1407 German adults. Genotyping was performed using the matrix assisted laser desorption ionisation-time of flight mass spectrometry method. Haplotypes were estimated using the SAS/Genetics module, and population-derived IgE percentiles (50% IgE>53 kU/l, 66% IgE>99 kU/l and 90% IgE>307 kU/l) were modelled as outcome variables in haplotype trend regression analysis. RESULTS: All polymorphisms were genotyped successfully. Haplotype reconstruction revealed 8/64 possible haplotypes, reaching estimated frequencies of 1% or more. One polymorphism in intron 2 (rs324011) showed a significant association with total serum IgE (p = 0.015). A STAT6 risk haplotype for elevated IgE showing odds ratios of 1.7 (p = 0.015) for IgE cut-off 100 kU/l, and 1.54 (p = 0.032), 1.6 (p = 0.025), and 2.54 (p = 0.007) for IgE percentiles 50%, 66%, and 90%, respectively was detected. The increased risk of this haplotype was confirmed by linear haplotype trend regression on log transformed IgE values (p = 0.007). Analysis further revealed a risk haplotype for specific sensitisation and a risk haplotype for asthma. CONCLUSION: The data indicate that genetic variants within STAT6 contribute significantly to IgE regulation and manifestation of atopic diseases.

Association study of mast cell chymase polymorphisms with atopy.

BACKGROUND: Atopic disorders are the result of complex interactions between genetic and environmental factors. Associations analyses between the promoter polymorphism rs1800875 in the mast cell chymase gene (CMA1) and atopy-related phenotypes have yielded inconsistent results. METHODS: We sequenced the CMA1 locus in 24 unrelated healthy individuals with serum IgE levels <50% percentile and 24 individuals with atopic eczema and serum IgE levels >90% percentile. Seven CMA1 single nucleotide polymorphisms (SNPs) were evaluated for evidence of associations with atopic phenotypes within a large population of German adults (n = 1875). Subjects were phenotyped by standardized questionnaires and interviews, skin prick testing and serum IgE measurements. Genotyping was performed using MALDI-TOF MS (Matrix-Assisted Laser Desorption Ionization-Time of Flight mass spectrometry). RESULTS: Promoter polymorphism rs1800875 was significantly associated with atopic eczema. No associations between any other single SNP and atopic phenotypes could be detected. Haplotype reconstruction revealed four of 128 possible haplotypes reaching estimated frequencies of 3% or more. Two of these haplotypes showed a borderline-significant association with atopic eczema, which did not remain significant after correction for multiple testing. CONCLUSIONS: Results confirm previous observations of a significant association between the CMA1 promoter polymorphism rs1800875 and atopic eczema, but not with serum IgE levels, and support the hypothesis that CMA1 serves as candidate gene for atopic eczema.

Association of CARD15 polymorphisms with atopy-related traits in a population-based cohort of Caucasian adults.

BACKGROUND: Influences of microbial pathogens are crucial for the maturation of the immune system. Caspase-recruitment domain containing protein 15 (CARD15) is a cytosolic receptor involved in bacterial recognition by antigen-presenting cells. CARD15 polymorphisms have been associated with Crohn's disease. Recently, associations with atopic phenotypes have been reported in children. OBJECTIVE: Within a large population of German adults (n=1875), we evaluated eight CARD15 polymorphisms for associations with atopic phenotypes. METHODS: Subjects were phenotyped by standardized questionnaires and interviews as well as total and allergen-specific IgE measurements. Genotyping was performed using matrix-assisted laser desorption ionization--time of flight mass spectrometry. Haplotypes were estimated using the SAS/Genetics module. RESULTS: Subjects with a T allele at rs1077861 had a decreased risk of developing asthma (odds ratio OR=0.648, P=0.013), whereas the presence of an A allele at rs3135500 was significantly associated with an increased risk (OR=1.374, P=0.023). In addition, a CARD15 haplotype revealed to be protective against the development of asthma (OR=0.326, P=0.003). Subjects with an A allele at position rs5743266 or a T allele at rs2066842 had a significantly decreased risk of developing allergic rhinoconjunctivitis with ORs of 0.820 (P=0.049) and 0.801 (P=0.025). Polymorphism rs2066845 showed a significant association with increased total serum IgE (OR=2.155, P=0.006). CONCLUSION: Genetic variants of CARD15 that might result in inappropriate immunomodulation are not only associated with autoimmune diseases but also with atopic disorders.