Role of genetic polymorhisms in the chemokine pathway in asthma and atopy
Possible associations between CCR5D32, CCR2V64I, CCR3Y17Y, and the RANTES-G403A promoter and asthma and related phenotypes in high-risk families. 154 families (453 individuals), with at least two affected children with physician-diagnosed asthma (PDA) and atopy defined as one or more skin prick test to common inhaled allergen (SPT wheal ³ 3mm), were studied. Overall allelic frequency for CCR5D32 was 26.1 %, and both TDT and PDT demonstrated similar non-significant associations with asthma or atopy (p=0.123) and (p=0.088). The strong associations with the asthma related phenotypes in child probands but less so in their parents support previous observations that this candidate, or others in linkage disequilibrium with it, contribute to the expression of childhood but not of adult asthma. An overall allele frequency of 19.5% was found for CCR2V64I and which was significantly associated with absence of asthma FEV1% predicted above the population median of 83% but not with s-IgE levels or specific sensitization. The overall allele frequency for CCR3Y17Y was 13.9% and which was preferentially transmitted with asthma (P=0.0001) and BHR (P=0.002). Case-control analysis in unrelated parents (3461y [median 43y]) revealed a significant association of the mutant allele for both asthma with/or without atopy (p=0.001), but in unrelated children a significant association was only observed for those with non-atopic asthma (P= 0.001). The -403 G®A RANTES polymorphism was transmitted with atopy and atopic asthma although its contribution appeared to relate more to atopy than asthma and BHR. Both linkage and haplotype analyses confirmed the association between chromosome 3 and asthma status. Haplotype analyses suggested significant linkage disequilibrium between these three polymorphisms and asthma status. Log linear analyses revealed that the CCR2 mutant allele was most strongly associated with protection against atopic asthma (O.R.= 0.09, C.I.= 0.07-0.40) whereas the CCR3 mutant allele was associated with increased the risk of disease (O.R.=3.51, C.I.=1.30-9.47). Imprinting analyses failed to demonstrate an increased risk of disease when effector alleles were transmitted from the mother. A significant interaction was found between maternal smoking, and carriage of the -17Y mutant allele of chemokine receptor 3 for an increased the risk of atopic asthma in child probands (O.R.=3.47, C.I.=1.28-9.38). Domestic animal exposure (cat or dog) showed no significant interaction with the polymorphisms of interest. These analyses suggested that environmental exposures could interact with genetic constitution in influencing disease expression.