The −403 G→A promoter polymorphism in the RANTES gene is associated with atopy and asthma

Abstract

Asthma is a complex inflammatory condition often associated with bronchial hyperreactivity and atopy. Genetic and environmental factors are implicated and several candidate genes have been implicated. Of these, the chemokine RANTES is responsible for the recruitment of inflammatory cells such as eosinophils and T-lymphocytes. We have recently identified a polymorphism within the RANTES promoter (−403 G →A) and have examined its role, using a PCR-RFLP assay, in the development of atopy and asthma in 201 Caucasian subjects. Atopic status was determined using skin prick testing and serum IgE levels. Severity of airway dysfunction was assessed using spirometric measurement (FEV 1 ) and methacholine challenge (PC 20 ). The −403 A allele was associated with an increased susceptibility to both atopy and asthma. Thus, the proportion of subjects carrying this allele was higher in each of atopic non-asthmatics, nonatopic asthmatics and atopic asthmatics compared with non-atopic, non-asthmatic controls. In particular, this allele was associated with skin test positivity but not IgE level. Homozygosity for the −403 A allele conferred a 6.5-fold increased risk of moderate/severe airway obstruction (FEV 1 р80% predicted), a marker for established asthma. Our data, whilst preliminary, indicate that the association of RANTES genotype with both atopy and asthma reflect independent effects, suggesting different mechanisms for the role of this chemokine in atopy and development of airway obstruction. Genes and Immunity (2000) 1, 509-514.

Preferential transmission and association of the −403 G → A promoter RANTES polymorphism with atopic asthma

“…In the younger generation we studied, we were able to confirm the suggestion by Fryer et al 16 that the mutant allele might be related to disease severity, assessed in our case as baseline FEV1, although even in this population it was not possible to separate the influence of atopy as few of the younger population with PDA were nonatopic. Our data appear to confirm the association of the À403A allele with atopy (defined as specific allergen sensitization) but are less supportive of the view that this allele contributes directly to asthma, to airway function and to disease severity independently of its contribution to atopy.…”

“…That the frequency of individual genotypes and the À403A allele was strongly associated with positive SPT but not significance with serum IgE suggests that RANTES contributes to the recruitment of inflammatory cells such as basophils, mast cells and memory T cells in response to allergen exposure, 18 rather than in regulating IgE production. The same trends were observed by Fryer et al 16 in their population (24-46 years), using similar diagnostic criteria for atopy and asthma, although our population was larger and we were able to study the association in two generations (children aged 8-24 years and adults aged 34-61years) and the transmission of the allele with phenotypes.…”

“…As the age range in association studies is often wide, 16 we also examined these associations separately in children and parents. These analyses suggested that the association was with atopy independent of asthma in parents in contrast to the association with both asthma and atopy in their children (Table 3).…”

“…The À403G/A single-nucleotide polymorphism has been found to be independently associated with both atopy and asthma suggesting that this chemokine may have a role both in the development of airway obstruction and atopy. 16 In view of the plausible role of the À403G/A polymorphism in promoting allergic responses and its high alleleic frequency in Caucasian populations, we sought to confirm or refute the previous reported casecontrol study 16 using a family-based population in order to account for the inherent problems associated with casecontrol studies such as linkage disequilibrium, population admixture and sampling error. We also sought to confirm the allelic frequencies of both À403G/A and À28C/G in our population and, to our knowledge and for the first time, assess whether the mutant alleles were preferentially transmitted with physician diagnosed asthma (PDA) atopy and/or other associated phenotypes including elevated serum IgE, baseline lung function and nonspecific bronchial hyper-responsiveness (BHR).…”

RANTES Gene Promoter Polymorphisms Are Associated with Bronchial Hyperresponsiveness in Korean Children with Asthma

“…There are two functional polymorphisms that increase transcriptional activity and subsequent RANTES expression in human cell lines, a G-to-A change at position -403 and a C-to-G change at position -28 in the proximal promoter region of the RANTES gene [14,15]. Fryer et al [16] reported that the -403 A allele was associated with an increased susceptibility to both atopy and asthma, while Yao et al [17] showed that the RANTES -28G allele is associated with asthma severity in Chinese children. Nickel et al [15] have reported that the RANTES -403A allele is associated with increased susceptibility to atopic dermatitis in German children.…”