Atopic Dermatitis Is Associated with a Functional Mutation in the Promoter of the C-C Chemokine RANTES

Abstract

Up-regulation of C-C chemokine expression characterizes allergic inflammation and atopic diseases. A functional mutation in the proximal promoter of the RANTES gene has been identified, which results in a new consensus binding site for the GATA transcription factor family. A higher frequency of this allele was observed in individuals of African descent compared with Caucasian subjects (p < 0.00001). The mutant allele was associated with atopic dermatitis in children of the German Multicenter Allergy Study (MAS-90; p < 0.037), but not with asthma. Transient transfections of the human mast cell line HMC-1 and the T cell line Jurkat with reporter vectors driven by either the mutant or wild-type RANTES promoter showed an up to 8-fold higher constitutive transcriptional activity of the mutant promoter. This is the first report to our knowledge of a functional mutation in a chemokine gene promoter. Our findings suggest that the mutation contributes to the development of atopic dermatitis. Its potential role in other inflammatory and infectious disorders, particularly among individuals of African ancestry, remains to be determined.

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

“…The less common −403 A allele was associated with atopic dermatitis in German children but not with asthma. 13 Transient transfections of human mast cell line and T cell line with reporter vector controlled by the wild or mutant allele of RANTES promoter (−403 G/A) showed an 8-fold increased constitutive transcription activity of the mutant allele. 13 In the current study, we have examined the hypothesis that this polymorphism is associated with asthma and the related phenotypes, atopy and physiological airway dysfunction.…”

“…13 Transient transfections of human mast cell line and T cell line with reporter vector controlled by the wild or mutant allele of RANTES promoter (−403 G/A) showed an 8-fold increased constitutive transcription activity of the mutant allele. 13 In the current study, we have examined the hypothesis that this polymorphism is associated with asthma and the related phenotypes, atopy and physiological airway dysfunction. We have determined, for the first time, the frequency of RANTES genotypes in a population of subjects stratified by atopic status (serum IgE level and skin prick tests), as well as degree of obstruction (airway calibre) and BHR.…”

“…10 In addition, the number of eosinophils recruited to the lung is strongly correlated with the concentration of immunoreactive RANTES. 11 We 12 and others 13 have recently described a single nucleotide polymorphism (G→A at position −403) in the promoter region of the RANTES gene. The less common −403 A allele was associated with atopic dermatitis in German children but not with asthma.…”

Atopic eczema/dermatitis syndrome – a genetically complex disease. New advances in discovering the genetic contribution

“…The mutation of the RANTES gene results in a new consensus binding site for the GATA transcription factor family. The point mutation at base pair )401 is strikingly more frequent in individuals of African descent compared to Caucasian subjects (64).…”

“…A functional mutation in the proximal promoter of the RANTES gene (RANTES ¼ small inducible cytokine A5, gene: SCYAS, # 17q11.2) has been identified (64). Up-regulation of C-C chemokine expression via C-C chemokine receptor 5 (gene: CCR5, # 3p21) characterizes allergic inflammation and AEDS.…”