A cysteinyl leukotriene 2 receptor variant is associated with atopy in the population of Tristan da Cunha

The clinical heterogeneity of asthma suggests that the contribution of genetic variability in candidate gene loci to well-defined phenotypes, such as atopy, may be examined to identify appropriate genetic risk factors for asthma. The gene encoding the cysteinyl leukotriene 2 (CysLT(2)) receptor has been implicated in atopy since it is localized to a region of chromosome 13q14 that has been linked to atopy in several populations and the cysteinyl leukotrienes are known to activate eosinophils and mast cells in atopy. Accordingly, we analysed the contribution of CysLT(2) receptor gene variation to atopy in the inhabitants of Tristan da Cunha, a population characterized by both a founder effect and a 47% prevalence of atopy. Single-stranded conformational polymorphism analysis revealed four variants. Among these, the M2O2V variant was activated with four-fold less potency by leukotriene D-4 (LTD4) in a calcium flux assay. The CysLT(2) receptor partial agonist, BAY u9773, also showed four-fold lower potency on the M2O2V variant. The M2O2V mutation is located within the extracellular region of the fifth transmembrane spanning domain of CysLT(2) receptor, a position that may alter ligand binding and effector signalling. The novel M2O2V CysLT(2) receptor variant was associated with atopy (21%) on Tristan da Cunha compared with those who were non-atopic (7%) (Fisher's exact test, P = 0.0016) in a manner that was independent of asthma (two-way ANOVA, P = 0.0015). This represents the first association of a coding mutation in the CysLT(2) receptor gene, located on chromosome 13q14, with the atopic phenotype found in the Tristan da Cunha population. (C) 2003 Lippincott Williams Wilkins.