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

Abstract

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 (CysLT2) 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 CysLT2 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 M201V [corrected] variant was activated with four-fold less potency by leukotriene D4 (LTD4) in a calcium flux assay. The CysLT2 receptor partial agonist, BAY u9773, also showed four-fold lower potency on the M201V [corrected] variant. The M201V [corrected] mutation is located within the extracellular region of the fifth transmembrane spanning domain of CysLT2 receptor, a position that may alter ligand binding and effector signalling. The novel M201V [corrected] CysLT2 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 CysLT2 receptor gene, located on chromosome 13q14, with the atopic phenotype found in the Tristan da Cunha population.

• Authors: Miles D Thompson, Karin Storm van's Gravesande, Helen Galczenski, W McIntyre Burnham, Kathy A Siminovitch, Noe Zamel, Arthur Slutsky, Jeffrey M Drazen, Susan R George, Jilly F Evans, Brian F O'Dowd
• Journal: Pharmacogenetics (Pharmacogenetics) Vol. 13 Issue 10 Pg. 641-9 (Oct 2003) ISSN: 0960-314X [Print] England
• PMID: 14515063 (Publication Type: Clinical Trial, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• BAY u9773
• DNA Primers
• Membrane Proteins
• Receptors, Leukotriene
• SRS-A
• Leukotriene D4
• DNA
• cysteinyl leukotriene receptor 2
• Calcium

Topics

• Black or African American (genetics)
• Asthma (blood, ethnology, genetics)
• Atlantic Islands (epidemiology)
• Calcium (metabolism)
• Case-Control Studies
• Chromosomes, Human, Pair 13 (genetics)
• DNA (blood, genetics)
• DNA Primers (chemistry)
• Founder Effect
• Genetic Variation
• Humans
• Hypersensitivity, Immediate (epidemiology, ethnology, genetics)
• Leukotriene D4 (metabolism)
• Membrane Proteins (agonists, genetics)
• Phenotype
• Polymerase Chain Reaction
• Polymorphism, Restriction Fragment Length
• Polymorphism, Single-Stranded Conformational
• Receptors, Leukotriene (agonists, genetics)
• SRS-A (analogs & derivatives, pharmacology)
• White People (genetics)