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

Author

George, Siminovitch Ka, Jilly F. Evans, Brian F O'Dowd, Burnham Wm, Noe Zamel, Storm van's Gravesande K, Galczenski H, Arthur S. Slutsky, Thompson, and Jeffrey M. Drazen

Subjects
Hypersensitivity, Immediate, Allergy, Candidate gene, Population, Biology, Polymerase Chain Reaction, White People, Leukotriene D4, Atopy, Genetic variation, Atlantic Islands, Genetics, medicine, Humans, Genetic variability, General Pharmacology, Toxicology and Pharmaceutics, Allele, education, Polymorphism, Single-Stranded Conformational, DNA Primers, Receptors, Leukotriene, education.field_of_study, Chromosomes, Human, Pair 13, Genetic Variation, Membrane Proteins, DNA, medicine.disease, Asthma, Founder Effect, respiratory tract diseases, Black or African American, Phenotype, Case-Control Studies, Immunology, Calcium, SRS-A, Polymorphism, Restriction Fragment Length, Founder effect
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.

Published
2003
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4. Rheumatoid arthritis association with the FCRL3 -169C polymorphism is restricted to PTPN22 1858T-homozygous individuals in a Canadian population.

Author

Newman WG, Zhang Q, Liu X, Walker E, Ternan H, Owen J, Johnson B, Greer W, Mosher DP, Maksymowych WP, Bykerk VP, Keystone EC, Amos CI, and Siminovitch KA

Abstract

OBJECTIVE: Variants in genes encoding the Fc receptor-like 3 (FcRL-3) and the class II major histocompatibility complex (MHC) transactivator proteins have been associated with an increased risk of rheumatoid arthritis (RA) in Japanese and Nordic populations, respectively. The aim of this study was to investigate these associations in a Canadian Caucasian cohort of RA cases and healthy controls. METHODS: A total of 1,187 RA patients and 462 healthy controls were genotyped for FCRL3 and MHC2TA gene variants associated with RA. Epistasis between the FCRL3 -169C and the PTPN22 1858T variants was also examined. RESULTS: An association was detected between RA and both the FCRL3 -169C allele (OR 1.19, P = 0.023) and the homozygous genotype (OR 1.41, P = 0.027), but association of the MHC2TA promoter region variant (-168G) with RA was not replicated. Stratification of the RA cohort by PTPN22 genotypes revealed the FCRL3 risk variant and RA association was stronger in the patient subgroup lacking PTPN22 1858T variants (P = 0.004) and was not detectable in the subgroup with PTPN22 1858T variants (P = 0.52). The PTPN22 association with RA was greater in the absence than in the presence of the FCRL3 -169C allele (P = 0.0008 versus P = 0.001). The PTPN22 1858T variant also increased the risk of autoimmune thyroid disease (AITD) in the RA patients, whereas the FCRL3 risk variant was protective against AITD. CONCLUSION: Our findings support an association of RA with an FCRL3 functional polymorphism and reveal that this association is stronger in the absence of PTPN22 risk genotypes. These findings support a genetic heterogeneity across RA populations, suggesting that both the FCRL3 and PTPN22 genes play roles in RA susceptibility, but in different individuals. [ABSTRACT FROM AUTHOR]

Published
2006
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