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Open Access Research article

Leukotriene B4 receptor locus gene characterisation and association studies in asthma

Asif S Tulah15, Bianca Beghé2, Sheila J Barton3, John W Holloway4 and Ian Sayers1*

Author affiliations

1 Division of Therapeutics and Molecular Medicine, University of Nottingham, Queen’s Medical Centre, Nottingham, United Kingdom

2 Department of Oncology, Haematology and Respiratory Diseases, University of Modena & Reggio Emilia, Modena, Italy

3 MRC Lifecourse Epidemiology Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom

4 Human Genetics and Medical Genomics, Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom

5 Present address: Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom

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Citation and License

BMC Medical Genetics 2012, 13:110  doi:10.1186/1471-2350-13-110

Published: 20 November 2012

Abstract

Background

Polymorphisms spanning genes involved in the production of leukotriene B4 (LTB4) e.g. ALOX5AP and LTA4H are associated with asthma susceptibility, suggesting a role for LTB4 in disease. The contribution of LTB4receptor polymorphism is currently unknown. The aim of this study was to characterise the genes for the two pivotal LTB4 receptors, LTB4R1 and LTB4R2 in lung tissue and determine if polymorphisms spanning these genes are associated with asthma and disease severity.

Methods

Rapid amplification of cDNA ends (RACE) was used to characterise the LTB4R1 and LTB4R2 gene structure in lung. The LTB4R1/2 locus on chromosome 14q11.2 was screened for polymorphic variation. Six LTB4R single nucleotide polymorphisms (SNPs) were genotyped in 370 Caucasian asthma families and 299 Adult Asthma Individuals (n=1877 total) and were evaluated for association with asthma and severity (BTS) outcome measures using Family Based Association Test, linear regression and chi square.

Results

LTB4R1 has complex mRNA arrangement including multiple 5′-untranslated exons, suggesting additional levels of regulation. Three potential promoter regions across the LTB4R1/2 locus were identified with some airway cell specificity. 22 SNPs (MAF>0.01) were validated across the LTB4R locus in the Caucasian population. LTB4R1 and LTB4R2 SNPs were not associated with asthma susceptibility, FEV1 or severity.

Conclusions

LTB4R1 and LTB4R2 shows splice variation in the 5′-untranslated region and multiple promoter regions. The functional significance of this is yet to be determined. Both receptor genes were shown to be polymorphic. LTB4R polymorphisms do not appear to be susceptibility markers for the development of asthma in Caucasian subjects.

Keywords:
Association; Asthma; Family based association test; Leukotriene; Leukotriene B4 receptor; RACE; Severity