The role of ALOX5AP, LTA4H and LTB4R polymorphisms in determining baseline lung function and COPD susceptibility in UK smokers

Asif S Tulah,Martin J Connolly,Ian Sayers,Stuart G Parker,Miriam F Moffatt,Andrew J Wardlaw

doi:10.1186/1471-2350-12-173

Abstract

BackgroundWe have previously shown evidence that polymorphisms within genes controlling leukotriene B4 (LTB4) production (ALOX5AP and LTA4H) are associated with asthma susceptibility in children. Evidence also suggests a potential role of LTB4 in COPD disease mechanisms including recruitment of neutrophils to the lung. The aim of the current study was to see if these SNPs and those spanning the receptor genes for LTB4 (LTB4R1 and LTB4R2) influence baseline lung function and COPD susceptibility/severity in smokers.MethodsEight ALOX5AP, six LTA4H and six LTB4R single nucleotide polymorphisms (SNPs) were genotyped in a UK Smoking Cohort (n = 992). Association with baseline lung function (FEV1 and FEV1/FVC ratio) was determined by linear regression. Logistic regression was used to compare smoking controls (n = 176) with spirometry-defined COPD cases (n = 599) and to more severe COPD cases (GOLD stage 3 and 4, n = 389).ResultsNo association with ALOX5AP, LTA4H or LTB4R survived correction for multiple testing. However, we showed modest association with LTA4H rs1978331C (intron 11) with increased FEV1 (p = 0.029) and with increased FEV1/FVC ratio (p = 0.020).ConclusionsThese data suggest that polymorphisms spanning ALOX5AP, LTA4H and the LTB4R locus are not major determinants of baseline lung function in smokers, but provide tentative evidence for LTA4H rs1978331C (intron 11) in determining baseline FEV1 and FEV1/FVC ratio in Caucasian Smokers in addition to our previously identified role in asthma susceptibility.

Highlights

We have previously shown evidence that polymorphisms within genes controlling leukotriene B4 (LTB4) production (ALOX5AP and leukotriene A4 hydrolase (LTA4H)) are associated with asthma susceptibility in children
Single nucleotide polymorphisms (SNPs) in two 5-LO pathway genes; 5-lipoxygenase activating protein (ALOX5AP) and leukotriene A4 hydrolase (LTA4H) have shown an association with LTB4 overproduction from ionomycinstimulated neutrophils and with myocardial infarction (MI) susceptibility [11,12]. 5-lipoxygenase activating protein (FLAP) with 5-LO is involved in the synthesis of LTA4 which can be conjugated with glutathione by LTC4 synthase to form LTC4 and subsequent cysteinyl leukotrienes (CysLTs) or converted to LTB4 by the enzyme LTA4 hydrolase (LTA4H) [13]
The aim of the current study was to determine whether polymorphisms spanning ALOX5AP, LTA4H and the LTB4R locus influence baseline lung function (FEV1 and FEV1/FVC ratio) in smokers and whether they contribute to susceptibility to develop Chronic obstructive pulmonary disease (COPD) or a more severe form of COPD in smokers

Summary

Introduction

We have previously shown evidence that polymorphisms within genes controlling leukotriene B4 (LTB4) production (ALOX5AP and LTA4H) are associated with asthma susceptibility in children. Evidence suggests a potential role of LTB4 in COPD disease mechanisms including recruitment of neutrophils to the lung. Evidence suggests the dihydroxy leukotriene, leukotriene B4 (LTB4), plays a role in this disease as its production is elevated in the airways of COPD subjects [3,4]. Single nucleotide polymorphisms (SNPs) in two 5-LO pathway genes; 5-lipoxygenase activating protein (ALOX5AP) and leukotriene A4 hydrolase (LTA4H) have shown an association with LTB4 overproduction from ionomycinstimulated neutrophils and with myocardial infarction (MI) susceptibility [11,12]. FLAP is involved in the production of all leukotrienes; LTA4H is involved in LTB4 production

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