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

Eight 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).No 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).These 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.Chronic obstructive pulmonary disease (COPD) is a complex respiratory disease with genetic and environmental contributors to pathophysiology [1,2]. 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]. The altered inflammatory response of the airways of COPD sufferers is a result of lymphocytes and neutrophils, suggested in part to be the result of cigarette smoke inhalation [5]. Importantly, LTB4 has been shown to have chemotactic activity recruiting inflammatory cells to the lung [6,7]. LTB4 is implicated in the neutrophillic inflammation of COPD and has been suggested as the major chemotactic agent in more severe forms of this disease [8]. It has been established that the cysteinyl leukotrienes (CysLTs; LTC4, LTD4 and LTE4) play a significant role in bronchoconstriction and airway inflammation in asthma [9] but their role in COPD is less clear.Studies have suggested that polymorphism