Division of Therapeutics and Molecular Medicine, Nottingham Respiratory Biomedical Research Unit, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
BMC Med Genet. 2011 Dec 29;12:173. doi: 10.1186/1471-2350-12-173.
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 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.
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.
我们之前的研究表明，控制白三烯 B4（LTB4）产生的基因（ALOX5AP 和 LTA4H）中的多态性与儿童哮喘易感性有关。有证据表明，LTB4 可能在 COPD 发病机制中发挥作用，包括将中性粒细胞募集到肺部。本研究的目的是观察这些 SNP 以及跨越 LTB4 受体基因（LTB4R1 和 LTB4R2）的 SNP 是否影响吸烟者的基线肺功能和 COPD 易感性/严重程度。
在英国吸烟队列中（n = 992），对 8 个 ALOX5AP、6 个 LTA4H 和 6 个 LTB4R 单核苷酸多态性（SNP）进行基因分型。通过线性回归确定与基线肺功能（FEV1 和 FEV1/FVC 比值）的相关性。使用逻辑回归比较吸烟对照组（n = 176）和肺功能诊断的 COPD 病例（n = 599）以及更严重的 COPD 病例（GOLD 分期 3 和 4，n = 389）。
在经过多次检验校正后，ALOX5AP、LTA4H 或 LTB4R 与基因多态性之间没有相关性。然而，我们发现 LTA4H rs1978331C（内含子 11）与 FEV1 增加（p = 0.029）和 FEV1/FVC 比值增加（p = 0.020）有适度相关性。
这些数据表明，跨越 ALOX5AP、LTA4H 和 LTB4R 基因座的多态性不是吸烟者基线肺功能的主要决定因素，但提供了 LTA4H rs1978331C（内含子 11）在确定除我们之前发现的在哮喘易感性中的作用之外，在确定高加索裔吸烟者的基线 FEV1 和 FEV1/FVC 比值中的作用的初步证据。
