Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002, Basel, Switzerland.
University of Basel, Basel, Switzerland.
Respir Res. 2018 Aug 22;19(1):156. doi: 10.1186/s12931-018-0850-8.
The pathophysiological role of SERPINA1 in respiratory health may be more strongly determined by the regulation of its expression than by common genetic variants. A family based study of predominantly smoking adults found methylation at two Cytosine-phosphate-Guanine sites (CpGs) in SERPINA1 gene to be associated with chronic obstructive pulmonary disease risk. The objective of this study was to confirm the association of lung function with SERPINA1 methylation in general population samples by testing a comprehensive set of CpGs in the SERPINA gene cluster. We considered lung function level and decline in adult smokers from three European population-based cohorts and lung function level and growth in tobacco-smoke exposed children from a birth cohort.
DNA methylation using Illumina Infinium Human Methylation 450 k and EPIC beadchips and lung function were measured at two time points in 1076 SAPALDIA, ECRHS and NFBC adult cohort participants and 259 ALSPAC children. Associations of methylation at 119 CpG sites in the SERPINA gene cluster (PP4R4-SERPINA13P) with lung functions and circulating alpha-1-antitripsin (AAT) were assessed using multivariable cross-sectional and longitudinal regression models.
Methylation at cg08257009 in the SERPINA gene cluster, located 32 kb downstream of SERPINA1, not annotated to a gene, was associated with FEV/FVC at the Bonferroni corrected level in adults, but not in children. None of the methylation signals in the SERPINA1 gene showed associations with lung function after correcting for multiple testing.
The results do not support a role of SERPINA1 gene methylation as determinant of lung function across the life course in the tobacco smoke exposed general population exposed.
SERPINA1 在呼吸健康方面的病理生理作用可能更多地取决于其表达的调节，而不是常见的遗传变异。一项以主要吸烟成年人为主的基于家庭的研究发现，SERPINA1 基因中两个胞嘧啶-磷酸-鸟嘌呤（CpG）位点的甲基化与慢性阻塞性肺疾病（COPD）风险相关。本研究的目的是通过测试 SERPINA 基因簇中的一组综合 CpG 来确认 SERPINA1 甲基化与一般人群样本中肺功能的关联。我们考虑了三个欧洲基于人群的队列中成年吸烟者的肺功能水平和下降，以及一个出生队列中烟草烟雾暴露儿童的肺功能水平和增长。
使用 Illumina Infinium Human Methylation 450 k 和 EPIC 芯片进行 DNA 甲基化，在 1076 名 SAPALDIA、ECRHS 和 NFBC 成年队列参与者和 259 名 ALSPAC 儿童的两个时间点测量肺功能。使用多变量横断面和纵向回归模型评估 SERPINA 基因簇（PP4R4-SERPINA13P）中 119 个 CpG 位点的甲基化与肺功能和循环中的α-1-抗胰蛋白酶（AAT）之间的关联。
SERPINA 基因簇中位于 SERPINA1 下游 32 kb 处、未注释到基因的 cg08257009 位点的甲基化与成人的 FEV/FVC 在 Bonferroni 校正水平上相关，但与儿童无关。在进行多次检验校正后，SERPINA1 基因中的任何甲基化信号都与肺功能无关。
这些结果不支持 SERPINA1 基因甲基化作为烟草烟雾暴露人群中整个生命周期肺功能决定因素的作用。
