Gao Xu, Thomsen Hauke, Zhang Yan, Breitling Lutz Philipp, Brenner Hermann
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
Clin Epigenetics. 2017 Aug 17;9:87. doi: 10.1186/s13148-017-0387-6. eCollection 2017.
Methylation quantitative trait loci (mQTLs) are the genetic variants that may affect the DNA methylation patterns of CpG sites. However, their roles in influencing the disturbances of smoking-related epigenetic changes have not been well established. This study was conducted to address whether mQTLs exist in the vicinity of smoking-related CpG sites (± 50 kb) and to examine their associations with smoking exposure and all-cause mortality in older adults.
We obtained DNA methylation profiles in whole blood samples by Illumina Infinium Human Methylation 450 BeadChip array of two independent subsamples of the ESTHER study (discovery set, = 581; validation set, = 368) and their corresponding genotyping data using the Illumina Infinium OncoArray BeadChip. After correction for multiple testing (FDR), we successfully identified that 70 out of 151 previously reported smoking-related CpG sites were significantly associated with 192 SNPs within the 50 kb search window of each locus. The 192 mQTLs significantly influenced the active smoking-related DNA methylation changes, with percentage changes ranging from 0.01 to 18.96%, especially for the weakly/moderately smoking-related CpG sites. However, these identified mQTLs were not directly associated with active smoking exposure or all-cause mortality.
Our findings clearly demonstrated that if not dealt with properly, the mQTLs might impair the power of epigenetic-based models of smoking exposure to a certain extent. In addition, such genetic variants could be the key factor to distinguish between the heritable and smoking-induced impact on epigenome disparities. These mQTLs are of special importance when DNA methylation markers measured by Illumina Infinium assay are used for any comparative population studies related to smoking-related cancers and chronic diseases.
甲基化数量性状基因座（mQTL）是可能影响CpG位点DNA甲基化模式的基因变异。然而，它们在影响吸烟相关表观遗传变化紊乱中的作用尚未完全明确。本研究旨在探讨mQTL是否存在于吸烟相关CpG位点附近（±50 kb），并研究它们与老年人吸烟暴露及全因死亡率的关联。
我们通过Illumina Infinium Human Methylation 450 BeadChip芯片获得了ESTHER研究两个独立子样本（发现集，n = 581；验证集，n = 368）全血样本的DNA甲基化谱，并使用Illumina Infinium OncoArray BeadChip获得了相应的基因分型数据。经过多重检验校正（FDR）后，我们成功鉴定出151个先前报道的吸烟相关CpG位点中的70个与每个位点50 kb搜索窗口内的192个单核苷酸多态性（SNP）显著相关。这192个mQTL显著影响了与主动吸烟相关的DNA甲基化变化，变化百分比范围为0.01%至18.96%，尤其是对于与轻度/中度吸烟相关的CpG位点。然而，这些鉴定出的mQTL与主动吸烟暴露或全因死亡率无直接关联。
我们的研究结果清楚地表明，如果处理不当，mQTL可能在一定程度上削弱基于表观遗传学的吸烟暴露模型的效力。此外，这种基因变异可能是区分遗传和吸烟对表观基因组差异影响的关键因素。当使用Illumina Infinium检测法测量的DNA甲基化标记用于任何与吸烟相关癌症和慢性病的比较人群研究时，这些mQTL具有特殊重要性。
