Department of Public Health Sciences, University of Chicago, Chicago, IL 60637, USA; Interdisciplinary Scientist Training Program, University of Chicago, Chicago, IL 60637, USA.
Department of Public Health Sciences, University of Chicago, Chicago, IL 60637, USA; Committee on Genetics, Genomics, Systems Biology, University of Chicago, Chicago, IL 60637, USA.
Am J Hum Genet. 2024 Apr 4;111(4):636-653. doi: 10.1016/j.ajhg.2024.02.012. Epub 2024 Mar 14.
Cigarette smoking adversely affects many aspects of human health, and epigenetic responses to smoking may reflect mechanisms that mediate or defend against these effects. Prior studies of smoking and DNA methylation (DNAm), typically measured in leukocytes, have identified numerous smoking-associated regions (e.g., AHRR). To identify smoking-associated DNAm features in typically inaccessible tissues, we generated array-based DNAm data for 916 tissue samples from the GTEx (Genotype-Tissue Expression) project representing 9 tissue types (lung, colon, ovary, prostate, blood, breast, testis, kidney, and muscle). We identified 6,350 smoking-associated CpGs in lung tissue (n = 212) and 2,735 in colon tissue (n = 210), most not reported previously. For all 7 other tissue types (sample sizes 38-153), no clear associations were observed (false discovery rate 0.05), but some tissues showed enrichment for smoking-associated CpGs reported previously. For 1,646 loci (in lung) and 22 (in colon), smoking was associated with both DNAm and local gene expression. For loci detected in both lung and colon (e.g., AHRR, CYP1B1, CYP1A1), top CpGs often differed between tissues, but similar clusters of hyper- or hypomethylated CpGs were observed, with hypomethylation at regulatory elements corresponding to increased expression. For lung tissue, 17 hallmark gene sets were enriched for smoking-associated CpGs, including xenobiotic- and cancer-related gene sets. At least four smoking-associated regions in lung were impacted by lung methylation quantitative trait loci (QTLs) that co-localize with genome-wide association study (GWAS) signals for lung function (FEV1/FVC), suggesting epigenetic alterations can mediate the effects of smoking on lung health. Our multi-tissue approach has identified smoking-associated regions in disease-relevant tissues, including effects that are shared across tissue types.
吸烟对人类健康的许多方面都有不利影响，而吸烟引起的表观遗传反应可能反映了介导或抵御这些影响的机制。先前关于吸烟和 DNA 甲基化（DNAm）的研究，通常在白细胞中进行，已经确定了许多与吸烟相关的区域（例如 AHRR）。为了在通常无法获取的组织中识别与吸烟相关的 DNAm 特征，我们生成了来自 GTEx（基因型-组织表达）项目的 916 个组织样本的基于阵列的 DNAm 数据，这些样本代表了 9 种组织类型（肺、结肠、卵巢、前列腺、血液、乳腺、睾丸、肾脏和肌肉）。我们在肺组织（n=212）中确定了 6350 个与吸烟相关的 CpG，在结肠组织（n=210）中确定了 2735 个与吸烟相关的 CpG，其中大多数以前没有报道过。对于所有其他 7 种组织类型（样本量为 38-153），没有观察到明显的关联（错误发现率为 0.05），但一些组织显示出先前报道的与吸烟相关的 CpG 富集。对于 1646 个（在肺中）和 22 个（在结肠中）基因座，吸烟与 DNAm 和局部基因表达都有关联。对于在肺和结肠中都检测到的基因座（例如，AHRR、CYP1B1、CYP1A1），顶级 CpG 通常在组织之间存在差异，但观察到了相似的超甲基化或低甲基化 CpG 簇，调节元件的低甲基化对应于表达的增加。对于肺组织，有 17 个标志性基因集与与吸烟相关的 CpG 富集，包括与外源性和癌症相关的基因集。肺组织中至少有四个与吸烟相关的区域受到与肺功能（FEV1/FVC）全基因组关联研究（GWAS）信号共定位的肺甲基化定量性状基因座（QTL）的影响，这表明表观遗传改变可以介导吸烟对肺部健康的影响。我们的多组织方法已经在与疾病相关的组织中识别出与吸烟相关的区域，包括在组织类型之间共享的影响。
