Epigenome-wide association study of asthma and wheeze in childhood and adolescence.
Epigenome-wide association study of asthma and wheeze in childhood and adolescence.
复制标题
DOI：
10.1186/s13148-017-0414-7
复制
发表时间：
2017
影响因子：
5.7
通讯作者：
Relton CL
中科院分区：
文献类型：
--
作者：
Arathimos R;Suderman M;Sharp GC;Burrows K;Granell R;Tilling K;Gaunt TR;Henderson J;Ring S;Richmond RC;Relton CL
哮喘遗传能力仅部分由遗传变异解释，并且已知对环境因素敏感，暗示表观遗传修饰如DNA甲基化在其发病机制中。使用雅芳父母和儿童纵向研究（ALSPAC）收集的数据，我们评估了7.5岁和16.5岁时哮喘和喘息与DNA甲基化的关系，这些DNA甲基化涉及来自大约50岁儿童的外周血中超过450,000个CpG位点。1000名参与者。我们使用孟德尔随机化（MR），一种使用遗传变异作为工具变量的因果推理方法，来推断DNA甲基化与哮喘之间的关联方向。我们确定了302个CpGs与当前哮喘状态相关（经fdr调整的P值< 0.05），445个CpGs与7.5岁时当前喘息状态相关，两者之间存在大量重叠。302个相关CpGs的注释基因富集于与细胞/亚细胞组分运动、运动、白细胞介素-4产生和嗜酸性粒细胞迁移相关的途径。当对嗜酸性粒细胞和中性粒细胞计数进行调整时，所有的关联都减弱了。在16.5岁时，调整细胞计数后，两个部位与当前哮喘相关。CpGs定位于AP2A2和IL5RA基因，哮喘病例甲基化百分比差异分别为- 2.32 [95% CI - 1.47, - 3.18]和- 2.49 [95% CI - 1.56, - 3.43]。双样本双向MR显示哮喘在7.5岁时对几个CpG位点的DNA甲基化有因果影响。然而，在调整多重测试后，这种关联并不持续存在。在16.5岁时，没有证据表明哮喘对两个CpG位点的DNA甲基化有因果影响。大多数观察到的关联是由哮喘病例中较高的嗜酸性细胞计数驱动的，作为一种中间表型，这对未来特应性疾病中DNA甲基化的研究具有重要意义。本文的在线版本（10.1186/s13148-017-0414-7）包含补充材料，授权用户可使用。
Asthma heritability has only been partially explained by genetic variants and is known to be sensitive to environmental factors, implicating epigenetic modifications such as DNA methylation in its pathogenesis. Using data collected in the Avon Longitudinal Study of Parents and Children (ALSPAC), we assessed associations of asthma and wheeze with DNA methylation at 7.5 and 16.5 years, at over 450,000 CpG sites in DNA from the peripheral blood of approx. 1000 participants. We used Mendelian randomization (MR), a method of causal inference that uses genetic variants as instrumental variables, to infer the direction of association between DNA methylation and asthma. We identified 302 CpGs associated with current asthma status (FDR-adjusted P value < 0.05) and 445 with current wheeze status at 7.5 years, with substantial overlap between the two. Genes annotated to the 302 associated CpGs were enriched for pathways related to movement of cellular/subcellular components, locomotion, interleukin-4 production and eosinophil migration. All associations attenuated when adjusted for eosinophil and neutrophil cell count estimates. At 16.5 years, two sites were associated with current asthma after adjustment for cell counts. The CpGs mapped to the AP2A2 and IL5RA genes, with a − 2.32 [95% CI − 1.47, − 3.18] and − 2.49 [95% CI − 1.56, − 3.43] difference in percentage methylation in asthma cases respectively. Two-sample bi-directional MR indicated a causal effect of asthma on DNA methylation at several CpG sites at 7.5 years. However, associations did not persist after adjustment for multiple testing. There was no evidence of a causal effect of asthma on DNA methylation at either of the two CpG sites at 16.5 years. The majority of observed associations are driven by higher eosinophil cell counts in asthma cases, acting as an intermediate phenotype, with important implications for future studies of DNA methylation in atopic diseases. The online version of this article (10.1186/s13148-017-0414-7) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
4.4
作者：
Bibikova, Marina;Barnes, Bret;Shen, Richard
通讯作者：
Shen, Richard
影响因子：
2.9
作者：
Cornish RP;Henderson J;Boyd AW;Granell R;Van Staa T;Macleod J
通讯作者：
Macleod J
影响因子：
30.8
作者：
Gudbjartsson, Daniel F.;Bjornsdottir, Unnur S.;Stefansson, Kari
通讯作者：
Stefansson, Kari
影响因子：
12.3
作者：
Gaunt TR;Shihab HA;Hemani G;Min JL;Woodward G;Lyttleton O;Zheng J;Duggirala A;McArdle WL;Ho K;Ring SM;Evans DM;Davey Smith G;Relton CL
通讯作者：
Relton CL
影响因子：
7.7
作者：
Brion, Marie-Jo A.;Shakhbazov, Konstantin;Visscher, Peter M.
通讯作者：
Visscher, Peter M.