随着时间的推移，DNA 甲基化与 Th2 途径遗传变异相互作用对哮喘风险和哮喘的时间转变的影响。
The interplay of DNA methylation over time with Th2 pathway genetic variants on asthma risk and temporal asthma transition.
机构信息
Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, 236A Robison Hall, Memphis, TN 38152, USA.
Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, 800 Sumter Street, Columbia, SC 29208, USA.
出版信息
Clin Epigenetics. 2014 Apr 15;6(1):8. doi: 10.1186/1868-7083-6-8. eCollection 2014.
BACKGROUND
Genetic effects on asthma of genes in the T-helper 2 (Th2) pathway may interact with epigenetic factors including DNA methylation. We hypothesized that interactions between genetic variants and methylation in genes in this pathway (IL4, IL4R, IL13, GATA3, and STAT6) influence asthma risk, that such influences are age-dependent, and that methylation of some CpG sites changes over time in accordance with asthma transition. We tested these hypotheses in subsamples of girls from a population-based birth cohort established on the Isle of Wight, UK, in 1989.
RESULTS
Logistic regression models were applied to test the interaction effect of DNA methylation and SNP on asthma within each of the five genes. Bootstrapping was used to assess the models identified. From 1,361 models fitted at each age of 10 and 18 years, 8 models, including 4 CpGs and 8 SNPs, showed potential associations with asthma risk. Of the 4 CpGs, methylation of cg26937798 (IL4R) and cg23943829 (IL4) changes between ages 10 and 18 (both higher at 10; P = 9.14 × 10(-6) and 1.07 × 10(-5), respectively). At age 10, the odds of asthma tended to decrease as cg12405139 (GATA3) methylation increased (log-OR = -12.15; P = 0.049); this effect disappeared by age 18. At age 18, methylation of cg09791102 (IL4R) was associated with higher risk of asthma among subjects with genotype GG compared to AG (P = 0.003), increased cg26937798 methylation among subjects with rs3024685 (IL4R) genotype AA (P = 0.003) or rs8832 (IL4R) genotype GG (P = 0.01) was associated with a lower asthma risk; these CpGs had no effect at age 10. Increasing cg26937798 methylation over time possibly reduced the risk of positive asthma transition (asthma-free at age 10 → asthma at age 18; log-OR = -3.11; P = 0.069) and increased the likelihood of negative transition (asthma at age 10 → asthma-free at age 18; log-OR = 3.97; P = 0.074).
CONCLUSIONS
The interaction of DNA methylation and SNPs in Th2 pathway genes is likely to contribute to asthma risk. This effect may vary with age. Methylation of some CpGs changed over time, which may influence asthma transition.
背景
Th2 途径基因的遗传效应对哮喘的影响可能与包括 DNA 甲基化在内的表观遗传因素相互作用。我们假设，该途径中基因（IL4、IL4R、IL13、GATA3 和 STAT6）的遗传变异与甲基化之间的相互作用会影响哮喘风险，这种影响具有年龄依赖性，并且某些 CpG 位点的甲基化会随着时间的推移而发生变化，与哮喘的转变相一致。我们在英国怀特岛于 1989 年建立的基于人群的出生队列的女孩亚组中检验了这些假设。
结果
逻辑回归模型用于在每个基因的五个基因中的 DNA 甲基化和 SNP 对哮喘的交互作用进行检验。使用自举法来评估所确定的模型。在每个年龄为 10 岁和 18 岁的 1361 个模型中，有 8 个模型，包括 4 个 CpG 和 8 个 SNP，显示出与哮喘风险相关的潜在关联。在 4 个 CpG 中，IL4R 的 cg26937798 和 IL4 的 cg23943829 的甲基化在 10 至 18 岁之间发生变化（均在 10 岁时更高；P=9.14×10(-6)和 1.07×10(-5)）。在 10 岁时，随着 cg12405139（GATA3）甲基化的增加，哮喘的几率趋于降低（对数 OR=-12.15；P=0.049）；到 18 岁时，这种影响消失了。在 18 岁时，与 AG 相比，IL4R 的 cg09791102 甲基化与 GG 基因型受试者中更高的哮喘风险相关（P=0.003），与 IL4R 的 rs3024685（P=0.003）或 rs8832（IL4R）基因型 GG（P=0.01）相比，IL4R 的 cg26937798 甲基化增加与哮喘风险降低相关；这些 CpG 在 10 岁时没有影响。随着时间的推移，cg26937798 甲基化的增加可能降低阳性哮喘转变的风险（10 岁时无哮喘→18 岁时哮喘；对数 OR=-3.11；P=0.069），并增加阴性转变的可能性（10 岁时哮喘→18 岁时无哮喘；对数 OR=3.97；P=0.074）。
结论
Th2 途径基因的 DNA 甲基化和 SNP 的相互作用可能导致哮喘风险增加。这种影响可能随年龄而变化。一些 CpG 的甲基化随时间发生变化，这可能会影响哮喘的转变。
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