Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06516, USA.
Alcohol Clin Exp Res. 2013 Jan;37 Suppl 1(Suppl 1):E108-15. doi: 10.1111/j.1530-0277.2012.01928.x. Epub 2012 Aug 24.
Epigenetic regulation through DNA methylation may influence vulnerability to numerous disorders, including alcohol dependence (AD).
Peripheral blood DNA methylation levels of 384 CpGs in the promoter regions of 82 candidate genes were examined in 285 African Americans (AAs; 141 AD cases and 144 controls) and 249 European Americans (EAs; 144 AD cases and 105 controls) using Illumina GoldenGate Methylation Array assays. Association of AD and DNA methylation changes was analyzed using multivariate analyses of covariance with frequency of intoxication, sex, age, and ancestry proportion as covariates. CpGs showing significant methylation alterations in AD cases were further examined in a replication sample (49 EA cases and 32 EA controls) using Sequenom's MassARRAY EpiTYPER technology.
In AAs, 2 CpGs in 2 genes (GABRB3 and POMC) were hypermethylated in AD cases compared with controls (p ≤ 0.001). In EAs, 6 CpGs in 6 genes (HTR3A, NCAM1, DRD4, MBD3, HTR2B, and GRIN1) were hypermethylated in AD cases compared with controls (p ≤ 0.001); CpG cg08989585 in the HTR3A promoter region showed a significantly higher methylation level in EA cases than in EA controls after Bonferroni correction (p = 0.00007). Additionally, methylation levels of 6 CpGs (including cg08989585) in the HTR3A promoter region were analyzed in the replication sample. Although the 6 HTR3A promoter CpGs did not show significant methylation differences between EA cases and EA controls (p = 0.067 to 0.877), the methylation level of CpG cg08989585 was nonsignificantly higher in EA cases (26.9%) than in EA controls (18.6%; p = 0.139).
The findings from this study suggest that DNA methylation profile appears to be associated with AD in a population-specific way and the predisposition to AD may result from a complex interplay of genetic variation and epigenetic modifications.
通过 DNA 甲基化的表观遗传调控可能会影响包括酒精依赖（AD）在内的许多疾病的易感性。
使用 Illumina GoldenGate 甲基化阵列分析，对 285 名非裔美国人（AA；141 例 AD 病例和 144 例对照）和 249 名欧洲裔美国人（EA；144 例 AD 病例和 105 例对照）的 82 个候选基因启动子区域中的 384 个 CpG 的外周血 DNA 甲基化水平进行了检测。使用协方差的多变量分析，以中毒频率、性别、年龄和祖裔比例作为协变量，分析 AD 与 DNA 甲基化改变之间的关系。在一个复制样本（49 例 EA 病例和 32 例 EA 对照）中，使用 Sequenom 的 MassARRAY EpiTYPER 技术进一步研究了 AD 病例中显示出显著甲基化改变的 CpG。
在 AA 中，与对照组相比，AD 病例中有 2 个基因（GABRB3 和 POMC）中的 2 个 CpG 发生了超甲基化（p ≤ 0.001）。在 EA 中，与对照组相比，AD 病例中有 6 个基因（HTR3A、NCAM1、DRD4、MBD3、HTR2B 和 GRIN1）中的 6 个 CpG 发生了超甲基化（p ≤ 0.001）；HTR3A 启动子区域的 CpG cg08989585 在经过 Bonferroni 校正后，在 EA 病例中的甲基化水平显著高于 EA 对照组（p = 0.00007）。此外，还对 HTR3A 启动子区域的 6 个 CpG（包括 cg08989585）的甲基化水平进行了复制样本分析。尽管 6 个 HTR3A 启动子 CpG 在 EA 病例和 EA 对照组之间的甲基化差异没有统计学意义（p = 0.067 至 0.877），但 CpG cg08989585 在 EA 病例中的甲基化水平（26.9%）略高于 EA 对照组（18.6%；p = 0.139）。
这项研究的结果表明，DNA 甲基化图谱似乎与特定人群的 AD 相关，AD 的易感性可能是遗传变异和表观遗传修饰复杂相互作用的结果。
