Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, J.B. Winsløws Vej 9 B., 5000, Odense C, Denmark.
Department of Epidemiology and Health Statistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China.
Clin Epigenetics. 2021 Feb 15;13(1):35. doi: 10.1186/s13148-021-01009-5.
Epigenetic inactivation of O-methylguanine DNA-methyltransferase (MGMT) is associated with increased sensitivity to alkylating chemotherapeutic agents in glioblastoma patients. The genetic background underlying MGMT gene methylation may explain individual differences in treatment response and provide a clue to a personalized treatment strategy. Making use of the longitudinal twin design, we aimed, for the first time, to estimate the genetic contributions to MGMT methylation in a Danish twin cohort.
DNA-methylation from whole blood (18 monozygotic (MZ) and 25 dizygotic (DZ) twin pairs) repeated 10 years apart from the Longitudinal Study of Aging Danish Twins (LSADT) were used to search for genetic and environmental contributions to DNA-methylation at 170 CpG sites of across the MGMT gene. Both univariate and bivariate twin models were applied. The intraclass correlations, performed on cross-sectional data (246 MZ twin pairs) from an independent study population, the Middle-Aged Danish Twins (MADT), were used to assess the genetic influence at each CpG site of MGMT for replication.
Univariate twin model revealed twelve CpG sites showing significantly high heritability at intake (wave 1, h > 0.43), and seven CpG sites with significant heritability estimates at end of follow-up (wave 2, h > 0.5). There were six significant CpG sites, located at the gene body region, that overlapped among the two waves (h > 0.5), of which five remained significant in the bivariate twin model, which was applied to both waves. Within MZ pair correlation in these six CpGs from MADT demarks top level of genetic influence. There were 11 CpGs constantly have substantial common environmental component over the 10 years.
We have identified 6 CpG sites linked to the MGMT gene with strong and persistent genetic control based on their DNA methylation levels. The genetic basis of MGMT gene methylation could help to explain individual differences in glioblastoma treatment response and most importantly, provide references for mapping the methylation Quantitative Trait Loci (meQTL) underlying the genetic regulation.
甲基鸟嘌呤-DNA-甲基转移酶（MGMT）的表观遗传失活与胶质母细胞瘤患者对烷化化疗药物的敏感性增加有关。MGMT 基因甲基化的遗传背景可能解释了治疗反应的个体差异，并为个性化治疗策略提供了线索。利用纵向双胞胎设计，我们首次旨在估计丹麦双胞胎队列中 MGMT 甲基化的遗传贡献。
利用来自纵向老龄化丹麦双胞胎研究（LSADT）的全血 DNA-甲基化（18 对同卵（MZ）和 25 对异卵（DZ）双胞胎，相隔 10 年），搜索 across 整个 MGMT 基因的 170 个 CpG 位点的 DNA 甲基化的遗传和环境贡献。应用了单变量和双变量双胞胎模型。在一个独立的研究人群——中年丹麦双胞胎（MADT）的横断面数据（246 对 MZ 双胞胎）上进行的内类相关分析，用于复制 MGMT 每个 CpG 位点的遗传影响。
单变量双胞胎模型显示，在摄入时（第 1 波，h > 0.43）有 12 个 CpG 位点表现出明显高的遗传度，在随访结束时（第 2 波，h > 0.5）有 7 个 CpG 位点表现出显著的遗传度估计值。有六个位于基因体区域的显著 CpG 位点在两个波之间重叠（h > 0.5），其中五个在应用于两个波的双变量双胞胎模型中仍然具有显著意义。在 MADT 中的这些六个 CpG 的 MZ 对相关性标志着遗传影响的最高水平。在这 10 年中，有 11 个 CpG 一直具有相当大的共同环境成分。
我们已经确定了 6 个与 MGMT 基因相关的 CpG 位点，这些位点的 DNA 甲基化水平具有强烈和持久的遗传控制。MGMT 基因甲基化的遗传基础可以帮助解释胶质母细胞瘤治疗反应的个体差异，最重要的是，为映射遗传调控下的甲基化定量性状基因座（meQTL）提供参考。
