Murray Robert, Bryant Jennifer, Titcombe Phil, Barton Sheila J, Inskip Hazel, Harvey Nicholas C, Cooper Cyrus, Lillycrop Karen, Hanson Mark, Godfrey Keith M
Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust (UHSFT) and University of Southampton, Southampton, UK ; MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK ; Radiology, UHSFT, Southampton, UK.
Clin Epigenetics. 2016 Sep 2;8(1):90. doi: 10.1186/s13148-016-0259-5. eCollection 2016.
Antisense non-coding RNA in the INK4 locus (ANRIL) fixed genetic variants have consistently been linked with coronary heart disease (CHD) risk. We investigated relationships between perinatal ANRIL promoter DNA methylation and CHD risk markers in children aged 9 years. Genetic variants in the non-coding RNA ANRIL identify it as an important CHD risk locus. Increasing evidence suggests that the early life environment may act through epigenetic processes to influence later CHD risk markers such as increased arterial pulse wave velocity (PWV, a measure of arterial stiffness) blood pressure or heart rate.
Using pyrosequencing, ANRIL DNA methylation at nine CpG sites was measured in the umbilical cord from 144 children in a UK mother-offspring cohort and related to the descending aorta PWV measured by velocity-encoded phase contrast MRI at age 9 years. Perinatal methylation was not associated with child's later blood pressure, but higher methylation at CpG5 was associated with increased childhood PWV (β = 0.066 m/s/10 % methylation increase [95 % CI, 0.004 to 0.128], p = 0.037); 10 % decreases in methylation at CpG1 and CpG2 were associated with increased heart rate (CpG1 β = 1.93 [0.07 to 3.8] beats/min, p = 0.041; CpG2 β = 2.30 [0.18 to 4.41] beats/min, p = 0.033, accounting for potential confounding variables). The associations with perinatal ANRIL promoter methylation were independent of neighbouring fixed genetic variants.
Our findings suggest developmental epigenetic regulation of ANRIL promoter methylation as a factor in later CHD risk in children.
INK4基因座中的反义非编码RNA（ANRIL）固定遗传变异一直与冠心病（CHD）风险相关。我们研究了9岁儿童围产期ANRIL启动子DNA甲基化与CHD风险标志物之间的关系。非编码RNA ANRIL中的遗传变异将其确定为一个重要的CHD风险基因座。越来越多的证据表明，早期生活环境可能通过表观遗传过程影响后期的CHD风险标志物，如动脉脉搏波速度增加（PWV，一种动脉僵硬度的测量指标）、血压或心率。
采用焦磷酸测序法，在英国一个母婴队列中，对144名儿童脐带血中9个CpG位点的ANRIL DNA甲基化进行了测量，并将其与9岁时通过速度编码相位对比MRI测量的降主动脉PWV相关联。围产期甲基化与儿童后期血压无关，但CpG5处较高的甲基化与儿童期PWV增加相关（β = 0.066 m/s/甲基化增加10% [95% CI，0.004至0.128]，p = 0.037）；CpG1和CpG2处甲基化降低10%与心率增加相关（CpG1 β = 1.93 [0.07至3.8]次/分钟，p = 0.041；CpG2 β = 2.30 [0.18至4.41]次/分钟，p = 0.033，考虑了潜在的混杂变量）。围产期ANRIL启动子甲基化的关联独立于相邻的固定遗传变异。
我们的研究结果表明，ANRIL启动子甲基化的发育表观遗传调控是儿童后期CHD风险的一个因素。
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