背景:DNA甲基化(DNAm)在脂质代谢中起重要作用,然而,尚未在儿童癌症幸存者中进行血脂水平的全表观基因组关联研究(EWAS).这里,我们对St.Jude终身队列研究中的幸存者纵向收集的血脂数据进行了EWAS分析.
方法:在2052名欧洲血统(EA)的儿童癌症幸存者和370名非洲血统(AA)的幸存者中,四种类型的血脂,包括高密度脂蛋白(HDL),低密度脂蛋白(LDL),总胆固醇(TC),和甘油三酯(TG),在儿童癌症诊断后5年以上的随访期间进行测量。对于暴露EWAS(即,抽血前测量的脂质用于DNAm),DNAm水平是一个结果变量,每个血脂水平是一个暴露变量;反之亦然,对于结果EWAS(即,抽血后测量的脂质用于DNAm)。
结果:在EA幸存者中,我们在HDL中鉴定了43个与脂质相关的CpG(n=7),TC(n=3),和TG(n=33)暴露EWAS,和HDL中106个脂质相关的CpG(n=5),LDL(n=3),TC(n=4),TG(n=94)结果为EWAS。在AA幸存者中,我们在TG暴露中确定了15个与脂质相关的CpG(n=6),HDL(n=1),LDL(n=1),TG(n=5)和TC(n=2)结果EWAS具有表观基因组意义(P<9×10-8)。EA和AA幸存者的暴露与结果EWAS之间没有重叠的脂质相关CpG,提示不同CpG的DNAm变化可能是血脂水平的原因或结果。在元EWAS中,12个额外的CpG达到了表观基因组范围的显著性。值得注意的是,74个与脂质相关的CpG中有32个在EA和AA幸存者之间显示出实质性的异质性(Phet<0.1或I2>70%),强调具有不同遗传血统的人群之间血脂的DNAm标记的差异。10个与脂质相关的CpGs是顺式表达数量性状甲基化,其DNAm水平与相应基因的表达相关,其中七个是负相关的。
结论:我们确定了DNAm对血脂的不同特征作为暴露或结果,在EA和AA幸存者之间,揭示参与脂质代谢的其他基因和控制儿童癌症幸存者血脂的潜在新目标。
DNA methylation (DNAm) plays an important role in lipid metabolism, however, no epigenome-wide association study (
EWAS) of lipid levels has been conducted among childhood cancer survivors. Here, we performed
EWAS analysis with longitudinally collected blood lipid data from survivors in the St. Jude lifetime cohort study.
Among 2052 childhood cancer survivors of European ancestry (EA) and 370 survivors of African ancestry (AA), four types of blood lipids, including high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG), were measured during follow-up beyond 5-years from childhood cancer diagnosis. For the exposure
EWAS (i.e., lipids measured before blood draw for DNAm), the DNAm level was an outcome variable and each of the blood lipid level was an exposure variable; vice versa for the outcome
EWAS (i.e., lipids measured after blood draw for DNAm).
Among EA survivors, we identified 43 lipid-associated CpGs in the HDL (n = 7), TC (n = 3), and TG (n = 33) exposure EWAS, and 106 lipid-associated CpGs in the HDL (n = 5), LDL (n = 3), TC (n = 4), and TG (n = 94) outcome EWAS. Among AA survivors, we identified 15 lipid-associated CpGs in TG exposure (n = 6), HDL (n = 1), LDL (n = 1), TG (n = 5) and TC (n = 2) outcome EWAS with epigenome-wide significance (P < 9 × 10-8). There were no overlapping lipids-associated CpGs between exposure and outcome EWAS among EA and AA survivors, suggesting that the DNAm changes of different CpGs could be the cause or consequence of blood lipid levels. In the meta-
EWAS, 12 additional CpGs reached epigenome-wide significance. Notably, 32 out of 74 lipid-associated CpGs showed substantial heterogeneity (Phet < 0.1 or I2 > 70%) between EA and AA survivors, highlighting differences in DNAm markers of blood lipids between populations with diverse genetic ancestry. Ten lipid-associated CpGs were cis-expression quantitative trait methylation with their DNAm levels associated with the expression of corresponding genes, out of which seven were negatively associated.
We identified distinct signatures of DNAm for blood lipids as exposures or outcomes and between EA and AA survivors, revealing additional genes involved in lipid metabolism and potential novel targets for controlling blood lipids in childhood cancer survivors.