Abstract 3764: Epigenome-wide association study of blood lipids among survivors of childhood cancer in the St. Jude Lifetime Cohort
Authors: Dong Qian , Song Nan , Chen Cheng , Li Zhenghong , Easton John , Mulder Heather , Zhang Jinghui , Neale Geoffrey , Walker Emily , Huang I-Chan , Ness Kirsten K. , Hudson Melissa M. , Robison Leslie L. , Wang Zhaoming 
Published: June 2022

Epigenetic studies of blood lipid traits have identified genes underlying lipid metabolism in the general population. However, investigation of this association has not been conducted in survivors of childhood cancer, a population with a much higher burden of dyslipidemia and other cardiometabolic conditions due to exposures of genotoxic cancer therapies. We performed epigenome-wide association studies (EWAS) to identify blood DNA methylation (DNAm) 5’-cytosine-phosphate-guanine-3′ (CpGs) associated with lipid concentrations, including high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG), for childhood cancer survivors from the St. Jude Lifetime (SJLIFE) cohort. DNAm was generated with blood derived DNA using Illumina MethylationEPIC BeadChip array. Adjusted M-value of DNAm for each CpG was calculated based on a linear regression of M-value against a set of covariates, including sex, age at DNA sampling, leukocyte subtype proportions, top four significant genetic principal components, and top four methylation principal components. In the exposure EWAS, a linear regression model was used for lipid levels prior to DNA sampling as an exposure variable and DNAm as an outcome variable, adjusting for cancer treatments, age at lipid measurement, BMI, cigarette smoking and lipid lowering medicine use. In the outcome EWAS, a linear regression model was used for DNAm as an exposure variable and lipid levels after DNA sampling as outcome variables, adjusting for cancer treatments, age at lipid measurement, BMI, smoking, lipid lowering medicine use, lipid levels measured at DNA sampling, age at DNA sampling, and polygenic risk score for specific lipid levels. Among survivors of European ancestry (N=2052), we identified 43 significant CpGs (P&lt;9×10-8) associated with HDL (n=7), TC (n=3) and TG (n=33) as exposures; and 106 CpGs associated with HDL (n=5), LDL (n=3), TC (n=4), and TG (n=94) as outcomes. Among survivors of African ancestry (N=370), we identified 3 CpGs associated with TG as an exposure, and 5 CpGs associated with LDL (n=1) and TC (n=4) as outcomes. A comparison of effect sizes of significant CpGs between survivors of European and African ancestry suggests moderate to substantial racial differences in epigenetic associations with lipid exposures (14/46 with I2&gt;50) and lipid outcomes (106/111 with I2&gt;50). Additionally, no overlap between CpGs associated with lipid exposures and lipid outcomes suggests that the DNAm levels of these CpGs could be either the cause or consequence of lipid levels. Examination of the EWAS catalog and recent literature, suggests that most of the lipid associated CpGs identified in our study are novel. Blood lipid associated CpGs may be epigenetic biomarkers for identification of survivors with higher risk of dyslipidemia and may inform potential drug targets for future interventions.

Citation Format: Qian Dong, Nan Song, Cheng Chen, Zhenghong Li, John Easton, Heather Mulder, Jinghui Zhang, Geoffrey Neale, Emily Walker, I-Chan Huang, Kirsten K. Ness, Melissa M. Hudson, Leslie L. Robison, Zhaoming Wang. Epigenome-wide association study of blood lipids among survivors of childhood cancer in the St. Jude Lifetime Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3764.