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. 2023 Feb 28;15(1):32.
doi: 10.1186/s13148-023-01447-3.

Distinct DNA methylation signatures associated with blood lipids as exposures or outcomes among survivors of childhood cancer: a report from the St. Jude lifetime cohort

Qian Dong #  1 , Cheng Chen #  1   2 , Nan Song  3 , Na Qin  4 , Noel-Marie Plonski  1 , Emily R Finch  1 , Kyla Shelton  1 , John Easton  5 , Heather Mulder  5 , Emily Plyer  5 , Geoffrey Neale  6 , Emily Walker  6 , Qian Li  7 , I-Chan Huang  1 , Jinghui Zhang  5 , Hui Wang  2 , Melissa M Hudson  1   8 , Leslie L Robison  1 , Kirsten K Ness  1 , Zhaoming Wang  9   10
Affiliations

Distinct DNA methylation signatures associated with blood lipids as exposures or outcomes among survivors of childhood cancer: a report from the St. Jude lifetime cohort

Qian Dong et al. Clin Epigenetics. .

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Keywords: African ancestry; Childhood cancer survivors; DNA methylation; EWAS; European ancestry; Lipid levels.

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Conflict of interest statement

We declare no competing interests.

Figures

Fig. 1
Fig. 1
Schematic framework of study design. EWAS epigenome-wide association study, DNAm DNA methylation, SJLIFE St. Jude lifetime cohort study. Median (range) of time, the median/range of time between DNAm sampling age and median age of multiple lipid measurements
Fig. 2
Fig. 2
Manhattan plots of exposure and outcome EWAS of blood lipids among survivors of European ancestry in SJLIFE cohort. EWAS epigenome-wide association study, SJLIFE St. Jude lifetime cohort study, HDL high-density lipoprotein, LDL low-density lipoprotein, TG triglycerides, TC total cholesterol
See this image and copyright information in PMC

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