Early-Life Exposure to Severe Famine Is Associated with Higher Methylation Level in the IGF2 Gene and Higher Total Cholesterol in Late Adulthood: The Genomic Research of the Chinese Famine (GRECF) Study

Abstract

Objective: To evaluate the association of early-life exposure to the Chinese Great Famine (1959-1961) with DNA methylation in IGF2 and its subsequent influence on blood lipid levels in late adulthood among participants of the Genomic Research of the Chinese Famine (GRECF) study. Methods: Among a random sample of 188 GRECF participants, DNA methylation within the IGF2 gene were quantified at 8 cytosine-phosphate-guanine dinucleotides (CpG) sites. Multivariate linear regressions were used to evaluate pairwise associations among famine severity, DNA methylation in the IGF2 gene, and lipids levels. Mediation analysis was applied to assess the mediation effect of DNA methylation at the IGF2 gene on the association between early-life exposure to severe famine and adult lipids levels. Results: Exposure to severe famine was associated with elevated methylation at CpG1 of the IGF2 gene (β=0.07; P=0.0008) and total cholesterol (TC) (β=0.72; P=1.09x10-7). After adjustment for age and sex, each unit increase in methylation of the CpG1 site was associated with 1.09-unit increase in TC (P=0.03). After additional adjustment for education, smoking, and drinking, these associations were still significant (Pfamine-CpG1=0.002, Pfamine-TC=1.28x10-6, and PCpG1-TC= 0.05). Methylation of the CpG1 site mediated 5% (P=0.30) of the association between exposure to severe famine and adult TC. Interpretation: Increased methylation level in the IGF2 gene was associated with early-life exposure to severe famine and this change was also positively associated with TC in late adulthood. Funding: The GRECF study was funded by the National Science Foundation of China (NSFC81402692). Declaration of Interest: None Ethical Approval: The GRECF study was approved by the Institute Review Board at the Peking University Health Science Center. All participants have signed consent forms.