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: The GRECF study recruited 790 participants born between 1956 and 1964 from 2 neighbor provinces, Anhui and Jiangxi, in China through a multistage, clustered, random sampling. The current study included a random sample of 188 GRECF participants. IGF2 differential methylation region (DMR) is an intragenic DMR located upstream of the imprinted promoters of IGF2 exon 3. DNA methylation were quantified at 8 cytosine-phosphate-guanine dinucleotides (CpG) sites at the IGF2 DMR (chr11p15.5) using the Sequenom EpiTYPER method and the MassARRAY system. Multivariate linear regressions were used to evaluate pairwise associations among famine severity, DNA methylation in the IGF2 gene, and lipid levels. We controlled for age and sex in the base model and additionally controlled for education, smoking, and drinking status in the fully adjusted model. 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 lipid levels. Results: Exposure to severe famine was associated with elevated methylation at CpG1 (chr11: 2126041, build 36) of the IGF2 DMR (β = 0.07; P = 0.0008) and total cholesterol (β = 0.72; P = 1.09 × 10-7). After adjustment for age and sex, each unit increase in methylation of the CpG1 site was associated with 1.09-unit increase in total cholesterol (P = 0.03). After further adjustment for all covariates, these associations were still significant (P famine-CpG1 = 0.002, P famine-total cholesterol = 1.28 × 10-6, and P CpG1-total cholesterol = 0.05). Conclusion: Increased methylation level in the IGF2 gene was associated with early-life exposure to severe famine, and this change was also positively associated with total cholesterol in late adulthood.