Abstract

ObjectiveTo 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.MethodsThe 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.ResultsExposure 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 (Pfamine-CpG1 = 0.002, Pfamine-total cholesterol = 1.28 × 10−6, and PCpG1-total cholesterol = 0.05).ConclusionIncreased 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.

Highlights

  • Malnutrition during childhood has been associated with a series of health problems indicated by high mortality, morbidity, and mental disability [1,2,3,4,5,6]

  • In studies of the Dutch famine in 1944–1945, individuals exposed to famine up to 6 months during gestation was associated with elevated total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), LDL-C to high-density lipoprotein cholesterol (HDL-C) ratio, and apolipoprotein B, and lower levels of HDL-C and apolipoprotein A [7,8,9]

  • The Dutch famine study identified that associations of prenatal undernutrition with elevated total cholesterol concentrations and triglycerides only existed among women, but not men [7]

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Summary

Introduction

Malnutrition during childhood has been associated with a series of health problems indicated by high mortality, morbidity, and mental disability [1,2,3,4,5,6]. Some natural disasters, such as famine, were widely studied as an ideal (quasi-) natural experiment to investigate the longterm effect of childhood malnutrition. In studies of the Dutch famine in 1944–1945, individuals exposed to famine up to 6 months during gestation was associated with elevated total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), LDL-C to high-density lipoprotein cholesterol (HDL-C) ratio, and apolipoprotein B, and lower levels of HDL-C and apolipoprotein A [7,8,9]. Similar studies of the Chinese Great Famine (1959–1961) indicated that early-life exposure to severe famine had excessive risk of dyslipidemia [10]. The Dutch famine study identified that associations of prenatal undernutrition with elevated total cholesterol concentrations and triglycerides only existed among women, but not men [7]. The phenomenon was found in studies of the Chinese Great Famine [10]

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