Edematous Severe Acute Malnutrition is Characterized by Hypomethylation of DNA

A slower transmethylation of one-carbon substrates in the edematous form of severe acute malnutrition (ESAM) suggests that downstream aberrations in DNA methylation could drive differences in acute pathogenesis between ESAM and non-edematous malnutrition (NESAM). Here, we integrate genome-wide assessments of DNA methylation with corresponding gene expression profiles and sequence variation to show that relative to NESAM, acute ESAM is characterized by significant hypomethylation at 99% of differentially methylated loci in two SAM cohorts, whereas recovered adults show no significant differences in methylation. Hypomethylated loci correlate with both up- and down-regulation of proximal genes, which are associated with the clinical sub-phenotypes of kwashiorkor and enriched for GWAS hits linked to over-nutrition, including fatty liver and diabetes. Methylation at these loci also appears to be influenced by nearby genetic variation in a manner that varies with nutritional status. Our findings implicate epigenetic and genetic variation in ESAM pathophysiology and support methyl-group supplementation in ESAM management. DNA obtained from buccal epithelial cells of 309 children with severe acute malnutrition and 65 adults with a history of severe acute malnutrition, who have since recovered, was bisulfite converted and hybridized to the Illumina Infinium HumanMethylation450K BeadChip array. We then compared genome-wide methylation between 164 acutely ill children with edematous malnutrion (ESAM) to that of 145 children with non-edematous malnutrition (NESAM) to identify epigenetic differences between the two manifestations of severe acute malnutrition. Of these acutely ill children, 109 were Jamaican (ESAM n=61, NESAM n=48) and 200 were Malawian (ESAM n=103, NESAM=97). Genome-wide methylation comparison was repeated between recovered adults from Jamaica, of which 31 had a history of ESAM and 34 of NESAM.