Molecular Evidence for Differential Long-term Outcomes of Early Life Severe Acute Malnutrition.
BACKGROUND
Severe acute malnutrition (SAM) in infants may present as one of two distinct syndromic forms: non-edematous (marasmus), with severe wasting and no nutritional edema; or edematous (kwashiorkor) with moderately severe wasting. These differences may be related to developmental changes prior to the exposure to SAM and phenotypic changes appear to persist into adulthood with differences between the two groups. We examined whether the different response to SAM and subsequent trajectories may be explained by developmentally-induced epigenetic differences.


METHODS
We extracted genomic DNA from muscle biopsies obtained from adult survivors of kwashiorkor (n=21) or marasmus (n=23) and compared epigenetic profiles (CpG methylation) between the two groups using the Infinium® 450K BeadChip array.


RESULTS
We found significant differences in methylation of CpG sites from 63 genes in skeletal muscle DNA. Gene ontology studies showed significant differential methylation of genes in immune, body composition, metabolic, musculoskeletal growth, neuronal function and cardiovascular pathways, pathways compatible with the differences in the pathophysiology of adult survivors of SAM.


CONCLUSIONS
These findings suggest persistent developmental influences on adult physiology in survivors of SAM. Since children who develop marasmus have lower birth weights and after rehabilitation have different intermediary metabolism, these studies provide further support for persistent developmentally-induced phenomena mediated by epigenetic processes affecting both the infant response to acute malnutrition and later life consequences.


BACKGROUND
Supported by a Grant from the Bill and Melinda Gates Foundation (Global Health OPP1066846), Grand Challenge "Discover New Ways to Achieve Healthy Growth."
Previous research has shown that infants who develop either kwashiorkor or marasmus in response to SAM differ in birth weight and subsequently have different metabolic patterns in both infancy and adulthood.
This study demonstrates epigenetic differences in the skeletal muscle of adult survivors of marasmus versus kwashiorkor and these differences are in genes that may underlie the longer-term consequences.
These data are compatible with the different clinical responses to SAM arising from developmentally-induced epigenetic changes laid down largely before birth and provide evidence for the predictive adaptive response model operating in human development.
The Liggins Institute, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand.
Allan
A
Sheppard
The Liggins Institute, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand.
Sherry
S
Ngo
The Liggins Institute, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand.
Xiaoling
X
Li
Tropical Medicine Research Institute, The University of the West Indies, Mona, Kingston 7, Jamaica.
Michael
M
Boyne
Tropical Medicine Research Institute, The University of the West Indies, Mona, Kingston 7, Jamaica.
Debbie
D
Thompson
The Liggins Institute, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand.
Anthony
A
Pleasants
The Liggins Institute, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand.
Peter
P
Gluckman
The Liggins Institute, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand; UWI Solutions for Developing Countries, The University of the West Indies, Mona, Kingston 7, Jamaica. Electronic address: terrence.forrester@uwimona.edu.jm.
Terrence
T
Forrester
D000328:Adult; D002097:C-Reactive Protein / Q000235:genetics; D018899:CpG Islands; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D019175:DNA Methylation; D057890:Epigenomics; D005260:Female; D015894:Genome, Human; D006593:Hexokinase / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007732:Kwashiorkor; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011502:Protein-Energy Malnutrition; D012044:Regression Analysis; D000067011:Severe Acute Malnutrition / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics; D055815:Young Adult; D000097577:Homeobox Protein PITX2
D002097:C-Reactive Protein; D004247:DNA; D006593:Hexokinase; D018398:Homeodomain Proteins; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C000609700:HK2 protein, human; C510751:LRRK1 protein, human
Birthweight; Epigenetic; Jamaica; Muscle; Severe acute malnutrition