Edematous severe acute malnutrition is characterized by hypomethylation of DNA.

Edematous severe acute childhood malnutrition (edematous SAM or ESAM), which includes kwashiorkor, presents with more overt multi-organ dysfunction than non-edematous SAM (NESAM). Reduced concentrations and methyl-flux of methionine in 1-carbon metabolism have been reported in acute, but not recovered, ESAM, suggesting downstream DNA methylation changes could be relevant to differences in SAM pathogenesis. Here, we assess genome-wide DNA methylation in buccal cells of 309 SAM children using the 450 K microarray. Relative to NESAM, ESAM is characterized by multiple significantly hypomethylated loci, which is not observed among SAM-recovered adults. Gene expression and methylation show both positive and negative correlation, suggesting a complex transcriptional response to SAM. Hypomethylated loci link to disorders of nutrition and metabolism, including fatty liver and diabetes, and appear to be influenced by genetic variation. Our epigenetic findings provide a potential molecular link to reported aberrant 1-carbon metabolism in ESAM and support consideration of methyl-group supplementation in ESAM.

Exploring putative genetic determinants of inter-individual phenotypic heterogeneity in sickle cell disease: A cross-sectional Jamaican cohort-based study.

Patients with sickle cell disease (SCD) display puzzling inter-individual phenotypic heterogeneity, conceivably related to inherent differences in antioxidant protection, hemoglobin binding, bilirubin catabolism and methyl group handling. Therefore, we explored putative associations between clinically important phenotypic measures and functional polymorphisms within specific candidate genes encoding glutathione S-transferase, haptoglobin, uridine 5'-diphospho-glucuronosyltransferase 1A1, methyl tetrahydrofolate reductase, 5-methyltetrahydrofolate-homocysteine methyltransferase, and cystathionine beta-synthase. Two-hundred and thirty SCD participants (mean age 25.1 ±â€¯2.8) were recruited from Jamaica's Annual Sickle Cell Unit Cohort Review - two-hundred and five had homozygous hemoglobin SS (HbSS) disease, twenty-five had hemoglobin SC (HbSC) disease. Regression analyses revealed some novel genotype-phenotype associations. HbSC participants had significantly lower mean lactate dehydrogenase (p = 0.01) and glutathione (p < 0.001) values than HbSS participants. Glutathione S-transferase P1 (GSTP1) was significantly associated with mean corpuscular hemoglobin concentration using univariate (p = 0.044) and multivariable regression (p = 0.012). 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) was significantly associated with hemoglobin F % using univariate (p = 0.010) and multivariable regression (p = 0.009). In conclusion, this exploratory cross-sectional study generated novel, useable, and informative genotype-phenotype estimates of association, but larger studies are needed to determine whether these specific variants are related to inter-individual phenotypic variability in SCD.

A cross-sectional clinic-based study exploring whether variants within the glutathione S-transferase, haptoglobin and uridine 5'-diphospho-glucuronosyltransferase 1A1 genes are associated with interindividual phenotypic variation in sickle cell anaemia in Jamaica.

OBJECTIVES: To explore putative associations between specific variants in either the glutathione S-transferase (GST), haptoglobin (HP) or uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1) genes and clinically important phenotypes in sickle cell anaemia (HbSS). METHODS: 371 HbSS participants were recruited from the Sickle Cell Clinic of the Sickle Cell Unit at the University of the West Indies, Kingston, Jamaica. Markers within four GST superfamily genes, the HP gene and the UGT1A1 gene were analysed using PCR-based assays. RESULTS: Multivariable regression revealed statistically significant associations between the GSTP1 Ile105Val heterozygote and HbA2 levels (P = .016), HbF percentage (P = .001), MCH concentration (P = .028) and reticulocyte count (P = .032), while the GSTM3 D/D homozygote was significantly associated with HbA2 levels (P = .032). The UGT1A1 (TA)6 /(TA)8 heterozygote showed statistically significant associations with HbA2 levels (P = .019), HbF percentage (P < .001), haemoglobin levels (P = .008), PCV values (P = .007) and RBC counts (P = .041). CONCLUSION: This exploratory cross-sectional study has generated novel and informative genotype-phenotype estimates of association, but larger studies are needed to determine whether these specific variants within the GST, UGT1A1 and HP genes are related to interindividual phenotypic variability in HbSS.

Glutathione S-transferase polymorphisms may be associated with risk of oedematous severe childhood malnutrition.

It has been estimated that more than 50 % of deaths before the age of 5 years have undernutrition as an underlying cause. Severe childhood malnutrition, an extreme form of undernutrition, occurs as oedematous and non-oedematous syndromes. The reasons why only some children develop oedematous severe childhood malnutrition (OSCM) have remained elusive, but the heterogeneity of clinical appearances among children from relatively homogeneous backgrounds suggests that interindividual variation in susceptibility to OSCM may exist. We investigated variants of four glutathione S-transferase (GST) genes in a retrospective study among subjects (n 136) previously admitted to the Tropical Metabolism Research Unit, Jamaica, for the treatment of either OSCM (cases) or non-oedematous severe childhood malnutrition (controls). We found that GSTP1 Val(105) homozygotes were significantly more common among the cases (odds ratio (OR) 3.5; 95 % CI 1.1, 10.8). We also found an association of borderline significance between non-deletion GSTT1 genotypes (i.e. +/+ or +/0) and OSCM (OR 2.4; 95 % CI 1.0, 5.9). There was no significant association between OSCM and any of the other GST variants. These preliminary findings suggest that genetic variation within the GST superfamily may contribute to the risk of OSCM. Additional, larger data sets and studies of variants in other candidate genes are required in order to properly assess the true contribution, if any, of genetic variation to risk of OSCM. Such studies may improve our understanding of the causes of clinical heterogeneity in malnutrition.

Polymorphisms in genes involved in folate metabolism as risk factors for oedematous severe childhood malnutrition: a hypothesis-generating study.

BACKGROUND: Severe childhood malnutrition (SCM) occurs as both oedematous and non-oedematous syndromes. The reasons why some children develop oedematous SCM (OSCM) have remained elusive but differences in clinical presentation among malnourished children from similar backgrounds suggests that there might be inter-individual variation in susceptibility to OSCM. AIM: To estimate the strength of the association between variants of three genes involved in folate/methyl group metabolism [methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and cystathionine beta-synthase (CBS)] and risk of OSCM. METHODS: Patients previously admitted to the Tropical Metabolism Research Unit (TMRU) for treatment of either OSCM (cases, n = 74) or non-oedematous SCM (NOSCM, controls, n = 50) were recruited. Genotypes at four sites within the three genes (MTHFR C677T, MTHFR A1298C, MTR A2756G and CBS 844ins68) were determined using PCR-based assays. RESULTS: The MTHFR 677T [odds ratio (OR) 0.63, 95% CI 0.2-1.7] and MTR 2756G (OR 0.74, 95% CI 0.4-1.4) alleles were associated with moderate reduction in risk of OSCM whereas the CBS 844ins68 allele (OR 1.4, 0.7-2.4) was associated with an increased risk. None of these risks was significant at the 5% level. CONCLUSIONS: Genetic variation within folate/methyl group metabolic pathways might have a small but potentially important influence on risk of OSCM. Additional, larger data-sets will be required to test the specific hypotheses (about the putative effect size and direction of association) generated in this preliminary study. Such observations have the potential to improve our understanding of the pathogenesis of clinical heterogeneity in severe malnutrition.