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.

Vitamin D levels are low in adult patients with sickle cell disease in Jamaica and West Africa.

BACKGROUND: Patients with sickle cell disease in the USA have been noted to have lower levels of vitamin D - measured as 25-hydroxyvitamin D (25(OH)D) - compared to controls. Average serum 25(OH)D levels are also substantially lower in African Americans than whites, while population distributions of 25(OH)D among Jamaicans of African descent and West Africans are the same as among USA whites. The purpose of this study was to examine whether adult patients with sickle cell disease living in tropical regions had reduced 25(OH)D relative to the general population. METHODS: We analyzed serum 25(OH)D in stored samples collected from studies in Jamaica and West Africa of adult patients with sickle cell disease and adult population controls. RESULTS: In samples of 20 Jamaicans and 50 West Africans with sickle cell disease mean values of 25(OH)D were 37% and 39% lower than controls, respectively. Metabolic abnormalities in the absorption and conversion pathways are possible causes for the consistent relative deficiency of 25(OH)D in sickle cell disease. CONCLUSIONS: Low 25(OH)D levels in tropical Africa where the burden of sickle cell disease is highest, deserve further investigation, and a randomized trial is warranted to address efficacy of supplementation.

Genome-wide association of anthropometric traits in African- and African-derived populations.

Genome-wide association (GWA) studies have identified common variants that are associated with a variety of traits and diseases, but most studies have been performed in European-derived populations. Here, we describe the first genome-wide analyses of imputed genotype and copy number variants (CNVs) for anthropometric measures in African-derived populations: 1188 Nigerians from Igbo-Ora and Ibadan, Nigeria, and 743 African-Americans from Maywood, IL. To improve the reach of our study, we used imputation to estimate genotypes at approximately 2.1 million single-nucleotide polymorphisms (SNPs) and also tested CNVs for association. No SNPs or common CNVs reached a genome-wide significance level for association with height or body mass index (BMI), and the best signals from a meta-analysis of the two cohorts did not replicate in approximately 3700 African-Americans and Jamaicans. However, several loci previously confirmed in European populations showed evidence of replication in our GWA panel of African-derived populations, including variants near IHH and DLEU7 for height and MC4R for BMI. Analysis of global burden of rare CNVs suggested that lean individuals possess greater total burden of CNVs, but this finding was not supported in an independent European population. Our results suggest that there are not multiple loci with strong effects on anthropometric traits in African-derived populations and that sample sizes comparable to those needed in European GWA studies will be required to identify replicable associations. Meta-analysis of this data set with additional studies in African-ancestry populations will be helpful to improve power to detect novel associations.

Ethnic differences in F cell levels in Jamaica: a potential tool for identifying new genetic loci controlling fetal haemoglobin.

High levels of fetal haemoglobin (HbF) are protective in beta-haemoglobinopathies. The proportion of erythrocytes containing HbF (F-cells, FC) was measured in healthy adults of African and Caucasian ancestry to assess the feasibility of localizing genes for the FC trait using admixture mapping. Participants were Afro-Caribbean (AC) blood donors and residents of a rural enclave with a history of recent German admixture (Afro-German, AG) recruited in Jamaica, and Caucasian Europeans recruited in Jamaica and the UK. FC levels were significantly different between groups (P < 0.001); the geometric mean FC level in the AC sample (n = 176) was 3.75% [95% confidence interval (CI) 3.36-4.18], AG sample (n = 631) was 2.77% (95% CI 2.63-2.92), and among Caucasians (n = 1099) was 3.26% (95% CI 3.13-3.39). After adjustment for age, sex, haemoglobin electrophoresis pattern, and HBG2 genotype, FC levels in the AC group remained significantly different (P < 0.001) from those in the Caucasian and the AG group but the difference between the Caucasian and AG groups became non-significant (P = 0.46) despite substantial differences in average ancestry. The data confirm ethnic differences in FC levels and indicate the potential usefulness of these populations for admixture mapping of genes for FC levels.

A genome-wide search replicates evidence of a quantitative trait locus for circulating angiotensin I-converting enzyme (ACE) unlinked to the ACE gene.

BACKGROUND: Angiotensin I-converting enzyme (ACE) plays an important role in cardiovascular homeostasis. There is evidence from different ethnic groups that circulating ACE levels are influenced by a quantitative trait locus (QTL) at the ACE gene on chromosome 17. The finding of significant residual familial correlations in different ethnic groups, after accounting for this QTL, and the finding of support for linkage to a locus on chromosome 4 in Mexican-American families strongly suggest that there may well be QTLs for ACE unlinked to the ACE gene. METHODS: A genome-wide panel of microsatellite markers, and a panel of biallelic polymorphisms in the ACE gene were typed in Nigerian families. Single locus models with fixed parameters were used to test for linkage to circulating ACE with and without adjustment for the effects of the ACE gene polymorphisms. RESULTS: Strong evidence was found for D17S2193 (Zmax = 3.5); other nearby markers on chromosome 17 also showed modest support. After adjustment for the effects of the ACE gene locus, evidence of "suggestive linkage" to circulating ACE was found for D4S1629 (Zmax = 2.2); this marker is very close to a locus previously shown to be linked to circulating ACE levels in Mexican-American families. CONCLUSION: In this report we have provided further support for the notion that there are QTLs for ACE unlinked to the ACE gene; our findings for chromosome 4, which appear to replicate the findings of a previous independent study, should be considered strong grounds for a more detailed examination of this region in the search for genes/variants which influence ACE levels.The poor yields, thus far, in defining the genetic determinants of hypertension risk suggest a need to look beyond simple relationships between genotypes and the ultimate phenotype. In addition to incorporating information on important environmental exposures, a better understanding of the factors which influence the building blocks of the blood pressure homeostatic network is also required. Detailed studies of the genetic determinants of ACE, an important component of the renin-angiotensin system, have the potential to contribute to this strategic objective.

Childhood malnutrition is associated with a reduction in the total melanin content of scalp hair.

Childhood malnutrition is known to be associated with visible lightening of hair colour (hypochromotrichia). Nevertheless, no systematic investigations have been carried out to determine the biochemical basis of this change. We used an HPLC method to measure melanins in the scalp hair of thirteen Jamaican children, diagnosed as having primary malnutrition, during various stages of their treatment and after recovery. During treatment for malnutrition, a progressive decrease in total melanin content along the hair shaft from tip to root (root:tip ratio: 0.62 (sd 0.31)) was observed. This ratio was significantly different (P = 0.003) from the ratio observed among children sampled several months after discharge from hospital (0.93 (sd 0.23)) and among normal control children (0.97 (sd 0.12)). Thus, it appears that a decrease in melanin content is associated with periods of malnutrition. The low root:tip ratio during malnutrition presumably arises because the tips reflect prior hair growth during 'normal' nutrition and the roots reflect hair growth during malnutrition; a return of the root:tip ratio to that seen among controls reflects 'recovery' from malnutrition. It is possible that reduced intake or availability of tyrosine, a key substrate in melanin synthesis, may play a role in the reduction of hair melanin content during periods of malnutrition. The precise mechanisms by which melanin content is reduced, and the role of aromatic amino acid availability in hair colour change and other features of childhood malnutrition remain to be explored.

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.

Angiotensin I-converting enzyme polymorphisms, ACE level and blood pressure among Nigerians, Jamaicans and African-Americans.

The genes in the renin-angiotensin system are important physiologic candidates in studies of the genetic susceptibility to hypertension. Limited information has been available in most studies on the extent of variation in the candidate loci or the modifying effects of different environmental settings. We consequently genotyped 13 polymorphisms at the angiotensin I-converting enzyme (ACE) locus at an average distance of 2 kb in 2776 family members from Nigeria, Jamaica and an African-American community in the US. Allele and haplotype frequencies were similar in the three populations, with modest evidence of European admixture in the US. Two markers were consistently associated with ACE level in the three samples and the proportion of variance accounted for by ACE8 was similar in the three groups. No evidence of consistent association of single markers was noted with blood pressure across the three population samples, however. Likewise, in a haplotype-based analysis, despite significant associations within each population, the findings were not replicated consistently across all three samples. We did observe, however, that the overtransmitted haplotypes among hypertensives were drawn from a single clade, suggesting that susceptibility may cluster in patterns not captured directly by our markers.

A case of severe ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) is the serious physiological complication in patients undergoing controlled ovarian hyperstimulation. In a recently concluded treatment cycle of 28 women at the fertility management unit at the University Hospital of the West Indies, one patient developed symptoms and signs of severe ovarian hyperstimulation syndrome. Administration of human chorionic gonadotrophin (HCG) had a direct influence on the development of the syndrome. High risk cases, such as young patients, particularly those with polycystic ovaries or those with serum oestradiol levels >10,000 pmol/l and a large number of follicles, must be identified. Preventative measures include cylce cancellation, reduction of HCG dosage, egg retrieval and cryopreservation of embryos rather than embryo transfer.(Au)

Birth weight may influence susceptibility to oedematous forms of severe protein-energy malnutrition [abstract]

OBJECTIVE: To determine whether an association exists between reported birth weight and oedematous forms of severe protein energy malnutrition (PEM). METHODS: Severe PEM continues to be a major public health problem worldwide. However, the causes of oedematous PEM (OPEM) have not yet been elucidated. Recently, birth weight was reported to be associated with risk of ischaemic heart disease and Type 2 diabetes mellitus in adults. It is possible that the examination of the relationship between birth weight and OPEM in children may give clues, not only about the mechanisms underlying the developing of OPEM, but also about the mechanism by which associations between birth weight and adult disease may arise. As part of a larger project to create a database containing information on children admitted to the ward of the Tropical Metabolism Research Unit, the authors reviewed the clinical records of 884 children. Children were categorised as having either OPEM or non-OPEM. Multiple logisitic regression was used to examine the relationship between reported birth weight and the odds ratio (OR) for having OPEM. RESULTS: In this sample of children, the OR for having OPEM was 1.40 (95 percent CI 1.15 - 1.70) for each increase of 1 pound in birth weight. Birth weight remained significant even after inclusion of gender, mother's age and birth rank in the mutliple logistic regression model. CONCLUSION: These results suggest that among children with severe PEM, higher birth weights are associated withan increased risk of oedematous malnutrition. Replication of this result in a large sample is required.(Au)

Primary malnutrition - can we always tell?

OBJECTIVE: To determine if there was a decrease in admissions for primary malnutrition and an increase in those for initially undiagnosed secondary malnutrition over the period January 1, 1990 to October 31, 1999 at the Tropical Metabolism Research Unit (TMRU). DESIGN AND METHODS: A retrospective review of all admissions, for treatment of malnutrition, to TMRU using admission books and patient records was done. Children were classified with secondary malnutrition if diagnosed after admission with illnesses known to cause malnutrition. Those known to have such conditions on admission or who were over 10 years old were eliminated. Nutritional diagnosis according to the Wellcome classification, age at presentation, sex and birth weight were reviewed. RESULLTS: A total of 411 patients were admitted to the TMRU during this 10-year period and 23 of these had secondary malnutrition have increased, especially since 1998. Children with secondary malnutrition were usually marasmic (78 percent), had low normal birth weight (2.8kg) and presented at a later age (15.3 months). The most common secondary cause of malnutrition was HIV infection (56 percent). CONCLUSION: There has been an increase in initially undiagnosed secondary malnutrition seen at TMRU over the last ten years even with a decrease in admissions for primary malnutrition. This may be due to subtlety of presentation and indicates a need for increased vigilance in assessment by health professionals in order to optimize management.(Au)

Dumping syndrome in a young Jamaican child

The dumping syndrome in childhood is an uncommon complication of gastro-oesophageal surgery, principally Nissen fundoplication. A Jamaican child developed the syndrome after fundoplication and pyloroplasty to relieve gastro-oesophageal reflux complicating the repair of a congenital tracheo-oesophageal fistula. He developed marasmus and failed to gain weight on the standard remedial milk-based high energy diet. An oral glucose tolerance test confirmed the diagnosis of dumping syndrome. A low sugar low milk diet based on adult type meals with continous nibbling of fried dumplings relieved his diarrhoea and hypoglycaemia and he gained weight. This is a cheaper and more practical dietary therapy than the regimens described previously(AU)

Segregation and linkage analysis of serum angiotensin I-converting enzyme levels : evidence for two quantitative-trait loci - abstract

Human serum angiotensin I-converting enzyme (ACE) levels vary substantially between individuals and are highly heritable. Segregation analysis in European families has shown that more than half of the total variability in ACE levels is influenced by quantitative-trait loci (QTL). One of these QTLs is located within or close to the ACE locus itself. Combined segretation/linkage analysis in a series of African Caribbean families from Jamaica shows that the ACE insertion-deletion polymorphism is in moderate linkage disequilibrium with an ACE-linked QTL. Linkage analysis with a highly informative polymorphism at the neighbouring growth-hormone gene (GH) shows surprisingly little support for linkage (LOD score [Z] = 0.12). An extended analysis with a two-QTL model, where an ACE-linked QTL interacts additively with an unlinked QTL, significantly improves both the fit of the model (P = .002) and the support for linkage between the ACE-linked QTL and GH polymorphism (Z = 5.0). We conclude that two QTLs jointly influence serum ACE levels in this population. One QTL is located within or close to the ACE locus and explains 27 per cent of the total variability; the second QTL is unlinked to the locus and explains 52 per cent of the variability. The identification of the molecular mechanisms underlying both QTLs is necessary in order to interpret the role of ACE in cardiovascular disease (AU)

Bio-specific purification of folate-requiring enzymes - abstract

Despite the use of a variety of anti-folate agent in chemotherapy, detailed understanding of the metabolism of folates is scant due largely to the instability of folate coenzymes in vitro, and the low levels of the enzymes involved in vivo. Commercially available tetrahydrofolate preparations contain at least 25 percent unspecified impurities, and are racemic mixture of biologically active and inactive isomers. The object of this study was to investigate the application of purified substrates in the isolation of folate-metabolising enzymes by affinity chromatography. Methylenetetrahydrofolate, which is both oxygen - and photo-labile, was prepared by reducing folic acid with borohydride and subsequent reaction with formaldehyde. The biologically active isomer, d-methylenetetrahydrofolate, was isolate by ion-exchange chromatgraphy, with a yield of 35 percent from folic acid. Methylenetetrahdrofolate reductase, an allosteric enzyme regulating the biosynthesis of S-adenosylmethionine, was partially purified from rat liver by ion-exchange chromatography and applied to a column of the affinity matrix procion red HE-3B - sepharose. The loaded column was washed with buffer to remove unbound proteins and active enzyme was bio-specifically eluted with a gradient of d-methylenetetrahydrofolate with greater than 90 percent recovery of activity. Hereditary deficiency of this enzyme has been implicated in cases of schizophrenia and homocystinuria. The quantitative determination of enzyme levels in vivo, and kinetic data obtained from purified preparations in vitro are prerequisites for the understanding of metabolic fluxes in the intact animal. The technique investigated in this study may facilitate analysis of other folate-requiring enzymes (AU)