[Show abstract][Hide abstract] ABSTRACT: In populations of European ancestry, the genetic contribution to body mass index (BMI) increases with age during childhood but then declines during adulthood, possibly due to the cumulative effects of environmental factors. How the effects of genetic factors on BMI change with age in other populations is unknown.
In a rural Gambian population (N=2535), we used a combined allele risk score, comprising genotypes at 28 'Caucasian adult BMI-associated' single nucleotide polymorphisms (SNPs), as a marker of the genetic influence on body composition, and related this to internally-standardised z-scores for birthweight (zBW), weight-for-height (zWT-HT), weight-for-age (zWT), height-for-age (zHT), and zBMI cross-sectionally and longitudinally.
Cross-sectionally, the genetic score was positively associated with adult zWT (0.018±0.009 per allele, p=0.034, N=1426) and zWT-HT (0.025±0.009, p=0.006), but not with size at birth or childhood zWT-HT (0.008±0.005, p=0.11, N=2211). The effect of the genetic score on zWT-HT strengthened linearly with age from birth through to late adulthood (age interaction term: 0.0083 z-scores/allele/year; 95% CI 0.0048 to 0.0118, p=0.0000032).
Genetic variants for obesity in populations of European ancestry have direct relevance to bodyweight in nutritionally deprived African settings. In such settings, genetic obesity susceptibility appears to regulate change in weight status throughout the life course, which provides insight into its potential physiological role.
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Journal of Medical Genetics 04/2015; 52(6). DOI:10.1136/jmedgenet-2014-102784 · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vitamin D is well known for its role in promoting skeletal health. Vitamin D status is determined conventionally by circulating 25-dihydroxyvitamin D (25OHD) concentration. There is evidence indicating that circulating 25OHD concentration is affected by variation in Gc, the gene encoding the vitamin D binding protein (DBP). The composite genotype of two single nucleotide polymorphisms (rs7041 and rs4588) results in different DBP isotypes (Gc1f, Gc1s and Gc2). The protein configurational differences among DBP isotypes affect DBP substrate binding affinity.
The aims of this study were to determine 1) Gc variant frequencies in a population from an isolated rural region of The Gambia, West Africa (n = 3129) with year-round opportunity for cutaneous vitamin D synthesis and 2) the effects of Gc variants on 25OHD concentration (n = 237) in a genetically representative sub-group of children (mean (SD) age: 11.9 (4.8) years).
The distribution of Gc variants was Gc1f: 0.86, Gc1s: 0.11 and Gc2: 0.03. The mean (SD) concentration of 25OHD was 59.6 (12.9) nmol/L and was significantly higher in those homozygous for Gc1f compared to other Gc variants (60.7 (13.1) vs. 56.6 (12.1) nmol/L, P = 0.03). Plasma 25OHD and 1,25(OH)2D concentration was significantly associated with parathyroid hormone in Gc1f-1f but not in the other Gc variants combined.
This study demonstrates that different Gc variants are associated with different 25OHD concentrations in a rural Gambian population. Gc1f-1f, thought to have the highest affinity for 25OHD, had the highest 25OHD concentration compared with lower affinity Gc variants.
The considerable difference in Gc1f frequency observed in Gambians compared with other non-West African populations and associated differences in plasma 25OHD concentration, may have implications for the way in which vitamin D status should be interpreted across different ancestral groups.
Bone 01/2015; 74. DOI:10.1016/j.bone.2014.12.068 · 4.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ready-to-use supplementary food supplements improve endothelial function, hemoglobin and growth in Tanzanian children with sickle cell anaemia: The Vascular Function Intervention Study (V-FIT), a random order crossover trial
[Show abstract][Hide abstract] ABSTRACT: Hepcidin inhibits ferroportin-mediated iron efflux, leading to intracellular macrophage iron retention, possibly favoring Mycobacterium tuberculosis iron acquisition and tuberculosis (TB) pathogenesis. Plasma hepcidin was measured at human immunodeficiency virus (HIV) diagnosis in a retrospective HIV-prevalent, antiretroviral-naïve African cohort to investigate the association with incident pulmonary and/or extra-pulmonary TB. One hundred ninety-six participants were followed between 5 August 1992 and 1 June 2002, with 32 incident TB cases identified. Greater hepcidin was associated with significantly increased likelihood of TB after a median time to TB of 6 months. Elucidation of iron-related causal mechanisms and time-sensitive biomarkers that identify individual changes in TB risk are needed.
The International Journal of Tuberculosis and Lung Disease 11/2014; 18(11). DOI:10.5588/ijtld.14.0143 · 2.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ethnic differences in renal calcium and phosphate excretion exist, which may depend on differences in their dietary intakes and regulatory factors. We report highly significant differences in urinary calcium and phosphate excretion between white British and Gambian adults after statistical adjustment for mineral intakes, indicating an independent effect of ethnicity.
Osteoporosis International 10/2014; 26(3). DOI:10.1007/s00198-014-2926-8 · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Summary Predictors of 25(OH)D3 half-life were factors associated with vitamin D metabolism, but were different between people in The Gambia and the UK. Country was the strongest predictor of plasma 25(OH)D concentration, probably as a marker of UVB exposure. 25(OH)D3 half-life may be applied as a tool to investigate vitamin D expenditure. Introduction The aim of this study was to investigate predictors of 25(OH)D3 half-life and plasma 25(OH)D concentration. Methods Plasma half-life of an oral tracer dose of deuterated-25(OH)D3 was measured in healthy men aged 24–39 years, resident in The Gambia, West Africa (n = 18) and in the UK during the winter (n = 18), countries that differ in calcium intake and vitamin D status. Plasma and urinary markers of vitamin D, calcium, phosphate and bone metabolism, nutrient intakes and anthropometry were measured. Results Normally distributed data are presented as mean (SD) and non-normal data as geometric mean (95 % CI). Gambian compared to UK men had higher plasma concentrations of 25(OH)D (69 (13) vs. 29 (11) nmol/L; P 2D (181 (165, 197) vs. 120 (109, 132) pmol/L; P P 3 half-life (14.7 (3.5) days vs. 15.6 (2.5) days) between countries (P = 0.2). In multivariate analyses, 25(OH)D, 1,25(OH)2D, vitamin D binding protein and albumin-adjusted calcium (Caalb) explained 79 % of variance in 25(OH)D3 half-life in Gambians, but no significant predictors were found in UK participants. For the countries combined, Caalb, PTH and plasma phosphate explained 39 % of half-life variability. 1,25(OH)2D, weight, PTH and country explained 81 % of variability in 25(OH)D concentration; however, country alone explained 74 %. Conclusion Factors known to affect 25(OH)D metabolism predict 25(OH)D3 half-life, but these differed between countries. Country predicted 25(OH)D, probably as a proxy measure for UVB exposure and vitamin D supply. This study supports the use of 25(OH)D half-life to investigate vitamin D metabolism.
Osteoporosis International 10/2014; 26(3). DOI:10.1007/s00198-014-2905-0 · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: During HIV type-1 (HIV-1), hepatitis C virus (HCV), and hepatitis B virus (HBV) infections, altered iron balance correlates with morbidity. The liver-produced hormone hepcidin dictates systemic iron homeostasis. We measured hepcidin, iron parameters, cytokines, and inflammatory markers in three cohorts: plasma donors who developed acute HIV-1, HBV, or HCV viremia during the course of donations; HIV-1-positive individuals progressing from early to chronic infection; and chronically HIV-1-infected individuals (receiving antiretroviral therapy or untreated). Hepcidin increased and plasma iron decreased during acute HIV-1 infection, as viremia was initially detected. In patients transitioning from early to chronic HIV-1 infection, hepcidin in the first 60 d of infection positively correlated with the later plasma viral load set-point. Hepcidin remained elevated in individuals with untreated chronic HIV-1 infection and in subjects on ART. In contrast to HIV-1, there was no evidence of hepcidin up-regulation or hypoferremia during the primary viremic phases of HCV or HBV infection; serum iron marginally increased during acute HBV infection. In conclusion, hepcidin induction is part of the pathogenically important systemic inflammatory cascade triggered during HIV-1 infection and may contribute to the establishment and maintenance of viral set-point, which is a strong predictor of progression to AIDS and death. However, distinct patterns of hepcidin and iron regulation occur during different viral infections that have particular tissue tropisms and elicit different systemic inflammatory responses. The hypoferremia of acute infection is therefore a pathogen-specific, not universal, phenomenon.
Proceedings of the National Academy of Sciences 08/2014; 111(33). DOI:10.1073/pnas.1402351111 · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Iron deficiency and malaria have similar global distributions, and frequently co-exist in pregnant women and young children. Where both conditions are prevalent, iron supplementation is complicated by observations that iron deficiency anaemia protects against falciparum malaria, and that iron supplements increase susceptibility to clinically significant malaria, but the mechanisms remain obscure. Here, using an in vitro parasite culture system with erythrocytes from iron-deficient and replete human donors, we demonstrate that Plasmodium falciparum infects iron-deficient erythrocytes less efficiently. In addition, owing to merozoite preference for young erythrocytes, iron supplementation of iron-deficient individuals reverses the protective effects of iron deficiency. Our results provide experimental validation of field observations reporting protective effects of iron deficiency and harmful effects of iron administration on human malaria susceptibility. Because recovery from anaemia requires transient reticulocytosis, our findings imply that in malarious regions iron supplementation should be accompanied by effective measures to prevent falciparum malaria.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
Whereas coverage of antenatal iron supplementation is low and benefits are uncertain, there are concerns that it can increase the burden of malaria, with potentially devastating effects on maternal and neonatal health outcomes. We aimed to measure the effect of iron supplementation during pregnancy on maternal Plasmodium infection assessed at delivery, birth weight, gestational age, fetal growth and maternal and infant iron status. Methods:
Rural Kenyan women (n=470) with singleton pregnancies, gestational age 13─23 weeks and haemoglobin concentration ≥ 90 g/L were randomised to supervised daily supplementation with iron (60 mg as ferrous fumarate) or placebo until 1 month postpartum. To prevent severe anaemia, all women additionally received 5.7 mg iron/day through flour fortification. Intermittent preventive treatment against malaria was given as usual. Plasmodium infection was assessed at birth by dipstick tests, PCR and histological examination of placental biopsies.
There was no evident effect on Plasmodium infection (both intervention groups: 45%; difference, 95% CI: 0%, ─9% to 9%). Iron supplementation increased birth weight by 143g (95% CI: 58─228g) and reduced the prevalence of low birth weight (<2,500g) by 65% (95% CI: 13%─86%). The effect on birth weight was larger in women who were initially iron-deficient than in those who were iron-replete (250 g versus ─13 g; p-interaction=0.008), and the improved birth weight seemed achieved mostly through improved fetal growth. Iron supplementation resulted in improved maternal iron status at 1 month postpartum, and improved infant iron stores.
Coverage of universal antenatal iron supplementation must be increased.
[Show abstract][Hide abstract] ABSTRACT: Context: There is uncertainty over the equivalence of vitamins D2 and D3 to maintain plasma 25-hydroxyvitamin D (25(OH)D). Objective: To compare the plasma half-lives of 25(OH)D2 and 25(OH)D3 in two distinct populations with different dietary calcium intake and 25(OH)D status. Participants: Healthy men (aged 24 and 39 years), resident in The Gambia (n=18) or UK (n=18). Interventions: Oral tracer dose of deuterated-25(OH)D2 and deuterated-25(OH)D3 (both 40 nmol). Blood samples were collected over 33 days. Main outcome measures: 25(OH)D2 and 25(OH)D3 plasma half-lives, concentrations of 25(OH)D and DBP and DBP genotypes. Results: 25(OH)D2 half-life (mean (SD)) (13.9 (2.6) d) was shorter than 25(OH)D3 half-life (15.1 (3.1) d; P=0.001) for countries combined, and in Gambians (12.8 (2.3) d vs. 14.7 (3.5) d; P<0.001), but not in the UK (15.1 (2.4) d vs. 15.6 (2.5) d; P=0.3). 25(OH)D concentration was 69 (13) and 29 (11) nmol/L (P<0.0001) and DBP concentration was 259 (33) and 269 (23) mg/l (P=0.4) in The Gambia and UK, respectively. Half-lives were positively associated with plasma DBP concentration for countries combined: (25(OH)D2 half-life: regression coefficient (SE) 0.03 (0.01) d per 1 mg/l DBP; P=0.03; 25(OH)D3 half-life: 0.04 (0.02) d; P=0.02) and in Gambians (25(OH)D2 half-life: 0.04 (0.01) d; P=0.02; 25(OH)D3 half-life: 0.06 (0.02) d; P=0.01), but not in UK participants. DBP concentration*country interactions were not significant. DBP Gc1f/1f homozygotes had shorter 25(OH)D2 half-lives compared to other combined genotypes (P=0.007), after correction for country. Conclusions: 25(OH)D2 half-life was shorter than 25(OH)D3 half-life, and half-lives were affected by DBP concentration and genotype. Stable isotope 25(OH)D half-life measurements provide a novel tool to investigate vitamin D metabolism and vitamin D expenditure, and aid in the assessment of vitamin D requirements.
[Show abstract][Hide abstract] ABSTRACT: Objective: To compare mothers' perceptions of their own infants' nutritional status with anthropometric indicators of undernutrition. Design: A qualitative study and cross-sectional quantitative survey. The qualitative study involved developing tools to assess mother's perception. Two methods of verbal description and a pictorial scale were developed. The quantitative survey involved measuring maternal perception and comparing it with the anthropometric measures of weight-for-age Z-score (WAZ) and mid-upper arm circumference-for-age Z-score (MUACZ). Setting: A rural community setting in Kenya. Subjects: Seventy-four infants aged between 4 and 6 months, and their mothers, living in rural Kenya were enrolled. Results: Using verbal description, the positive and negative likelihood ratios were 3.57 (95 % CI 1.44, 9.98) and 0.69 (95% CI 0.50, 0.96) respectively for MUACZ < -2; and 4.60 (95% CI 1.60, 13.3) and 0.67 (95% CI 0.49, 0.92) respectively for WAZ < -2. Using the pictorial scale, the positive and negative likelihood ratios were 8.30 (95% CI 1.91, 36.3) and 0.69 (95% CI 0.52, 0.93) respectively for MUACZ < -2; and 4.31 (95% CI 1.22, 15.0) and 0.78 (95% CI 0.61, 1.00) respectively for WAZ < -2. Conclusions: In a rural community, mothers better identify undernutrition in their infants using a pictorial scale than verbal description. However, neither can replace formal anthropometric assessment. Objective anthropometric tools should be validated for identification of severe acute malnutrition among infants aged less than 6 months.
Public Health Nutrition 05/2014; 18(05):1-8. DOI:10.1017/S1368980014001074 · 2.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Childhood anemia is a major global health problem resulting from multiple causes. Iron supplementation addresses iron deficiency anemia but is undesirable for other types of anemia and may exacerbate infections. The peptide hormone hepcidin governs iron absorption; hepcidin transcription is mediated by iron, inflammation, and erythropoietic signals. However, the behavior of hepcidin in populations where anemia is prevalent is not well established. We show that hepcidin measurements in 1313 African children from The Gambia and Tanzania (samples taken in 2001 and 2008, respectively) could be used to identify iron deficiency anemia. A retrospective secondary analysis of published data from 25 Gambian children with either postmalarial or nonmalarial anemia demonstrated that hepcidin measurements identified individuals who incorporated >20% oral iron into their erythrocytes. Modeling showed that this sensitivity of hepcidin expression at the population level could potentially enable simple groupings of individuals with anemia into iron-responsive and non-iron-responsive subtypes and hence could guide iron supplementation for those who would most benefit.
Science translational medicine 05/2014; 6(235):235re3. DOI:10.1126/scitranslmed.3008249 · 14.41 Impact Factor