RESUMO
Choline is an essential nutrient, and the amount needed in the diet is modulated by several factors. Given geographical differences in dietary choline intake and disparate frequencies of single-nucleotide polymorphisms (SNPs) in choline metabolism genes between ethnic groups, we tested the hypothesis that 3 SNPs that increase dependence on dietary choline would be under negative selection pressure in settings where choline intake is low: choline dehydrogenase (CHDH) rs12676, methylenetetrahydrofolate reductase 1 (MTHFD1) rs2236225, and phosphatidylethanolamine-N-methyltransferase (PEMT) rs12325817. Evidence of negative selection was assessed in 2 populations: one in The Gambia, West Africa, where there is historic evidence of a choline-poor diet, and the other in the United States, with a comparatively choline-rich diet. We used 2 independent methods, and confirmation of our hypothesis was sought via a comparison with SNP data from the Maasai, an East African population with a genetic background similar to that of Gambians but with a traditional diet that is higher in choline. Our results show that frequencies of SNPs known to increase dependence on dietary choline are significantly reduced in the low-choline setting of The Gambia. Our findings suggest that adequate intake levels of choline may have to be reevaluated in different ethnic groups and highlight a possible approach for identifying novel functional SNPs under the influence of dietary selective pressure.
Assuntos
Colina/genética , Colina/metabolismo , Etnicidade/genética , Polimorfismo de Nucleotídeo Único/genética , Colina Desidrogenase/genética , Colina Desidrogenase/metabolismo , Dieta/métodos , Feminino , Genótipo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Fosfatidiletanolamina N-Metiltransferase/genética , Fosfatidiletanolamina N-Metiltransferase/metabolismoRESUMO
BACKGROUND: 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. SUBJECTS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
Assuntos
População Negra/genética , Índice de Massa Corporal , Estudos de Associação Genética , Marcadores Genéticos , Vigilância da População , População Rural , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Estudos Transversais , Feminino , Gâmbia/epidemiologia , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/genética , Polimorfismo de Nucleotídeo Único , População Branca , Adulto JovemRESUMO
OBJECTIVE: Aflatoxin is known to cross the placental barrier and exposures in utero could influence genomic programming, foetal growth and development, resulting in long-term health effects. We aimed to determine aflatoxin exposure in Gambian women at two stages of pregnancy and during the rainy and dry seasons. METHODS: We examined aflatoxin exposure in pregnant Gambian women at early (<16 weeks) and later (16 weeks onward) stages of pregnancy and at different times of the year, during the rainy (June to October 2009) or dry (November to May 2010) season, using aflatoxin-albumin adducts (AF-alb). RESULTS: Mean AF-alb was higher during the dry season than in the rainy season, in both early and later pregnancy although the difference was strongest in later pregnancy. There was a modest increase in AF-alb in later than early pregnancy (geometric mean 41.8 vs. 34.5 pg/mg, P < 0.05), but this was restricted to the dry season when exposures were generally higher. CONCLUSIONS: The study confirmed that Gambian pregnant women were exposed to aflatoxin throughout the pregnancy, with higher levels in the dry season. There was some evidence in the dry season that women in later pregnancy had higher AF-alb levels than those in earlier pregnancy. Further research on the effects of exposure to this potent mutagen and carcinogen throughout pregnancy, including the epigenetic modification of foetal gene expression and impact on pre- and post-natal growth and development, are merited.
Assuntos
Aflatoxinas/metabolismo , Exposição Materna/estatística & dados numéricos , Venenos/metabolismo , Trimestres da Gravidez/sangue , Estações do Ano , Adolescente , Adulto , Aflatoxinas/sangue , Albuminas , Análise de Variância , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Contaminação de Alimentos , Gâmbia/epidemiologia , Idade Gestacional , Humanos , Pessoa de Meia-Idade , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Estatísticas não Paramétricas , Adulto JovemRESUMO
BACKGROUND: Identifying people at higher risk of developing tuberculosis with human immunodeficiency virus (HIV) infection may improve clinical management of co-infections. Iron influences tuberculosis (TB) pathogenesis, but understanding the exact mechanisms of how and timing of when iron is involved remains challenging since biological samples are rarely available from the disease susceptibility period due to the difficulty in predicting in who and when, if ever, TB will develop. The objective of this research was to determine how host iron status measured at HIV diagnosis and genotypes related to host iron metabolism were associated with incident TB. METHODS: Archived clinical data, plasma and DNA were analyzed from 1139 adult participants in a large HIV-1, HIV-2 and dual seroprevalent cohort based at the Medical Research Council Laboratories in The Gambia. Incident pulmonary and/or extrapulmonary TB diagnoses a minimum of 28 days after HIV diagnosis were independently re-confirmed using available evidence (n=152). Multiple host iron status biomarkers, Haptoglobin and solute carrier family 11, member 1 (SLC11A1) genotypes were modeled to characterize how indicators of host iron metabolism were associated with TB susceptibility. RESULTS: Hemoglobin (incidence rate ratio, IRR=0.88, 95% CI=0.79-0.98), plasma transferrin (IRR=0.53, 0.33-0.84) and ferritin (IRR=1.26, 1.05-1.51) were significantly associated with TB after adjusting for TB susceptibility factors. While genotype associations were not statistically significant, SLC11A1 associations replicated similar directions as reported in HIV-seronegative meta-analyses. CONCLUSIONS: Evidence of host iron redistribution at HIV diagnosis was associated with incident TB, and genetic influences on iron homeostasis may be involved. Low hemoglobin was associated with subsequent diagnosis of TB, but when considered in combination with additional iron status biomarkers, the collective findings point to a mechanism whereby anemia and iron redistribution are likely due to viral and/or bacteria-driven processes and the host immune response to infection. As a result, iron supplementation may not be efficacious or safe under these circumstances. Clinical and nutritional management of HIV and Mycobacterium tuberculosis co-infected individuals, especially in regions where food insecurity and malnutrition co-exist, may be further improved when the iron-related TB risk factors identified here are better understood and managed to favor host rather than pathogen outcomes.
Assuntos
Infecções por HIV/complicações , Infecções por HIV/metabolismo , Ferro/metabolismo , Tuberculose/etiologia , Adulto , Alelos , Biomarcadores , Contagem de Linfócito CD4 , Coinfecção , Feminino , Predisposição Genética para Doença , Genótipo , Infecções por HIV/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Tuberculose/diagnóstico , Adulto JovemRESUMO
Background: The use of mobile phone technology for reporting adverse drug reactions (ADRs) in pharmacovigilance is relatively new.The objective of the study was to explore challenges and facilitators for the use of the Med Safety App for reporting ADRs in Ghana. A comparative evaluation of ADR reports received through the app and the standard paper-based form was also conducted. Methods: This was a cross-sectional study with a purposive sampling technique. The study population was persons who had downloaded the Med Safety App launched in Ghana 18 months before the study. Results: Of the 350 participants, 121 provided answers to the questionnaire sent as a Google form, representing a response rate of 34.6%.Ninety-five (78.5%) of the participants were healthcare professionals, and the remaining were patients. Seventy-five (64.7%) of the participants were using the app after initial installation because they thought it had helpful features. However, only 33 (27.3%) participants used the app to report ADRs, and of these, seven (21.2%) participants indicated that they would continue to use the app because it was easier than the other means of reporting ADRs. Most of the respondents, 109 (94%), indicated that they would recommend the app to someone else. There were some differences between the reports received through the app and between the paper-based Council for International Organizations of Medical Sciences (CIOMS) 1 form and the app, which warrant further exploration. Conclusion: Most participants indicated that the app is a useful tool and easy to use, and they were satisfied with the features of the app. Given that only just under one-third of participants had used the app to report ADRs, more time and training may be required to fully evaluate the feasibility of the use of the app going forward. The findings will help improve introduction of the app in other countries.
RESUMO
The tenth conference of the African Society of Human Genetics was held in Egypt with the theme "Human Genetics and Genomics in Africa: Challenges for Both Rare and Common Genetic Disorders." Current research was presented, and we discussed visions for the future of genomic research on the African continent. In this report, we summarize the presented scientific research within and relevant to Africa as presented by both African and non-African scientists. We also discuss the current situation concerning genomic medicine and genomic research within the continent, difficulties in implementing genetic services and genomic medicine in Africa, and a road map to overcome those difficulties and meet the needs of the African researchers and patients.
Assuntos
Genoma Humano , Genômica , África , Genética Humana , Humanos , ConhecimentoRESUMO
BACKGROUND: Variation in the fat mass and obesity associated (FTO) gene has been reproducibly associated with body mass index (BMI) and obesity in populations of White European origin. Data from Asians and African-Americans is less conclusive. METHODS: We assessed the effect of 16 FTO polymorphisms on body mass in a large population of predominantly lean Gambians (N(max) 2208) participating in a long-term surveillance program providing contemporary and early-life anthropometric measurements. RESULTS: Sixteen FTO tagSNPs screened here, including several associated with BMI in Europeans, were not associated with birth weight (BWT), early weight gain in 1-2 year olds, BMI in adults (> or = 18 y), or weight-for-height (WFH) z-score across all ages. No association was seen between genotype and WFH z-score or other measures of body mass. The confidence limits indicate that the effect size for WFH z-score never exceeded 0.17 units per allele copy for any SNP (excluding the three SNPs with allele < 15%). with much the lowest allele frequency. The confidence interval of the effect size for rs9939609 did not overlap that reported previously in Europeans. CONCLUSION: To our knowledge this is the first study of FTO gene variation in a well-characterised African population. Our results suggest that FTO gene variation does not influence measures of body mass in Gambians living a traditional lifestyle, or has a smaller effect than that detected in Europeans. These findings are not directly comparable to results from previous studies in African-Americans due to differences in study design and analysis. It is also possible that any effect of FTO genotype on body mass is of limited relevance in a lean population where little excess food is available, compared to similar ethnic populations where food supply is plentiful.
Assuntos
População Negra/genética , Índice de Massa Corporal , Variação Genética , Proteínas/genética , Adulto , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Estatura/genética , Peso Corporal/genética , Feminino , Fertilidade/genética , Gâmbia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The world's poorest children are likely to be malnourished when receiving their childhood vaccines. It is uncertain whether this affects vaccine efficacy and whether the coadministration of nutrient supplements with vaccines has beneficial or detrimental effects. More recently, a detrimental interaction between vitamin A (VA) supplementation (VAS) and the killed diphtheria-tetanus-pertussis vaccine given in early childhood has been suggested. This report provides a critical review of the published interactions between nutritional status and/or supplementation and vaccine responses in children. Due to an absence of evidence for most nutrients, this analysis focused on protein-energy, vitamins A and D, and iron and zinc. All vaccines were considered. Both observational studies and clinical trials that led to peer-reviewed publications in English or French were included. These criteria led to a pool of 58 studies for protein-energy malnutrition, 43 for VA, 4 for vitamin D, 10 for iron, and 22 for zinc. Our analysis indicates that malnutrition has surprisingly little or no effect on vaccine responses. Evidence for definitive adjunctive effects of micronutrient supplementation at the time of vaccination is also weak. Overall, the paucity, poor quality, and heterogeneity of data make it difficult to draw firm conclusions. The use of simple endpoints that may not correlate strongly with disease protection adds uncertainty. A detailed examination of the immunological mechanisms involved in potential interactions, employing modern methodologies, is therefore required. This would also help us understand the proposed, but still unproven, negative interactions between VAS and vaccine safety, a resolution of which is urgently required.
Assuntos
Suplementos Nutricionais/estatística & dados numéricos , Vacina contra Difteria, Tétano e Coqueluche/imunologia , Estado Nutricional , Vacinas/imunologia , Anemia Ferropriva/diagnóstico , Criança , Vacina contra Difteria, Tétano e Coqueluche/normas , Humanos , Imunoterapia/métodos , Imunoterapia/normas , Desnutrição/imunologia , Seleção de Pacientes , Desnutrição Proteico-Calórica/imunologia , Segurança , Vitamina A/administração & dosagem , Vitamina A/uso terapêutico , Vitamina D/administração & dosagem , Vitamina D/uso terapêutico , Deficiência de Vitamina D/diagnóstico , Zinco/deficiênciaRESUMO
Africa is the ultimate source of modern humans and as such harbors more genetic variation than any other continent. For this reason, studies of the patterns of genetic variation in African populations are crucial to understanding how genes affect phenotypic variation, including disease predisposition. In addition, the patterns of extant genetic variation in Africa are important for understanding how genetic variation affects infectious diseases that are a major problem in Africa, such as malaria, tuberculosis, schistosomiasis, and HIV/AIDS. Therefore, elucidating the role that genetic susceptibility to infectious diseases plays is critical to improving the health of people in Africa. It is also of note that recent and ongoing social and cultural changes in sub-Saharan Africa have increased the prevalence of non-communicable diseases that will also require genetic analyses to improve disease prevention and treatment. In this review we give special attention to many of the past and ongoing studies, emphasizing those in Sub-Saharan Africans that address the role of genetic variation in human disease.
Assuntos
Doenças Transmissíveis/genética , Doenças Transmissíveis/terapia , Predisposição Genética para Doença , Testes Genéticos , Doenças Metabólicas/genética , Doenças Metabólicas/terapia , Neoplasias/genética , Neoplasias/terapia , África/epidemiologia , Doenças Transmissíveis/epidemiologia , Genoma Humano , Humanos , Imunoterapia Ativa , Doenças Metabólicas/epidemiologia , Polimorfismo de Nucleotídeo Único , Estudos SoroepidemiológicosRESUMO
Hypertension is fast becoming a major public health problem across sub-Saharan Africa. We sought to determine the prevalence of high blood pressure (BP) and associated risk factors as indicator of preclinical hypertension in a rural Gambian population.We analyzed data on 6160 healthy Gambians cross-sectionally. Attention was given to 5 to <18-year olds (Nâ=â3637), as data from sub-Saharan Africa on this young age group are scarce. High BP was defined as systolic blood pressure (SBP) above the 95th percentile for age-sex specific height z scores in <18-year olds employing population-specific reference values. Standard high BP categories were applied to ≥18-year olds.In <18-year olds, the multivariable analysis gave an adjusted high BP prevalence ratio of 0.95 (95% confidence interval [CI] 0.92-0.98; Pâ=â0.002) for age and 1.13 (95% CI 1.06-1.19; Pâ<â0.0001) for weight-for-height z score (zWT-HT); sex and hemoglobin were not shown to affect high BP. In adults age 1.05 (95% CI 1.04-1.05; Pâ<â0.0001), body mass index z score 1.28 (95% CI 1.16-1.40; Pâ<â0.0001), hemoglobin 0.90 (95% CI 0.85-0.96; Pâ<â0.0001) and high fasting glucose 2.60 (95% CI 2.02-3.36; Pâ<â0.0001, though the number was very low) were confirmed as risk factors for high BP prevalence; sex was not associated.The reported high BP prevalence and associated risk factors in adults are comparable to other studies conducted in the region. The observed high BP prevalence of 8.2% (95% CI 7.4-9.2) in our generally lean young Gambians (<18 years) is alarming, given that high BP tracks from childhood to adulthood. Hence there is an urgent need for further investigation into risk factors of pediatric high BP/hypertension even in rural African settings.
Assuntos
Hipertensão/epidemiologia , Pré-Hipertensão/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Gâmbia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prevalência , Adulto JovemRESUMO
We have developed recombinant fragment C based rapid point of care dipstick devices to assess tetanus immunization status using plasma or whole blood. The devices demonstrated specificity of 0.90 and sensitivity of 0.90 (whole blood)/0.94 (plasma) at field sites in Bangladesh and The Gambia when compared to a commercial ELISA with the immune cut-off titer set as ≥0.1IU/mL.
Assuntos
Anticorpos Antibacterianos/sangue , Fragmentos de Peptídeos/imunologia , Proteínas Recombinantes/imunologia , Toxina Tetânica/imunologia , Toxoide Tetânico/imunologia , Tétano/imunologia , Adulto , Bangladesh , Criança , Gâmbia , Humanos , Masculino , Fragmentos de Peptídeos/genética , Proteínas Recombinantes/genética , Sensibilidade e Especificidade , Toxina Tetânica/genética , VacinaçãoRESUMO
The estimated heritability of human BMI is close to 75%, but identified genetic variants explain only a small fraction of interindividual body-weight variation. Inherited epigenetic variants identified in mouse models named "metastable epialleles" could in principle explain this "missing heritability." We provide evidence that methylation in a variably methylated region (VMR) in the pro-opiomelanocortin gene (POMC), particularly in postmortem human laser-microdissected melanocyte-stimulating hormone (MSH)-positive neurons, is strongly associated with individual BMI. Using cohorts from different ethnic backgrounds, including a Gambian cohort, we found evidence suggesting that methylation of the POMC VMR is established in the early embryo and that offspring methylation correlates with the paternal somatic methylation pattern. Furthermore, it is associated with levels of maternal one-carbon metabolites at conception and stable during postnatal life. Together, these data suggest that the POMC VMR may be a human metastable epiallele that influences body-weight regulation.
Assuntos
Alelos , Metilação de DNA/genética , Obesidade/genética , Pró-Opiomelanocortina/genética , Adulto , Biomarcadores/sangue , Peso Corporal , Carbono/metabolismo , Estudos de Coortes , Ilhas de CpG/genética , Feminino , Variação Genética , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Hormônios Estimuladores de Melanócitos/metabolismo , Pessoa de Meia-Idade , Obesidade/sangue , Gravidez , Análise de Sequência de DNARESUMO
BACKGROUND: Exposure to environmental toxins during embryonic development may lead to epigenetic changes that influence disease risk in later life. Aflatoxin is a contaminant of staple foods in sub-Saharan Africa, is a known human liver carcinogen and has been associated with stunting in infants. METHODS: We have measured aflatoxin exposure in 115 pregnant women in The Gambia and examined the DNA methylation status of white blood cells from their infants at 2-8 months old (mean 3.6 ± 0.9). Aflatoxin exposure in women was assessed using an ELISA method to measure aflatoxin albumin (AF-alb) adducts in plasma taken at 1-16 weeks of pregnancy. Genome-wide DNA methylation of infant white blood cells was measured using the Illumina Infinium HumanMethylation450beadchip. RESULTS: AF-alb levels ranged from 3.9 to 458.4 pg/mg albumin. We found that aflatoxin exposure in the mothers was associated to DNA methylation in their infants for 71 CpG sites (false discovery rate < 0.05), with an average effect size of 1.7% change in methylation. Aflatoxin-associated differential methylation was observed in growth factor genes such as FGF12 and IGF1, and immune-related genes such as CCL28, TLR2 and TGFBI. Moreover, one aflatoxin-associated methylation region (corresponding to the miR-4520b locus) was identified. CONCLUSIONS: This study shows that maternal exposure to aflatoxin during the early stages of pregnancy is associated with differential DNA methylation patterns of infants, including in genes related to growth and immune function. This reinforces the need for interventions to reduce aflatoxin exposure, especially during critical periods of fetal and infant development.
Assuntos
Aflatoxina B1/sangue , Aflatoxinas/sangue , Metilação de DNA , Leucócitos/efeitos dos fármacos , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/genética , Adolescente , Adulto , Albuminas , Feminino , Gâmbia , Transtornos do Crescimento/etiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Gravidez , Primeiro Trimestre da Gravidez , Adulto JovemRESUMO
Seasonal variations are rarely considered a contributing component to human tissue function or health, although many diseases and physiological process display annual periodicities. Here we find more than 4,000 protein-coding mRNAs in white blood cells and adipose tissue to have seasonal expression profiles, with inverted patterns observed between Europe and Oceania. We also find the cellular composition of blood to vary by season, and these changes, which differ between the United Kingdom and The Gambia, could explain the gene expression periodicity. With regards to tissue function, the immune system has a profound pro-inflammatory transcriptomic profile during European winter, with increased levels of soluble IL-6 receptor and C-reactive protein, risk biomarkers for cardiovascular, psychiatric and autoimmune diseases that have peak incidences in winter. Circannual rhythms thus require further exploration as contributors to various aspects of human physiology and disease.
Assuntos
Fatores de Transcrição ARNTL/metabolismo , Regulação da Expressão Gênica/fisiologia , Genes MHC da Classe II/fisiologia , Estações do Ano , Fatores de Transcrição ARNTL/genética , Adaptação Fisiológica , Tecido Adiposo/metabolismo , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Europa (Continente) , Gâmbia , Humanos , Lactente , Recém-Nascido , Leucócitos/metabolismo , Pessoa de Meia-Idade , Oceania , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcriptoma , Adulto JovemRESUMO
BACKGROUND: Interindividual epigenetic variation that occurs systemically must be established prior to gastrulation in the very early embryo and, because it is systemic, can be assessed in easily biopsiable tissues. We employ two independent genome-wide approaches to search for such variants. RESULTS: First, we screen for metastable epialleles by performing genomewide bisulfite sequencing in peripheral blood lymphocyte (PBL) and hair follicle DNA from two Caucasian adults. Second, we conduct a genomewide screen for genomic regions at which PBL DNA methylation is affected by season of conception in rural Gambia. Remarkably, both approaches identify the genomically imprinted VTRNA2-1 as a top environmentally responsive epiallele. We demonstrate systemic and stochastic interindividual variation in DNA methylation at the VTRNA2-1 differentially methylated region in healthy Caucasian and Asian adults and show, in rural Gambians, that periconceptional environment affects offspring VTRNA2-1 epigenotype, which is stable over at least 10 years. This unbiased screen also identifies over 100 additional candidate metastable epialleles, and shows that these are associated with cis genomic features including transposable elements. CONCLUSIONS: The non-coding VTRNA2-1 transcript (also called nc886) is a putative tumor suppressor and modulator of innate immunity. Thus, these data indicating environmentally induced loss of imprinting at VTRNA2-1 constitute a plausible causal pathway linking early embryonic environment, epigenetic alteration, and human disease. More broadly, the list of candidate metastable epialleles provides a resource for future studies of epigenetic variation and human disease.
Assuntos
Alelos , Metilação de DNA , Epigênese Genética , Genes Supressores de Tumor , Impressão Genômica , Proteínas Proto-Oncogênicas c-cbl/genética , Adulto , Povo Asiático/genética , População Negra/genética , Gâmbia , Regulação da Expressão Gênica no Desenvolvimento , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Análise de Sequência de DNA , População Branca/genéticaRESUMO
In experimental animals, maternal diet during the periconceptional period influences the establishment of DNA methylation at metastable epialleles in the offspring, with permanent phenotypic consequences. Pronounced naturally occurring seasonal differences in the diet of rural Gambian women allowed us to test this in humans. We show that significant seasonal variations in methyl-donor nutrient intake of mothers around the time of conception influence 13 relevant plasma biomarkers. The level of several of these maternal biomarkers predicts increased/decreased methylation at metastable epialleles in DNA extracted from lymphocytes and hair follicles in infants postnatally. Our results demonstrate that maternal nutritional status during early pregnancy causes persistent and systemic epigenetic changes at human metastable epialleles.
Assuntos
Biomarcadores/sangue , Metilação de DNA/fisiologia , Epigênese Genética/fisiologia , Fertilização/fisiologia , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Estações do Ano , Adulto , Feminino , Gâmbia , Folículo Piloso/química , Humanos , Linfócitos/química , GravidezRESUMO
BACKGROUND: Animal models show that periconceptional supplementation with folic acid, vitamin B-12, choline, and betaine can induce differences in offspring phenotype mediated by epigenetic changes in DNA. In humans, altered DNA methylation patterns have been observed in offspring whose mothers were exposed to famine or who conceived in the Gambian rainy season. OBJECTIVE: The objective was to understand the seasonality of DNA methylation patterns in rural Gambian women. We studied natural variations in dietary intake of nutrients involved in methyl-donor pathways and their effect on the respective metabolic biomarkers. DESIGN: In 30 women of reproductive age (18-45 y), we monitored diets monthly for 1 y by using 48-h weighed records to measure intakes of choline, betaine, folate, methionine, riboflavin, and vitamins B-6 and B-12. Blood biomarkers of these nutrients, S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), homocysteine, cysteine, and dimethylglycine were also assessed monthly. RESULTS: Dietary intakes of riboflavin, folate, choline, and betaine varied significantly by season; the most dramatic variation was seen for betaine. All metabolic biomarkers showed significant seasonality, and vitamin B-6 and folate had the highest fluctuations. Correlations between dietary intakes and blood biomarkers were found for riboflavin, vitamin B-6, active vitamin B-12 (holotranscobalamin), and betaine. We observed a seasonal switch between the betaine and folate pathways and a probable limiting role of riboflavin in these processes and a higher SAM/SAH ratio during the rainy season. CONCLUSIONS: Naturally occurring seasonal variations in food-consumption patterns have a profound effect on methyl-donor biomarker status. The direction of these changes was consistent with previously reported differences in methylation of metastable epialleles. This trial was registered at www.clinicaltrials.gov as NCT01811641.
Assuntos
Biomarcadores/sangue , Metilação de DNA , Dieta , Comportamento Alimentar , População Rural , Adolescente , Adulto , Betaína/administração & dosagem , Betaína/sangue , Colina/administração & dosagem , Colina/sangue , Cisteína/sangue , Registros de Dieta , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Feminino , Ácido Fólico/administração & dosagem , Ácido Fólico/sangue , Gâmbia , Homocisteína/sangue , Humanos , Modelos Lineares , Metionina/administração & dosagem , Metionina/sangue , Pessoa de Meia-Idade , Avaliação Nutricional , Estudos Prospectivos , Riboflavina/administração & dosagem , Riboflavina/sangue , S-Adenosil-Homocisteína/sangue , S-Adenosilmetionina/sangue , Sarcosina/análogos & derivados , Sarcosina/sangue , Vitamina B 12/administração & dosagem , Vitamina B 12/sangue , Vitamina B 6/administração & dosagem , Vitamina B 6/sangue , Adulto JovemRESUMO
Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
Assuntos
Peso ao Nascer/genética , Estatura/genética , Desenvolvimento Fetal/genética , Ligação Genética , Locos de Características Quantitativas , Adulto , Pressão Sanguínea/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Masculino , Metanálise como Assunto , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The disease burden due to hepatitis B virus (HBV) infection remains significant; 350 million people are infected world-wide, and around half a million deaths each year are due to HBV-related liver disease and hepatocellular carcinoma (HCC). Infant immunisation against infection was introduced in the early 1980s, the vaccine is routinely administered across regions where the disease is endemic and has been shown to be safe and effective. However, the large number of older individuals with persistent infection means that disease will not be reduced significantly for several decades. Furthermore, failure to respond to the vaccination has been observed in about 5% of vaccinees and to date we have limited information on the durability of vaccine protection against infection. Hepatitis B infection and disease pathogenesis are known to be influenced by a number of factors including host genetics factors. This review aims to give an overview of the role of genetic variation in persistent HBV infection and the development of liver disease including HCC. Vaccine-induced immunity is, at least in part, heritable and we also discuss findings on the genetic control of responses to HBV vaccination. The epidemiology of HBV infection differs by world region, as does the genetic makeup of individuals originating from different regions. This review focuses on the situation in Africa, where hepatitis B is highly endemic.