Candidate genes linking maternal nutrient exposure to offspring health via DNA methylation: a review of existing evidence in humans with specific focus on one-carbon metabolism.

Background: Mounting evidence suggests that nutritional exposures during pregnancy influence the fetal epigenome, and that these epigenetic changes can persist postnatally, with implications for disease risk across the life course. Methods: We review human intergenerational studies using a three-part search strategy. Search 1 investigates associations between preconceptional or pregnancy nutritional exposures, focusing on one-carbon metabolism, and offspring DNA methylation. Search 2 considers associations between offspring DNA methylation at genes found in the first search and growth-related, cardiometabolic and cognitive outcomes. Search 3 isolates those studies explicitly linking maternal nutritional exposure to offspring phenotype via DNA methylation. Finally, we compile all candidate genes and regions of interest identified in the searches and describe their genomic locations, annotations and coverage on the Illumina Infinium Methylation beadchip arrays. Results: We summarize findings from the 34 studies found in the first search, the 31 studies found in the second search and the eight studies found in the third search. We provide details of all regions of interest within 45 genes captured by this review. Conclusions: Many studies have investigated imprinted genes as priority loci, but with the adoption of microarray-based platforms other candidate genes and gene classes are now emerging. Despite a wealth of information, the current literature is characterized by heterogeneous exposures and outcomes, and mostly comprise observational associations that are frequently underpowered. The synthesis of current knowledge provided by this review identifies research needs on the pathway to developing possible early life interventions to optimize lifelong health

DNA methylation signatures associated with cardiometabolic risk factors in children from India and The Gambia: results from the EMPHASIS study.

BACKGROUND: The prevalence of cardiometabolic disease (CMD) is rising globally, with environmentally induced epigenetic changes suggested to play a role. Few studies have investigated epigenetic associations with CMD risk factors in children from low- and middle-income countries. We sought to identify associations between DNA methylation (DNAm) and CMD risk factors in children from India and The Gambia. RESULTS: Using the Illumina Infinium HumanMethylation 850 K Beadchip array, we interrogated DNAm in 293 Gambian (7-9 years) and 698 Indian (5-7 years) children. We identified differentially methylated CpGs (dmCpGs) associated with systolic blood pressure, fasting insulin, triglycerides and LDL-Cholesterol in the Gambian children; and with insulin sensitivity, insulinogenic index and HDL-Cholesterol in the Indian children. There was no overlap of the dmCpGs between the cohorts. Meta-analysis identified dmCpGs associated with insulin secretion and pulse pressure that were different from cohort-specific dmCpGs. Several differentially methylated regions were associated with diastolic blood pressure, insulin sensitivity and fasting glucose, but these did not overlap with the dmCpGs. We identified significant cis-methQTLs at three LDL-Cholesterol-associated dmCpGs in Gambians; however, methylation did not mediate genotype effects on the CMD outcomes. CONCLUSION: This study identified cardiometabolic biomarkers associated with differential DNAm in Indian and Gambian children. Most associations were cohort specific, potentially reflecting environmental and ethnic differences

Efficiency of split-mouth designs

. The purpose of this paper is (1) to investigate the similarity of the amount, distribution, and, severity of periodontal disease of the within-patient experimental units, (2) to estimate the relative efficiencies of split-mouth designs when compared to whole-mouth designs, and (3) to discuss how stratification on initial pocket depth can result in large differences in the power of the test-statistics in the different disease categories. Periodontal disease characteristics are not always homogeneously distributed over the within-patient experimental units and this heterogeneity can reduce the efficiency of split-mouth designs. In particular, if analyses are stratified on initial pocket depth, sites with an initial probing depth deeper than 6 mm may be small in number and asymmetrically distributed when compared to sites with an initial probing depth less than 6 mm. This may result in large differences of the power of the test statistics among the different disease categories and should lead to a careful interpretation of the statistical significance tests. When disease characteristics are symmetrically distributed over the within-patient experimental units and a sufficient number of sites is present per experimental unit, the split-mouth design can provide moderate to large gains in relative efficiency. In the absence of a symmetric disease distribution, wholemouth clinical trials may be preferable.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75701/1/j.1600-051X.1990.tb01060.x.pd

Protocol for the EMPHASIS study; epigenetic mechanisms linking maternal pre-conceptional nutrition and children's health in India and Sub-Saharan Africa.

BACKGROUND: Animal studies have shown that nutritional exposures during pregnancy can modify epigenetic marks regulating fetal development and susceptibility to later disease, providing a plausible mechanism to explain the developmental origins of health and disease. Human observational studies have shown that maternal peri-conceptional diet predicts DNA methylation in offspring. However, a causal pathway from maternal diet, through changes in DNA methylation, to later health outcomes has yet to be established. The EMPHASIS study (Epigenetic Mechanisms linking Pre-conceptional nutrition and Health Assessed in India and Sub-Saharan Africa, ISRCTN14266771) will investigate epigenetically mediated links between peri-conceptional nutrition and health-related outcomes in children whose mothers participated in two randomized controlled trials of micronutrient supplementation before and during pregnancy. METHODS: The original trials were the Mumbai Maternal Nutrition Project (MMNP, ISRCTN62811278) in which Indian women were offered a daily snack made from micronutrient-rich foods or low-micronutrient foods (controls), and the Peri-conceptional Multiple Micronutrient Supplementation Trial (PMMST, ISRCTN13687662) in rural Gambia, in which women were offered a daily multiple micronutrient (UNIMMAP) tablet or placebo. In the EMPHASIS study, DNA methylation will be analysed in the children of these women (~1,100 children aged 5-7 y in MMNP and 298 children aged 7-9 y in PMMST). Cohort-specific and cross-cohort effects will be explored. Differences in DNA methylation between allocation groups will be identified using the Illumina Infinium MethylationEPIC array, and by pyrosequencing top hits and selected candidate loci. Associations will be analysed between DNA methylation and health-related phenotypic outcomes, including size at birth, and children's post-natal growth, body composition, skeletal development, cardio-metabolic risk markers (blood pressure, serum lipids, plasma glucose and insulin) and cognitive function. Pathways analysis will be used to test for enrichment of nutrition-sensitive loci in biological pathways. Causal mechanisms for nutrition-methylation-phenotype associations will be explored using Mendelian Randomization. Associations between methylation unrelated to supplementation and phenotypes will also be analysed. CONCLUSION: The study will increase understanding of the epigenetic mechanisms underpinning the long-term impact of maternal nutrition on offspring health. It will potentially lead to better nutritional interventions for mothers preparing for pregnancy, and to identification of early life biomarkers of later disease risk

Sero-Epidemiology of Rotavirus Gastroenteritis in Children in Ilorin, Kwara State

Rotavirus is responsible for the most severe dehydrating diarrhea among young children due to gastroenteritis. In this study, we aimed to ascertain the occurrence of childhood gastroenteritis caused by Rotavirus among infants and young children who are younger than 5 years of age in Ilorin, Kwara State and determined the risk factors posing the challenges to be susceptible to diarrhea associated with rotavirus in Ilorin, Kwara State. Diarrhea stool samples were collected from children who passed watery stools, who met predetermined inclusion criteria and who presented at the study hospitals Viz: General Hospital and Specialist Hospital Alagbado and Children Specialist Hospital, Igboro. All within Kwara State either on outpatient care basis or those admitted into the pediatric ward. Sample of stool habouring rotavirus antigens was detected by commercial Rotavirus IgM ELISA kit to target recent infections among the participants. Out of three hundred (300) stool samples that were collected from children suffering from acute diarrhea, a total number of eighty-six (86) were found to be Rotavirus positive (28.7 %) and two hundred and fourteen (214) were found to be negative (71.3%). The age group 3-5 years, showed the highest prevalence rate which is in line with some research findings that attribute this age range with certain feeding habits and cultural practices, predisposing them to gastroenteritis. It is therefore advised that parents and guardian alike should ensure that special care is given to children, with emphasis on their feeding habits and sanitation