Maternal age is related to offspring DNA methylation: A meta-analysis of results from the PACE consortium.

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5-10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR < 0.05). Eight of these CpGs were located near/in the MTNR1B gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near MTNR1B, at which higher DNAm was associated with greater maternal age (PFDR = 6.92 × 10-8) in newborns. In childhood blood samples, these differences in blood DNAm of MTNR1B CpGs were nominally significant (p < 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in RTEL1-TNFRSF6B at birth (PFDR < 0.05) and nominally in childhood (p < 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in YPEL3/BOLA2B in external data was associated with expression of ITGAL, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health.

DNA methylation at the suppressor of cytokine signaling 3 (SOCS3) gene influences height in childhood.

Human height is strongly influenced by genetics but the contribution of modifiable epigenetic factors is under-explored, particularly in low and middle-income countries (LMIC). We investigate links between blood DNA methylation and child height in four LMIC cohorts (n = 1927) and identify a robust association at three CpGs in the suppressor of cytokine signaling 3 (SOCS3) gene which replicates in a high-income country cohort (n = 879). SOCS3 methylation (SOCS3m)-height associations are independent of genetic effects. Mendelian randomization analysis confirms a causal effect of SOCS3m on height. In longitudinal analysis, SOCS3m explains a maximum 9.5% of height variance in mid-childhood while the variance explained by height polygenic risk score increases from birth to 21 years. Children's SOCS3m is associated with prenatal maternal folate and socio-economic status. In-vitro characterization confirms a regulatory effect of SOCS3m on gene expression. Our findings suggest epigenetic modifications may play an important role in driving child height in LMIC.

Echocardiography protocol and cardiometabolic phenotyping in Indian birth cohorts-the IndEcho study.

Background: Asian Indians are at higher risk of cardiometabolic disease compared to other ethnic groups, and the age of onset is typically younger. Cardiac structure and function are poorly characterized in this ethnic group. In this study, we describe image-acquisition methods and the reproducibility of measurements and detailed echocardiography characteristics in two large Indian population-based cohorts (the New Delhi and Vellore Birth Cohorts) from India. Methods: The IndEcho study captured transthoracic echocardiographic measurements of cardiac structure and function from 2,322 men and women aged 43-50 years. M-mode measurements in the parasternal long axis (PLAX) and 2-dimensional (2D) short axis recordings at the mitral valve, mid-papillary and apical level were recorded. Apical 2D recordings of two- three- and four-chamber (2C, 3C and 4C) views and Doppler images (colour, pulsed and continuous) were recorded in cine-loop format. Left ventricular (LV) mass, LV hypertrophy, and indices of LV systolic and diastolic function were derived. Results: Echocardiographic measurements showed good/excellent technical reproducibility. Hetero-geneity across sites, sex and rural/urban differences in cardiac structure and function were observed. Overall, this cohort of South Asian Indians had smaller LV mass and normal systolic and diastolic function when compared with published data on other Asian Indians and the West, (LV mass indexed for body surface area: Delhi men: 68 g/m2, women 63.9; Vellore men: 65.8, women 61.6) but were within ethnic-specific reference ranges. The higher prevalence of obesity, diabetes and hypertension is reflected by the higher proportion of LV remodelling and lesser hypertrophy. Conclusions: Our study adds to scarce population-based echocardiographic data for mid-life Asian Indians. Compared to published literature on other ethnic groups, the Asian Indian heart is characterised by smaller cardiac dimensions and normal range systolic and diastolic function on a background of a high prevalence of hypertension, diabetes and cardiac disease at a relatively young age. This data will form the basis for further analyses of lifecourse, metabolic and body composition predictors of cardiac structure and function, and echocardiographic predictors of future mortality. ISRCTN registration number: 13432279.

Periconceptional diet and the risk of gestational diabetes in south Indian women: findings from the BAngalore Nutrition Gestational diabetes LiFEstyle Study (BANGLES).

BACKGROUND: Gestational diabetes can predispose two generations-a mother and her child-to a higher risk of obesity and type 2 diabetes. Culture-specific strategies to prevent gestational diabetes are required. BANGLES investigated the associations between women's periconceptional diet and gestational diabetes risk. METHODS: BANGLES was a prospective observational study (n=785), in which women of various socioeconomic status were recruited at 5-16 weeks' gestation in Bangalore, India. Periconceptional diet was recalled at recruitment, using a validated 224-item food frequency questionnaire, that was reduced to 21 food groups for the food group-gestational diabetes analysis, and 68 food groups for the principal component analysis for a diet pattern-gestational diabetes analysis. Diet-gestational diabetes associations were examined using multivariate logistic regression, adjusting for a priori confounders determined from the literature. Gestational diabetes was assessed by a 75 g oral glucose tolerance test at 24-28 weeks' gestation, applying 2013 WHO criteria. FINDINGS: Women who consumed whole-grain cereals (adjusted odds ratio [OR] 0·58, 95% CI 0·34-0·97, p=0·03); had moderate egg consumption (>1-3 times per week) compared with less than once per week (adjusted OR 0·54, 95% CI 0·34-0·86, p=0·01); and a higher weekly intake of pulses and legumes (adjusted OR 0·81, 95% CI 0·66-0·98, p=0·03), nuts and seeds (adjusted OR 0·77, 95% CI 0·63-0·94, p=0·01), and fried and fast food (adjusted OR 0·72, 95% CI 0·59-0·89, p=0·002) had a lower gestational diabetes. None of these associations was significant after correction for multiple testing. A high-diversity, urban diet pattern characterised by diverse home-cooked and processed foods and associated with older, affluent, educated, urban women was associated with a lower risk (adjusted OR 0·80, 95% CI 0·64-0·99, p=0·04). BMI was the strongest risk factor for gestational diabetes and possibly mediated the diet pattern-gestational diabetes associations. INTERPRETATION: The same food groups that were associated with a lower gestational diabetes risk were components of the high-diversity, urban diet pattern. One healthy diet pattern might not be relevant to India. Findings support global recommendations to encourage women to attain a healthy pre-pregnancy BMI, increase diet diversity to prevent gestational diabetes, and have policies to increase food affordability. FUNDING: Schlumberger Foundation.

The Long-Term Consequences of Early Life Exposure to Tsunami and Conflict on Adolescents in Sri Lanka.

The consequences for adolescent health due to early life exposure to natural disasters combined with war are not known. We collected data from adolescents aged 12-13 years in Sri Lanka whose mothers were pregnant during the Indian Ocean tsunami in 2004 in a tsunami-affected region (n = 22), conflict-affected region (n = 35), conflict-plus-tsunami-affected region (n = 29), or controls in areas unaffected by either (n = 24). Adjusted body mass index (BMI)-for-age z-scores were 1.3, 1.0 and 2.0 for conflict, tsunami, and conflict-plus-tsunami, respectively, compared with the control group. Greater skinfold thickness and higher diastolic blood pressure were found in adolescents born in the conflict zone but no differences were found in height, head circumference, and waist circumference, or blood results, with the exception of serum insulin. Being born after a natural disaster or during conflict was associated with increased BMI and body fat during adolescent, which are associated with longer-term risk of noncommunicable disease.

Sexual dimorphism in the relationship between brain complexity, volume and general intelligence (g): a cross-cohort study.

Changes in brain morphology have been reported during development, ageing and in relation to different pathologies. Brain morphology described by the shape complexity of gyri and sulci can be captured and quantified using fractal dimension (FD). This measure of brain structural complexity, as well as brain volume, are associated with intelligence, but less is known about the sexual dimorphism of these relationships. In this paper, sex differences in the relationship between brain structural complexity and general intelligence (g) in two diverse geographic and cultural populations (UK and Indian) are investigated. 3D T1-weighted magnetic resonance imaging (MRI) data and a battery of cognitive tests were acquired from participants belonging to three different cohorts: Mysore Parthenon Cohort (MPC); Aberdeen Children of the 1950s (ACONF) and UK Biobank. We computed MRI derived structural brain complexity and g estimated from a battery of cognitive tests for each group. Brain complexity and volume were both positively corelated with intelligence, with the correlations being significant in women but not always in men. This relationship is seen across populations of differing ages and geographical locations and improves understanding of neurobiological sex-differences.

Tissue- and ethnicity-independent hypervariable DNA methylation states show evidence of establishment in the early human embryo.

We analysed DNA methylation data from 30 datasets comprising 3474 individuals, 19 tissues and 8 ethnicities at CpGs covered by the Illumina450K array. We identified 4143 hypervariable CpGs ('hvCpGs') with methylation in the top 5% most variable sites across multiple tissues and ethnicities. hvCpG methylation was influenced but not determined by genetic variation, and was not linked to probe reliability, epigenetic drift, age, sex or cell heterogeneity effects. hvCpG methylation tended to covary across tissues derived from different germ-layers and hvCpGs were enriched for proximity to ERV1 and ERVK retrovirus elements. hvCpGs were also enriched for loci previously associated with periconceptional environment, parent-of-origin-specific methylation, and distinctive methylation signatures in monozygotic twins. Together, these properties position hvCpGs as strong candidates for studying how stochastic and/or environmentally influenced DNA methylation states which are established in the early embryo and maintained stably thereafter can influence life-long health and disease.

Circulating microRNAs from early childhood and adolescence are associated with pre-diabetes at 18 years of age in women from the PMNS cohort.

With type 2 diabetes presenting at younger ages, there is a growing need to identify biomarkers of future glucose intolerance. A high (20%) prevalence of glucose intolerance at 18 years was seen in women from the Pune Maternal Nutrition Study (PMNS) birth cohort. We investigated the potential of circulating microRNAs in risk stratification for future pre-diabetes in these women. Here, we provide preliminary longitudinal analyses of circulating microRNAs in normal glucose tolerant (NGT@18y, N = 10) and glucose intolerant (N = 8) women (ADA criteria) at 6, 12 and 17 years of their age using discovery analysis (OpenArray™ platform). Machine-learning workflows involving Lasso with bootstrapping/leave-one-out cross-validation identified microRNAs associated with glucose intolerance at 18 years of age. Several microRNAs, including miR-212-3p, miR-30e-3p and miR-638, stratified glucose-intolerant women from NGT at childhood. Our results suggest that circulating microRNAs, longitudinally assessed over 17 years of life, are dynamic biomarkers associated with and predictive of pre-diabetes at 18 years of age. Validation of these findings in males and remaining participants from the PMNS birth cohort will provide a unique opportunity to study novel epigenetic mechanisms in the life-course progression of glucose intolerance and enhance current clinical risk prediction of pre-diabetes and progression to type 2 diabetes.

Health and development from preconception to 20 years of age and human capital.

Optimal health and development from preconception to adulthood are crucial for human flourishing and the formation of human capital. The Nurturing Care Framework, as adapted to age 20 years, conceptualises the major influences during periods of development from preconception, through pregnancy, childhood, and adolescence that affect human capital. In addition to mortality in children younger than 5 years, stillbirths and deaths in 5-19-year-olds are important to consider. The global rate of mortality in individuals younger than 20 years has declined substantially since 2000, yet in 2019 an estimated 8·6 million deaths occurred between 28 weeks of gestation and 20 years of age, with more than half of deaths, including stillbirths, occurring before 28 days of age. The 1000 days from conception to 2 years of age are especially influential for human capital. The prevalence of low birthweight is high in sub-Saharan Africa and even higher in south Asia. Growth faltering, especially from birth to 2 years, occurs in most world regions, whereas overweight increases in many regions from the preprimary school period through adolescence. Analyses of cohort data show that growth trajectories in early years of life are strong determinants of nutritional outcomes in adulthood. The accrual of knowledge and skills is affected by health, nutrition, and home resources in early childhood and by educational opportunities in older children and adolescents. Linear growth in the first 2 years of life better predicts intelligence quotients in adults than increases in height in older children and adolescents. Learning-adjusted years of schooling range from about 4 years in sub-Saharan Africa to about 11 years in high-income countries. Human capital depends on children and adolescents surviving, thriving, and learning until adulthood.

Environmentally sensitive hotspots in the methylome of the early human embryo.

In humans, DNA methylation marks inherited from gametes are largely erased following fertilisation, prior to construction of the embryonic methylome. Exploiting a natural experiment of seasonal variation including changes in diet and nutritional status in rural Gambia, we analysed three datasets covering two independent child cohorts and identified 259 CpGs showing consistent associations between season of conception (SoC) and DNA methylation. SoC effects were most apparent in early infancy, with evidence of attenuation by mid-childhood. SoC-associated CpGs were enriched for metastable epialleles, parent-of-origin-specific methylation and germline differentially methylated regions, supporting a periconceptional environmental influence. Many SoC-associated CpGs overlapped enhancers or sites of active transcription in H1 embryonic stem cells and fetal tissues. Half were influenced but not determined by measured genetic variants that were independent of SoC. Environmental 'hotspots' providing a record of environmental influence at periconception constitute a valuable resource for investigating epigenetic mechanisms linking early exposures to lifelong health and disease.

Body Composition and Cardiometabolic Risk Markers in Children of Women who Took Part in a Randomized Controlled Trial of a Preconceptional Nutritional Intervention in Mumbai, India.

BACKGROUND: Maternal nutrition influences fetal development and may permanently alter ("program") offspring body composition and metabolism, thereby influencing later risk of diabetes and cardiovascular (cardiometabolic) disease. The prevalence of cardiometabolic disease is rising rapidly in India. OBJECTIVES: To test the hypothesis that supplementing low-income Indian women with micronutrient-rich foods preconceptionally and during pregnancy has a beneficial impact on the children's body composition and cardiometabolic risk marker profiles. METHODS: Follow-up of 1255 children aged 5-10 y whose mothers took part in the Mumbai Maternal Nutrition Project [Project "SARAS"; International Standard Randomised Controlled Trial Number (ISRCTN)62811278]. Mothers were randomly assigned to receive a daily micronutrient-rich snack or a control snack of lower micronutrient content, both made from local foods, in addition to normal diet, from before pregnancy until delivery. Children's body composition was assessed using anthropometry and DXA. Their blood pressure, plasma glucose, insulin, and lipid concentrations were measured. Outcomes were compared between allocation groups with and without adjustment for confounding factors. RESULTS: Overall, 15% of children were stunted, 34% were wasted, and 3% were overweight. In the intention-to-treat analysis, there were no differences in body composition or risk markers between children in the intervention and control groups. Among children whose mothers started supplementation ≥3 mo before conception (the "per protocol" sample) the intervention increased adiposity among girls, but not boys. BMI in girls was increased relative to controls by 2% (95% CI: 1, 4; P = 0.01); fat mass index by 10% (95% CI: 3, 18; P = 0.004); and percent fat by 7% (95% CI: 1, 13; P = 0.01) unadjusted, with similar results in adjusted models. CONCLUSIONS: Overall, supplementing women with micronutrient-rich foods from before pregnancy until delivery did not alter body composition or cardiometabolic risk markers in the children. Subgroup analyses showed that, if started ≥3 mo before conception, supplementation may increase adiposity among female children.

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.

Babies of South Asian and European Ancestry Show Similar Associations With Genetic Risk Score for Birth Weight Despite the Smaller Size of South Asian Newborns.

Size at birth is known to be influenced by various fetal and maternal factors, including genetic effects. South Asians have a high burden of low birth weight and cardiometabolic diseases, yet studies of common genetic variations underpinning these phenotypes are lacking. We generated independent, weighted fetal genetic scores (fGSs) and maternal genetic scores (mGSs) from 196 birth weight-associated variants identified in Europeans and conducted an association analysis with various fetal birth parameters and anthropometric and cardiometabolic traits measured at different follow-up stages (5-6-year intervals) from seven Indian and Bangladeshi cohorts of South Asian ancestry. The results from these cohorts were compared with South Asians in UK Biobank and the Exeter Family Study of Childhood Health, a European ancestry cohort. Birth weight increased by 50.7 g and 33.6 g per SD of fGS (P = 9.1 × 10-11) and mGS (P = 0.003), respectively, in South Asians. A relatively weaker mGS effect compared with Europeans indicates possible different intrauterine exposures between Europeans and South Asians. Birth weight was strongly associated with body size in both childhood and adolescence (P = 3 × 10-5 to 1.9 × 10-51); however, fGS was associated with body size in childhood only (P < 0.01) and with head circumference, fasting glucose, and triglycerides in adults (P < 0.01). The substantially smaller newborn size in South Asians with comparable fetal genetic effect to Europeans on birth weight suggests a significant role of factors related to fetal growth that were not captured by the present genetic scores. These factors may include different environmental exposures, maternal body size, health and nutritional status, etc. Persistent influence of genetic loci on size at birth and adult metabolic syndrome in our study supports a common genetic mechanism that partly explains associations between early development and later cardiometabolic health in various populations, despite marked differences in phenotypic and environmental factors in South Asians.

Body Composition and Cardiometabolic Risk Markers in Children of Women who Took Part in a Randomized Controlled Trial of a Preconceptional Nutritional Intervention in Mumbai, India.

BACKGROUND: Maternal nutrition influences fetal development and may permanently alter ("program") offspring body composition and metabolism, thereby influencing later risk of diabetes and cardiovascular (cardiometabolic) disease. The prevalence of cardiometabolic disease is rising rapidly in India. OBJECTIVES: To test the hypothesis that supplementing low-income Indian women with micronutrient-rich foods preconceptionally and during pregnancy has a beneficial impact on the children's body composition and cardiometabolic risk marker profiles. METHODS: Follow-up of 1255 children aged 5-10 y whose mothers took part in the Mumbai Maternal Nutrition Project [Project "SARAS"; International Standard Randomised Controlled Trial Number (ISRCTN)62811278]. Mothers were randomly assigned to receive a daily micronutrient-rich snack or a control snack of lower micronutrient content, both made from local foods, in addition to normal diet, from before pregnancy until delivery. Children's body composition was assessed using anthropometry and DXA. Their blood pressure, plasma glucose, insulin, and lipid concentrations were measured. Outcomes were compared between allocation groups with and without adjustment for confounding factors. RESULTS: Overall, 15% of children were stunted, 34% were wasted, and 3% were overweight. In the intention-to-treat analysis, there were no differences in body composition or risk markers between children in the intervention and control groups. Among children whose mothers started supplementation ≥3 mo before conception (the "per protocol" sample) the intervention increased adiposity among girls, but not boys. BMI in girls was increased relative to controls by 2% (95% CI: 1, 4; P = 0.01); fat mass index by 10% (95% CI: 3, 18; P = 0.004); and percent fat by 7% (95% CI: 1, 13; P = 0.01) unadjusted, with similar results in adjusted models. CONCLUSIONS: Overall, supplementing women with micronutrient-rich foods from before pregnancy until delivery did not alter body composition or cardiometabolic risk markers in the children. Subgroup analyses showed that, if started ≥3 mo before conception, supplementation may increase adiposity among female children.

Intergenerational change in anthropometry of children and adolescents in the New Delhi Birth Cohort.

BACKGROUND: A comparison of the anthropometry of children and adolescents with that of their parents at the same age may provide a more precise measure of intergenerational changes in linear growth and body mass index (BMI). METHODS: New Delhi Birth Cohort participants (F1), born between 1969 and 1972, were followed up for anthropometry at birth and at 6-monthly intervals until 21 years of age. At variable intervals 1447 children, aged 0-19 years (F2) and born to 818 F1 participants, were measured (weight and height), providing 2236 sets of anthropometries. Intergenerational changes (F2-F1) in height and BMI [absolute and standard deviation (SD) units] were computed by comparing children with their parents at corresponding ages. RESULTS: F2 children were taller (P < 0.001) than their parents at corresponding ages; the increase {mean [95% confidence interval (CI)] World Health Organization SD units} was 0.97 (0.83, 1.11), 1.21 (1.10, 1.32), 1.09 (0.98, 1.19), 1.10 (1.00, 1.21) and 0.75 (0.65, 0.85) for age categories of 0-5, 5-7.5, 7.5-10, 10-12.5 and >12.5 years, respectively. In absolute terms, this increase ranged from 3.5 cm (0-5-year-olds) to 7.5 cm (10-12.5-year-olds). The corresponding increases in BMI SD scores were 0.32 (0.18, 0.47), 0.60 (0.45, 0.75), 1.13 (0.99, 1.27), 1.30 (1.15, 1.45) and 1.00 (0.85, 1.15), respectively. The absolute BMI increase ranged from 1-3 kg/m2 at >5 years age to ∼3 kg/m2 at >10-years of age. The intergenerational increases were comparable in both sexes, but were greater in children born and measured later. A positive change in socioeconomic status was associated with an increase in height across the generations. CONCLUSIONS: Children and adolescents, throughout the ages 0-19 years, have become considerably taller and have a higher BMI than their parents at corresponding ages in an urban middle-class Indian population undergoing socioeconomic improvements.

Maternal vitamin D deficiency and GDM risk: evidence for the case of investing more attention in antenatal clinics.

Gestational diabetes mellitus (GDM) is a global public health problem, and in India, it affects about 20% of pregnancies. India, despite being a tropical country with abundant sunshine has a high prevalence (80%) of vitamin D deficiency (VDD) among reproductive-aged women. Global and Indian evidence links VDD with a higher risk of hyperglycaemia in pregnancy and GDM. VDD has also been implicated in gestational hypertension, preterm birth and poorer offspring health. Global scientific consensus acknowledges the need for maternal vitamin D screening and supplementation, but knowledge gaps exist about optimal blood levels (50-100 nmol/l), and the required vitamin D dosage (400-4000 IU). Diet can provide <10% of the vitamin D requirements, food fortification can deliver limited amounts, and hence optimal antenatal supplementation is key. Prenatal calcium supplements containing 400 IU of vitamin D may be sufficient for calcium absorption and bone health, but may not provide immunomodulatory benefits, including GDM prevention. Increasing evidence calls for higher maternal vitamin D requirements (2000-4000 IU) for skeletal, metabolic and immune health benefits. Current screening and supplementation for maternal VDD in India is low. We need to invest in future studies to determine optimal maternal vitamin D requirements and formulate policies for vitamin D supplementation to prevent GDM. Improving the maternal vitamin D status is an important nutritional priority for policymakers to reduce the large economic burden of non-communicable diseases (10% of India's gross domestic product), and eventually achieve the 2030 UN sustainable development goals.

Poor In Utero Growth, and Reduced ß-Cell Compensation and High Fasting Glucose From Childhood, Are Harbingers of Glucose Intolerance in Young Indians.

OBJECTIVE: India is a double world capital of early-life undernutrition and type 2 diabetes. We aimed to characterize life course growth and metabolic trajectories in those developing glucose intolerance as young adults in the Pune Maternal Nutrition Study (PMNS). RESEARCH DESIGN AND METHODS: PMNS is a community-based intergenerational birth cohort established in 1993, with serial information on parents and children through pregnancy, childhood, and adolescence. We compared normal glucose-tolerant and glucose-intolerant participants for serial growth, estimates of insulin sensitivity and secretion (HOMA and dynamic indices), and ß-cell compensation accounting for prevailing insulin sensitivity. RESULTS: At 18 years (N = 619), 37% of men and 20% of women were glucose intolerant (prediabetes n = 184; diabetes n = 1) despite 48% being underweight (BMI <18.5 kg/m2). Glucose-intolerant participants had higher fasting glucose from childhood. Mothers of glucose-intolerant participants had higher glycemia in pregnancy. Glucose-intolerant participants were shorter at birth. Insulin sensitivity decreased with age in all participants, and those with glucose intolerance had consistently lower compensatory insulin secretion from childhood. Participants in the highest quintile of fasting glucose at 6 and 12 years had 2.5- and 4.0-fold higher risks, respectively, of 18-year glucose intolerance; this finding was replicated in two other cohorts. CONCLUSIONS: Inadequate compensatory insulin secretory response to decreasing insulin sensitivity in early life is the major pathophysiology underlying glucose intolerance in thin rural Indians. Smaller birth size, maternal pregnancy hyperglycemia, and higher glycemia from childhood herald future glucose intolerance, mandating a strategy for diabetes prevention from early life, preferably intergenerationally.

Size at birth, lifecourse factors, and cognitive function in late life: findings from the MYsore study of Natal effects on Ageing and Health (MYNAH) cohort in South India.

OBJECTIVE: To examine if smaller size at birth, an indicator of growth restriction in utero, is associated with lower cognition in late life, and whether this may be mediated by impaired early life brain development and/or adverse cardiometabolic programming. DESIGN: Longitudinal follow-up of a birth cohort. SETTING: CSI Holdsworth Memorial Hospital (HMH), Mysore South India. PARTICIPANTS: 721 men and women (55-80 years) whose size at birth was recorded at HMH. Approximately 20 years earlier, a subset (n = 522) of them had assessments for cardiometabolic disorders in mid-life. MEASUREMENTS: Standardized measurement of cognitive function, depression, sociodemographic, and lifestyle factors; blood tests and assessments for cardiometabolic disorders. RESULTS: Participants who were heavier at birth had higher composite cognitive scores (0.12 SD per SD birth weight [95% CI 0.05, 0.19] p = 0.001) in late life. Other lifecourse factors independently positively related to cognition were maternal educational level and participants' own educational level, adult leg length, body mass index, and socioeconomic position, and negatively were diabetes in mid-life and current depression and stroke. The association of birth weight with cognition was independent cardiometabolic risk factors and was attenuated after adjustment for all lifecourse factors (0.08 SD per SD birth weight [95% CI -0.01, 0.18] p = 0.07). CONCLUSIONS: The findings are consistent with positive effects of early life environmental factors (better fetal growth, education, and childhood socioeconomic status) on brain development resulting in greater long-term cognitive function. The results do not support a pathway linking poorer fetal development with reduced late life cognitive function through cardiometabolic programming.

Association of maternal vitamin B12 and folate levels in early pregnancy with gestational diabetes: a prospective UK cohort study (PRiDE study).

AIMS/HYPOTHESIS: The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide in all ethnic groups. Low vitamin B12 and low/high folate levels may contribute to GDM risk, but there is conflicting evidence. Our aim is to assess the relationships of early pregnancy vitamin B12 and folate levels with the risk of GDM status at 26-28 weeks of gestation. METHODS: This was a prospective, multi-centre, multi-ethnic cohort study (n = 4746) in the UK. Participants who were eligible to be selectively screened as per the National Institute for Health and Care Excellence (NICE) criteria were included in the study. RESULTS: GDM prevalence was 12.5% by NICE and 14.7% by International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Folate deficiency (1.3%) was rare but B12 insufficiency (42.3% at <220 pmol/l) and folate excess (36.5%) were common in early pregnancy. Early pregnancy median B12 levels were lower, and folate levels higher, in women who were diagnosed with GDM at 26-28 weeks. B12 was negatively associated with fasting plasma glucose (1 SD: -0.06 mmol/l; 95% CI -0.04, -0.08; p < 0.0001) and 2 h plasma glucose levels (-0.07 mmol/l; 95% CI -0.02, -0.12; p = 0.004). Higher B12 was associated with 14.4% lower RR of IADPSG-GDM (0.856; 95% CI 0.786, 0.933; p = 0.0004) after adjusting for key confounders (age, parity, smoking status, ethnicity, family history, household income and folate status). Approximately half of this association was mediated through BMI. Folate was positively associated with 2 h plasma glucose levels (0.08 mmol/l; 95% CI 0.04, 0.13; p = 0.0005) but its relationship with fasting plasma glucose was U-shaped (quadratic ß: 0.011; p = 0.05). Higher folate was associated with 11% higher RR of IADPSG-GDM (adjusted RR 1.11; 95% CI 1.036, 1.182; p = 0.002) (age, parity, smoking status, ethnicity, family history, household income and B12 status). Although no interactions were observed for B12 and folate (as continuous variables) with glucose levels and GDM risk, a low B12-high folate combination was associated with higher blood glucose level and risk of IADPSG-GDM (adjusted RR 1.742; 95% CI 1.226, 2.437; p = 0.003). CONCLUSIONS/INTERPRETATION: B12 insufficiency and folate excess were common in early pregnancy. Low B12 and high folate levels in early pregnancy were associated with small but statistically significant changes in maternal blood glucose level and higher RR of GDM. Our findings warrant additional studies on the role of unmetabolised folic acid in glucose metabolism and investigating the effect of optimising early pregnancy or pre-conception B12 and folate levels on subsequent hyperglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT03008824.

Distinct opposing associations of upper and lower body fat depots with metabolic and cardiovascular disease risk markers.

BACKGROUND: To examine the associations of total and regional adiposity with metabolic and cardiovascular disease (CVD) risk markers. METHODS: This cross-sectional study included 1080 (53.8% men, aged 39-44 years) individuals from South India. Anthropometry (height, weight, waist and hip circumference), body composition assessment using dual-energy X-ray absorptiometry (DXA), blood pressure (BP), and plasma glucose, insulin and lipids were measured. Regression analysis was used to examine associations of standardized fat measurements with type 2 diabetes (T2D), insulin resistance (IR), hypertension and hypertriglyceridemia and continuous measurements of BP, glucose, insulin, HOMA-IR and lipids. Contour plots were constructed to visualize the differential effect of upper and lower fat depots. RESULTS: DXA-measured fat depots were positively associated with metabolic and CVD risk markers. After adjusting for fat mass index, upper body fat remained positively, while lower body fat was negatively associated with risk markers. A one standard deviation (SD) increase in android fat showed higher odds ratios (ORs) for T2D (6.59; 95% CI 3.17, 13.70), IR (4.68; 95% CI 2.31, 9.50), hypertension (2.57; 95% CI 1.56, 4.25) and hypertriglyceridemia (6.39; 95% CI 3.46, 11.90) in men. A 1 SD increase in leg fat showed a protective effect with ORs for T2D (0.42; 95% CI 0.24, 0.74), IR (0.31; 95% CI 0.17, 0.57) and hypertriglyceridemia (0.61; 95% CI 0.38, 0.98). The magnitude of the effect was greater with DXA-measured fat compared with anthropometry. CONCLUSION: At any level of total body fat, upper and lower body fat depots demonstrate opposite risk associations with metabolic and CVD risk markers in Asian Indians.