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1.
Sci Rep ; 9(1): 14321, 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31586083

RESUMO

We tested the hypothesis that both postnatal feeding and conditions in utero affect lipid metabolism in infants. Infants who experienced restrictive growth conditions in utero and others exposed to maternal hyperglycaemia were compared to a control group with respect to feeding mode. Dried blood spots were collected from a pilot subset of infant participants of the Cambridge Baby Growth Study at 3mo. Groups: (a) a normal gestation (control, n = 40), (b) small for gestational age (SGA, n = 34) and (c) whose mothers developed hyperglycaemia (n = 59). These groups were further stratified by feeding mode; breastfed, formula-fed or received a mixed intake. Their phospholipid, glyceride and sterol fractions were profiled using direct infusion mass spectrometry. Statistical tests were used to identify molecular species that indicated differences in lipid metabolism. The abundance of several phospholipids identified by multivariate analysis, PC(34:1), PC(34:2) and PC-O(34:1), was 30-100% higher across all experimental groups. SM(39:1) was around half as abundant in in utero groups among breastfed infants only. The evidence from this pilot study shows that phospholipid metabolism is modulated by both conditions in utero and postnatal feeding in a cohort of 133 Caucasian infants, three months post partum.

2.
Diabetes ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506343

RESUMO

Epigenetic changes may contribute substantially to risks of diseases of ageing. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the population-based EPIC-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset to investigate the role of methylation in the aetiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM, and robustly confirmed three MVPs identified previously (near to TXNIP, ABCG1 and SREBF1). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesity-related pathways acting before the collection of baseline samples. We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs, and found one MVP, cg00574958 at CPT1A, with a possible direct causal role on T2DM. None of the implicated genes was previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia.

3.
Epigenomics ; 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31536415

RESUMO

Aim: Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for in utero exposure in newborns is unknown. Materials & methods: We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Results & conclusion: Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.

4.
Diabetologia ; 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31396660

RESUMO

AIMS/HYPOTHESIS: This study aimed to explore the infancy growth trajectories of 'recent' and 'earlier' offspring of mothers with gestational diabetes mellitus (OGDM), each compared with the same control infants, and investigate whether 'recent' OGDM still exhibit a classical phenotype, with macrosomia and increased adiposity. METHODS: Within a prospective observational birth cohort, 98 'earlier' OGDM born between 2001 and 2009 were identified using 75 g oral glucose tolerance testing at 28 weeks gestation, 122 recent OGDM born between 2011 and 2013 were recruited postnatally through antenatal diabetes clinics, and 876 normal birthweight infants of mothers with no history of diabetes were recruited across the full study period as the control group. All infants followed the same study protocol (measurements at birth, 3, 12 and 24 months, including weight, length and skinfold thickness indicating adiposity, and detailed demographic data). In all cases, GDM was defined using the International Association of Diabetes and Pregnancy Study Group criteria. RESULTS: Earlier OGDM had higher birthweight SD scores (SDS) than control infants. Conversely, recent OGDM had similar birthweight- and length SDS to control infants (mean ± SD, 0.1 ± 1.0 and- 0.1 ± 0.9, respectively), but lower mean skinfold thickness SDS (-0.4 ± 0.6 vs 0.0 ± 0.9; p < 0.001). After birth, earlier OGDM showed reduced gains in weight and length between 3 and 12 months. In contrast, recent OGDM had increased weight and skinfold thickness gains until 3 months, followed by reduced gains in those variables from 3 to 12 months, compared with control infants. At 24 months, recent OGDM had lower adiposity than control infants (mean skinfold thickness SDS -0.3 ± 0.7 vs 0.0 ± 0.8; p < 0.001). At all time points recent OGDM had lower growth measurements than earlier OGDM. CONCLUSIONS/INTERPRETATION: Recent OGDM showed different growth trajectories to the earlier group, namely normalisation of birthweight and reduced adiposity at birth, followed by initial rapid weight gain but subsequent reduced adiposity postnatally. While avoidance of macrosomia at birth may be advantageous, the longer-term health implications of these changing growth trajectories are uncertain.

5.
J Nutr ; 149(5): 716-722, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31050748

RESUMO

BACKGROUND: Presumed benefits of human milk (HM) in avoiding rapid infancy weight gain and later obesity could relate to its nutrient composition. However, data on breast milk composition and its relation with growth are sparse. OBJECTIVE: We investigated whether short-chain fatty acids (SCFAs), known to be present in HM and linked to energy metabolism, are associated with infancy anthropometrics. METHODS: In a prospective birth cohort, HM hindmilk samples were collected from 619 lactating mothers at 4-8 wk postnatally [median (IQR) age: 33.9 (31.3-36.5) y, body mass index (BMI) (kg/m2): 22.8 (20.9-25.2)]. Their offspring, born at 40.1 (39.1-41.0) wk gestation with weight 3.56 (3.22-3.87) kg and 51% male, were assessed with measurement of weight, length, and skinfold thickness at ages 3, 12, and 24 mo, and transformed to age- and sex-adjusted z scores. HM SCFAs were measured by 1H-nuclear magnetic resonance spectroscopy (NMR) and GC-MS. Multivariable linear regression models were conducted to analyze the relations between NMR HM SCFAs and infancy growth parameters with adjustment for potential confounders. RESULTS: NMR peaks for HM butyrate, acetate, and formic acid, but not propionate, were detected. Butyrate peaks were 17.8% higher in HM from exclusively breastfeeding mothers than mixed-feeding mothers (P = 0.003). HM butyrate peak values were negatively associated with changes in infant weight (standardized B  = -0.10, P = 0.019) and BMI (B = -0.10, P = 0.018) between 3 and 12 mo, and negatively associated with BMI (B = -0.10, P = 0.018) and mean skinfold thickness (B = -0.10, P = 0.049) at age 12 mo. HM formic acid peak values showed a consistent negative association with infant BMI at all time points (B < = -0.10, P < = 0.014), whereas HM acetate was negatively associated with skinfold thickness at 3 mo (B = -0.10, P = 0.028) and 24 mo (B = -0.10, P = 0.036). CONCLUSIONS: These results suggest that HM SCFAs play a beneficial role in weight gain and adiposity during infancy. Further knowledge of HM SCFA function may inform future strategies to support healthy growth.

6.
Acta Diabetol ; 56(10): 1133-1140, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31087162

RESUMO

AIMS: The incidence of gestational diabetes has been reported to have risen over the first decade of this century. Some studies have also found it to vary with seasons of the year. We investigated temporal and seasonal trends on gestational diabetes incidence in a single-centre cohort study from Cambridge, UK, and attempted to explain trends using associated risk factors. METHODS: Using a cosinor model, we tested both temporal and seasonal trends in gestational diabetes incidence in 1074 women recruited to the Cambridge Baby Growth Study in 2001-2009 who underwent oral glucose tolerance tests around week 28 of pregnancy. RESULTS: There was a temporal increase in gestational diabetes incidence over the course of recruitment to this study [0.014 (0.005, 0.022) proportional increase per year, p = 2.1 × 10-3], but no seasonal effect (p = 0.7). HOMA B [- 0.015 (- 0.025, - 0.005) per year, p = 3.0 × 10-3] and the insulin disposition index [- 0.036 (- 0.060, - 0.013) per year, p = 3.0 × 10-3], unlike HOMA S, showed negative temporal trends. Risk factor analyses showed a concomitant temporal slight increase in the index of multiple deprivation [0.191 (0.138, 0.257) units per year, p = 4.6 × 10-10]. This index was positively associated with HOMA B (p = 6.1 × 10-5) but not directly with gestational diabetes (p = 0.6), HOMA S (p = 0.2) or the insulin disposition index (p = 0.4). CONCLUSIONS: In this cohort, there were temporal, but not seasonal, increases in gestational diabetes incidence between the years 2001 and 2009, which appeared to be related more to reductions in insulin secretion than sensitivity. Possible mediators of this link include confounding factors related to deprivation.

7.
Sci Rep ; 9(1): 5444, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30931983

RESUMO

The findings of studies on the association between physical activity and adiposity are not consistent, and most are cross-sectional and used only self-reported measures. The aims of this study were to evaluate: 1) independent and combined cross-sectional associations of objectively-measured physical activity and sedentary time with body composition outcomes at 30 years, and 2) prospective associations of changes in self-reported physical activity from 23 to 30 years with the same outcomes in participants from the 1982 Pelotas (Brazil) Birth Cohort. Body mass index, waist circumference, visceral abdominal fat, fat mass index, and android/gynoid fat ratio were the outcomes. 3,206 participants were analysed. In cross-sectional analyses, higher objectively-measured moderate-to-vigorous physical activity was associated with lower body mass index (ß = 0.017, 95%CI: -0.026; -0.009), waist circumference (ß = -0.043, 95%CI: -0.061; -0.025), visceral abdominal fat (ß = -0.006, 95%CI: -0.009; -0.003), and fat mass index (ß = -0.015, 95%CI: -0.021; -0.009), independent of sedentary time. Sedentary time was independently associated only with higher fat mass index (ß = 0.003, 95%CI: 0.001; 0.005). In longitudinal analyses, using self-reported measure, adiposity was lower among those who were consistently active or who became active. Adiposity was similar among the "became inactive" and "consistently inactive" subjects. Our findings suggest metabolic benefits from engagement in physical activity throughout young adulthood, with stronger associations on concurrent levels.

8.
Pediatr Obes ; 14(5): e12496, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30702799

RESUMO

BACKGROUND: Many genetic polymorphisms identified by genome-wide association studies for adult body mass index (BMI) have been suggested to regulate food intake. OBJECTIVE: The objective was to study the associations between a genetic obesity risk score, appetitive traits, and growth of children up to age 5 years, with a longitudinal design. METHODS: In 1142 children from the Etude des Déterminants pre et post natals de la santé de l'ENfant (EDEN) birth cohort, a combined obesity risk-allele score (BMI genetic risk score [GRS]) was related to appetitive traits (energy intake up to 12 mo, a single item on appetite from 4 mo to 3 y, a validated appetite score at 5 y) using Poisson regressions with robust standard errors. The potential mediation of appetitive traits on the association between BMI-GRS and growth was assessed by the Sobel test. RESULTS: Children with a high BMI-GRS were more likely to have high energy intake at 1 year and high appetite at 2 and 5 years. High energy intake in infancy and high appetite from 1 year were related to higher subsequent BMI. High 2-year appetite seemed to partially mediate the associations between BMI-GRS and BMI from 2 to 5 years (all P ≤ 0.05). CONCLUSIONS: Genetic susceptibility to childhood obesity seems to be partially explained by appetitive traits in infancy, followed by an early childhood rise in BMI.


Assuntos
Apetite/genética , Desenvolvimento Infantil/fisiologia , Comportamento Alimentar/fisiologia , Obesidade Pediátrica/genética , Adulto , Alelos , Apetite/fisiologia , Índice de Massa Corporal , Pré-Escolar , Estudos de Coortes , Ingestão de Alimentos , Ingestão de Energia , Feminino , França , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Mães , Gravidez , Estudos Prospectivos , Fatores de Risco
9.
Paediatr Perinat Epidemiol ; 33(2): 172-180, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30714177

RESUMO

BACKGROUND: A range of postnatal and maternal factors influences childhood obesity, but their relative importance remains unclear. This study aimed to assess the relative impact of postnatal rapid growth and maternal factors on early childhood growth trajectories. SUBJECTS: Secondary longitudinal analysis of pooled data from the Melbourne Infant Feeding Activity and Nutrition Trial (InFANT) Program and the InFANT Extend Program (n = 977) was performed. Children's height and weight were collected at birth, 3, 9, 18, and 36/42 months. Body mass index-for-age and height-for-age z-scores (BAZ, HAZ) were computed using WHO growth standards. Mixed-effect polynomial regression models were fitted to examine BAZ and HAZ trajectories and their determinants. RESULTS: Rapid growth from birth to 3 months, maternal country of birth, and pre-pregnancy BMI were each independently associated with BAZ from 3 to 42 months. Children with rapid growth, those whose mothers were Australian-born, and those whose mothers were overweight/obese pre-pregnancy had higher BAZ from 3 to 42 months. Children with rapid growth had an increase in HAZ growth, but their average HAZ from 3 to 42 months was smaller than children without rapid growth. Children of tall mothers (above average height) had higher HAZ than those of short mothers (below average height). Average HAZ from 3 to 42 months did not differ by maternal country of birth. CONCLUSION: Children who experienced rapid growth from birth to 3 months, whose mothers were Australian-born or whose mothers were overweight/obese pre-pregnancy demonstrated less favourable growth trajectories across early childhood, potentially predispose them for development of future obesity.


Assuntos
Estatura/fisiologia , Obesidade Pediátrica/epidemiologia , Circunferência da Cintura/fisiologia , Austrália/epidemiologia , Índice de Massa Corporal , Fenômenos Fisiológicos da Nutrição Infantil , Pré-Escolar , Feminino , Humanos , Lactente , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Inquéritos Nutricionais , Estado Nutricional
10.
Pregnancy Hypertens ; 15: 134-140, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30713829

RESUMO

Objectives: To investigate whether age at menarche is related to maternal blood pressure in pregnancy and, if so, whether obesity and insulin resistance can modify the associations. Study Design: Analysis of data collected from 438 pregnant women from the longitudinal and prospective Cambridge Baby Growth Study. Main Outcome: Testing associations between questionnaire-derived age at menarche and blood pressure measurements in pregnancy collected from hospital notes, and investigating whether any associations were altered by maternal pre-pregnancy body mass index (BMI) and insulin resistance. Measures: Mean arterial blood pressure at four time points across pregnancy, age at menarche, (Homeostasis Model Assessment) insulin resistance around week 28 of pregnancy. Results: For each increased year in age at menarche there was a drop in mean arterial blood pressure (mmHg) of 0.6 at 11.9 weeks, 0.9 at 31.4 and 37.0 weeks, and 0.4 at 38.8 weeks (a maximal difference of over 7 mmHg across extremes of AAM). Each association was attenuated by both maternal pre-pregnancy BMI and insulin resistance. Conclusions: Age at menarche is negatively associated with future blood pressure in pregnancy, so those with the earliest age at menarche have the highest blood pressures. Either these associations may be mediated by links between age at menarche and obesity/insulin resistance, or there may be a confounder (e.g. systemic inflammation) that links age at menarche to each of them.


Assuntos
Pressão Arterial , Hipertensão Induzida pela Gravidez/epidemiologia , Hipotensão/epidemiologia , Resistência à Insulina/fisiologia , Menarca , Obesidade/fisiopatologia , Adolescente , Adulto , Fatores Etários , Índice de Massa Corporal , Criança , Feminino , Idade Gestacional , Humanos , Hipertensão Induzida pela Gravidez/fisiopatologia , Hipotensão/fisiopatologia , Gravidez
11.
Acta Paediatr ; 108(6): 1008-1015, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30588652

RESUMO

AIM: To systematically appraise and summarise published evidence on the association between childhood physical activity (PA) and subsequent age at menarche (AAM). METHODS: We searched PubMed (1990-2018) for studies that reported the relationship between childhood PA and AAM. We performed tabular synthesis of population-based studies and a random-effects meta-analysis of results of athlete/nonathlete studies. RESULTS: One randomised controlled trial was identified, in which an intervention to prevent obesity reduced the likelihood of menarche during the two-year study period (relative risk: 0.75, 95% CI: 0.66-0.87; n = 422 girls). One of five prospective cohort studies (total n = 4492) reported a significant association between self-reported PA duration and subsequent menarche timing. Four of five historical cohort studies (total n = 89 470) reported significant associations between recalled premenarcheal PA and later AAM. Meta-analysis across 12 athlete/nonathlete studies showed that menarche occurred 1.13 years later (95% CI: 0.80-1.47) in athletes compared to nonathletes. CONCLUSION: These findings suggest that AAM is a behaviourally modifiable trait. However, the quality of reported population-based study evidence is low and estimation of the true relationship between childhood PA and AAM is likely confounded by concomitant changes in diet and lifestyle behaviours.

12.
BMC Res Notes ; 11(1): 821, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30454065

RESUMO

OBJECTIVE: Previously we found that certain fetal imprinted genes represented as an allele score are associated with maternal pregnancy glucose concentrations. Recently it was reported that fetal polymorphisms with strong associations with birth weight tend to mediate these independently of increases in maternal pregnancy glucose concentrations. We therefore investigated whether potential associations between the fetal allele score and birth weight were related to maternal glucose concentrations in the Cambridge Baby Growth Study. RESULTS: The fetal imprinted gene allele score was positively associated with birth weight (ß = 63 (17-109) g/risk allele, ß' = 0.113, p = 7.6 × 10-3, n = 405). This association was partially attenuated by adjusting for maternal glucose concentrations (ß = 50 (4-95) g/risk allele, ß' = 0.089, p = 0.03, n = 405). The allele score was also positively associated with risk of being large for gestational age at birth (odds ratio 1.60 (1.19-2.15) per risk allele, p = 2.1 × 10-3, n = 660) and negatively associated with risk of being small for gestational age at birth (odds ratio 0.65 (0.44-0.96) per risk allele, p = 0.03, n = 660). The large for gestational age at birth association was also partially attenuated by maternal glucose concentrations. These results suggest that associations between the fetal imprinted gene allele score and size at birth are mediated through both glucose-dependent and glucose-independent mechanisms.

13.
PLoS One ; 13(11): e0207923, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30475885

RESUMO

BACKGROUND: The rising prevalence of obesity has made hepatic steatosis an increasingly common issue. Ultrasound is generally used in clinical practice to assess steatosis, but its accuracy has been inconsistent across studies. We aimed to determine the validity of ultrasound to diagnose hepatic steatosis when compared to the criterion method proton magnetic resonance spectroscopy (MRS) in older individuals. METHODS: A total of 72 healthy white European individuals (n = 42 men; n = 30 women aged 67-76 years) participating in the Hertfordshire Birth Cohort Physical Activity trial had hepatic steatosis assessed by ultrasound and MRS. The ultrasound scans were graded as normal, mild, moderate and severe steatosis, while hepatic fat content above 5.5% by MRS was used as a cut-off for steatosis. RESULTS: 18 participants (25%) had a level of hepatic fat measured by MRS consistent with diagnosis of steatosis. The sensitivity and specificity of ultrasound in diagnosing hepatic steatosis (mild/moderate/severe vs normal) were 96% (95% CI: 87-99.6%) and 94% (95% CI: 73-100%) respectively, although overlap in MRS hepatic fat content was observed between the ultrasound categories. CONCLUSIONS: Ultrasound is a valid method for detecting the presence or absence of hepatic steatosis in older adults and can be used as an alternative tool in both clinical investigations and epidemiological studies, when other imaging techniques are not feasible.

14.
Wellcome Open Res ; 3: 123, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30345390

RESUMO

Background: Although nausea and vomiting are very common in pregnancy, their pathogenesis is poorly understood. We tested the hypothesis that circulating growth and differentiation factor 15 (GDF15) concentrations in early pregnancy, whose gene is implicated in hyperemesis gravidarum, are associated with nausea and vomiting. Methods: Blood samples for the measurement of GDF15 and human chorionic gonadotrophin (hCG) concentrations were obtained early in the second trimester (median 15.1 (interquartile range 14.4-15.7) weeks) of pregnancy from 791 women from the Cambridge Baby Growth Study, a prospective pregnancy and birth cohort. During each trimester participants completed a questionnaire which included questions about nausea, vomiting and antiemetic use. Associations with pre-pregnancy body mass indexes (BMI) were validated in 231 pregnant NIPTeR Study participants. Results: Circulating GDF15 concentrations were higher in women reporting vomiting in the second trimester than in women reporting no pregnancy nausea or vomiting: 11,581 (10,977-12,219) (n=175) vs. 10,593 (10,066-11,147) (n=193) pg/mL, p=0.02). In women who took antiemetic drugs during pregnancy (n=11) the GDF15 levels were also raised 13,157 (10,558-16,394) pg/mL (p =0.04). Serum GFD15 concentrations were strongly positively correlated with hCG levels but were inversely correlated with maternal BMIs, a finding replicated in the NIPTeR Study. Conclusions: Week 15 serum GDF15 concentrations are positively associated with second trimester vomiting and maternal antiemetic use in pregnancy. Given GDF15's site of action in the chemoreceptor trigger zone of the brainstem and its genetic associations with hyperemesis gravidarum, these data support the concept that GDF15 may be playing a pathogenic role in pregnancy-associated vomiting.

15.
Commun Biol ; 1: 36, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271922

RESUMO

Risk-taking propensity is a trait of significant public health relevance but few specific genetic factors are known. Here we perform a genome-wide association study of self-reported risk-taking propensity among 436,236 white European UK Biobank study participants. We identify genome-wide associations at 26 loci (P < 5 × 10-8), 24 of which are novel, implicating genes enriched in the GABA and GABA receptor pathways. Modelling the relationship between risk-taking propensity and body mass index (BMI) using Mendelian randomisation shows a positive association (0.25 approximate SDs of BMI (SE: 0.06); P = 6.7 × 10-5). The impact of individual SNPs is heterogeneous, indicating a complex relationship arising from multiple shared pathways. We identify positive genetic correlations between risk-taking and waist-hip ratio, childhood obesity, ever smoking, attention-deficit hyperactivity disorder, bipolar disorder and schizophrenia, alongside a negative correlation with women's age at first birth. These findings highlight that behavioural pathways involved in risk-taking propensity may play a role in obesity, smoking and psychiatric disorders.

16.
Reprod Biol Endocrinol ; 16(1): 82, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30157874

RESUMO

BACKGROUND: Imprinted genes, which are expressed in a parent of origin-specific manner, are thought to mediate the genetic priorities of each parent in pregnancy. Recently we reported that some fetal imprinted gene variants are associated with maternal glucose concentrations and blood pressures in pregnancy. We suggest that the conflict between the effects of paternal and maternal transmitted genes starts at conception and may already be evident in measures of maternal metabolism in early pregnancy, before gestational diabetes is manifest. METHODS: Lipid fractions in maternal non-fasting serum collected around week 15 of pregnancy were profiled using direct infusion mass spectrometry in a subset Discovery Cohort (n = 200) of women from the Cambridge Baby Growth Study using direct infusion mass spectrometry. Associations between 151 haplotype-tag fetal polymorphisms in 16 imprinted genes and lipids were determined using partial least squares discriminant analysis. Variable importance in projection scores were used to identify those lipid species that contribute most to the underlying variation in the lipid profile and the concentrations of these species tested for associations with fetal imprinted gene alleles using linear regression. In an internal Validation Cohort (n = 567 women from the same cohort) the lipid fraction was profiled using liquid chromatography-mass spectrometry and tested for associations with the same fetal imprinted gene variants as above, followed by meta-analysis of associations from the Discovery and Validation Cohorts. RESULTS: The most significant associations were between a monounsaturated triglyceride (44:1) and both paternally-transmitted fetal H19 rs7950932 (R = 0.14, p = 2.9 × 10- 3, n = 386) and maternally-transmitted fetal FAM99A rs7131362 (R = 0.18, p = 6.2 × 10- 3, n = 351; association with maternal-untransmitted allele R = 0.08, p = 0.07, n = 328). This same triglyceride isoform was also associated with subsequent week 28 fasting glucose concentrations (R = 0.09, p = 9.9 × 10- 3, n = 673) and homeostasis model assessment of insulin resistance (R = 0.09, p = 0.01, n = 664). CONCLUSIONS: Fetal imprinted genes may influence maternal circulating clinically relevant triglyceride concentrations early in pregnancy.


Assuntos
Feto/metabolismo , Impressão Genômica , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Estudos de Coortes , Diabetes Gestacional/sangue , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/genética , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Espectrometria de Massas/métodos , Gravidez
17.
Acta Diabetol ; 55(12): 1209-1219, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30159746

RESUMO

Published studies show an inconsistent association between age at menarche and the subsequent risk of developing gestational diabetes mellitus when pregnant. This systematic review and meta-analysis was performed to clarify any trends in this association in published observational population studies. We searched online databases for relevant studies, entered into them up until June 21st 2017. Five eligible studies were found and a pooled random effects dose response meta-analysis of results from these was conducted. This included coverage of 58,133 pregnancies, from which 3,035 women developed gestational diabetes. There was evidence of a non-linear association between age at menarche and gestational diabetes (overall p = 1.4 × 10-8; p for non-linearity = 2.4 × 10-4), along with evidence of relatively low heterogeneity (I2 = 25.5%). The largest predicted risk of gestational diabetes was associated with having a low age at menarche; the mean (95% confidence interval) risk relative to that associated with menarche at age 13 years being: 9 years 2.0 (1.6, 2.4), 10 years 1.6 (1.4, 1.9), 11 years 1.3 (1.2, 1.4), 12 years 1.1 (1.1, 1.1), 13 years was the reference, 14 years 1.0 (1.0, 1.0), 15 years 1.1 (0.9, 1.2), 16 years 1.1 (0.9, 1.4). There was evidence of potential publication bias, such that the maximal true relative risk of gestational diabetes, associated with an age at menarche of 9 years, may be closer to 1.6 than 2. Nevertheless, the curvilinear relationship between age at menarche and the future risk of gestational diabetes in pregnancy appears robust.

18.
Genes Nutr ; 13: 24, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30123368

RESUMO

Background: Ninety-seven independent single nucleotide polymorphisms (SNPs) are robustly associated with adult body mass index (BMI kg/m2) in Caucasian populations. The relevance of such variants in African populations at different stages of the life course (such as childhood) is unclear. We tested whether a genetic risk score composed of the aforementioned SNPs was associated with BMI from infancy to early adulthood. We further tested whether this genetic effect was mediated by conditional weight gain at different growth periods. We used data from the Birth to Twenty Plus Cohort (Bt20+), for 971 urban South African black children from birth to 18 years. DNA was collected at 13 years old and was genotyped using the Metabochip (Illumina) array. The weighted genetic risk score (wGRS) for BMI was constructed based on 71 of the 97 previously reported SNPs. Results: The cross-sectional association between the wGRS and BMI strengthened with age from 5 to 18 years. The significant associations were observed from 11 to 18 years, and peak effect sizes were observed at 13 and 14 years of age. Results from the linear mixed effects models showed significant interactions between the wGRS and age on longitudinal BMI but no such interactions were observed in sex and the wGRS. A higher wGRS was associated with an increased relative risk of belonging to the early onset obese longitudinal BMI trajectory (relative risk = 1.88; 95%CI 1.28 to 2.76) compared to belonging to a normal longitudinal BMI trajectory. Adolescent conditional relative weight gain had a suggestive mediation effect of 56% on the association between wGRS and obesity risk at 18 years. Conclusions: The results suggest that genetic susceptibility to higher adult BMI can be tracked from childhood in this African population. This supports the notion that prevention of adult obesity should begin early in life. The genetic risk score combined with other non-genetic risk factors, such as BMI trajectory membership in our case, has the potential to be used to screen for early identification of individuals at increased risk of obesity and other related NCD risk factors in order to reduce the adverse health risk outcomes later.

19.
Nat Genet ; 50(8): 1112-1121, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30038396

RESUMO

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

20.
Horm Res Paediatr ; 90(1): 28-38, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29961064

RESUMO

BACKGROUND/AIMS: Exposure to obesity during pregnancy may lead to adverse changes in the offspring's metabolic profile. We compared appetite- and growth-related hormones in a cohort of infants born to obese mothers (SKOT-II) with infants born mainly to nonobese mothers (SKOT-I). METHODS: Infants from SKOT-I (n = 273) and SKOT-II (n = 132) were examined including anthropometric measurements and blood samples analyzed for glucose, insulin, insulin-like growth factor-I (IGF-I), adiponectin, and leptin. Information on breastfeeding and parental characteristics were also collected. RESULTS: At 9 months of age, SKOT-II infants were 3.6% heavier and 1.2% longer than SKOT-I infants even though their mothers were shorter. There was no difference in body mass index (BMI). SKOT-II infants had higher levels of insulin, adiponectin, and leptin but lower levels of IGF-I compared to SKOT-I infants (all p ≤ 0.015). These differences remained, except for leptin, when adjusted for current weight. Breastfeeding versus nonbreastfeeding at 9 months was associated with lower concentrations of all hormones (all p ≤ 0.003). In adjusted models, maternal BMI at 9 months was positively associated with insulin and adiponectin and negatively with IGF-I. CONCLUSIONS: Pre-pregnancy obesity confers symmetrically larger infant body size and higher levels of most growth- and appetite-related hormones but surprisingly lower levels of IGF-I, suggesting other possible infant growth-promoting effects through insulin.

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