To examine independent associations of serum 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH) and calcium with a range of cardiovascular risk factors in adolescents.
Cross-sectional population-based study.
A nationally representative sample of the US adolescent population.
Healthy adolescents (aged 12–19) participating in the National Health and Nutrition Examination Survey (NHANES) between 2001 and 2006. Numbers varied between 740 and 5609 for given exposure and outcome associations.
Main outcome measures
Systolic blood pressure (SBP), diastolic blood pressure (DBP), lipids (triglycerides, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C)), fasting insulin and glucose, postload glucose and glycohaemoglobin (HbA1c).
25(OH)D was inversely associated with SBP (−0.068 standard deviations (SD), 95% CI −0.118 to −0.018), and positively associated with HDL-C (0.101; 0.040 to 0.162) and HbA1c (0.073; 0.021 to 0.125) after adjustment for gender, age, ethnicity, socioeconomic status and waist circumference. In adjusted models, PTH was inversely associated with triglycerides (−0.115; −0.188 to −0.042) and LDL-C (−0.133; −0.207 to −0.060). In adjusted models, calcium was positively associated with fasting insulin (0.110; 0.060 to 0.160), postload glucose (0.116; 0.000 to 0.232), HbA1c (0.079; 0.035 to 0.123), triglycerides (0.182; 0.122 to 0.242), HDL-C (0.049; 0.010 to 0.088) and LDL-C (0.137; 0.080 to 0.195). The associations of each exposure with risk factors remained after mutual adjustment for each other.
Higher calcium levels might be a more important predictor of increased cardiovascular risk in adolescents than lower 25(OH)D levels or PTH levels, but the findings require replication in additional studies and examination in prospective studies.
Studies in adults have reported associations of low circulating total 25-hydroxyvitamin D with increased cardiovascular disease and risk factors. Evidence of associations in children, however, is limited, and it is unknown whether associations with risk factors differ for each 25-hydroxyvitamin D analog [25-hydroxyvitamin D2 (25[OH]D2) and 25-hydroxyvitamin D2 (25[OH]D3)].
The objective of the study was to compare associations of 25(OH)D2 and 25(OH)D3 with cardiovascular risk factors in children.
The design of the study was a cross-sectional study of 4274 children (mean age 9.9 yr) from the Avon Longitudinal Study of Parents and Children.
The main outcomes included blood pressure, lipids [triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C)], apolipoproteins (Apo-A1 and Apo-B), adiponectin, leptin, C-reactive protein, and IL-6.
In confounder-adjusted models, 25(OH)D2 was inversely associated with Apo-A1 (change per doubling of exposure: −0.74mg/dl; 95% confidence interval −0.14, −0.04) and triglycerides (relative percentage change per doubling of exposure: −1.64%; −3.27, 0.01) and positively associated with C-reactive protein (8.42%; 3.40, 13.58) and IL-6 (5.75%; 1.83, 9.25). 25(OH)D3 was positively associated with HDL-C (0.04 mmol/liter; 0.02, 0.06), Apo-A1 (1.96 mg/dl; 0.65, 3.24), and adiponectin (0.47 μg/ml; 0.15, 0.79). There was statistical evidence that associations of 25(OH)D2 and 25(OH)D3 with HDL-C, Apo-A1, and IL-6 differed from each other (all P values for differences ≤0.02).
Higher circulating 25(OH)D3 was associated with cardioprotective levels of HDL-C, Apo-A1, and adiponectin in children. Associations of 25(OH)D2 with cardiovascular risk factors were in mixed directions. It is necessary to see whether these associations are replicated in large prospective studies.
Iron deficiency is common during pregnancy. Experimental animal studies suggest that it increases cardiovascular risk in the offspring.
To examine the relationship between maternal pregnancy dietary and supplement iron intake and hemoglobin, with offspring’s arterial stiffness (measured by carotid-radial pulse wave velocity), endothelial function (measured by brachial artery flow mediated dilatation), blood pressure, and adiposity (measured by body mass index), test for mediation by cord ferritin, birth weight, gestational age, and child dietary iron intake, and for effect modification by maternal vitamin C intake and offspring sex.
Prospective data from 2958 mothers and children pairs at 10 years of age enrolled in an English birth cohort, the Avon Longitudinal Study for Parents and Children (ALSPAC), was analysed.
2639 (89.2%) mothers reported dietary iron intake in pregnancy below the UK reference nutrient intake of 14.8 mg/day. 1328 (44.9%) reported taking iron supplements, and 129 (4.4%) were anemic by 18 weeks gestation. No associations were observed apart from maternal iron intake from supplements with offspring systolic blood pressure (−0.8 mmHg, 99% CI −1.7 to 0, P = 0.01 in the sample with all relevant data observed, and −0.7 mmHg, 99% CI −1.3 to 0, P = 0.008 in the sample with missing data imputed).
There was no evidence of association between maternal pregnancy dietary iron intake, or maternal hemoglobin concentration (which is less likely to be biased by subjective reporting) with offspring outcomes. There was a modest inverse association between maternal iron supplement intake during pregnancy with offspring systolic blood pressure at 10 years.
Tourette syndrome and chronic tic disorder are heritable but aetiologically complex. Although environment plays a role in their development, existing studies of non-genetic risk factors are inconsistent.
To examine the association between pre- and perinatal exposures and Tourette syndrome/chronic tic disorder in the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective longitudinal pre-birth cohort.
Relationships between exposures and Tourette syndrome/chronic tic disorder were examined in 6090 children using logistic regression.
Maternal alcohol and cannabis use, inadequate maternal weight gain and parity were associated with Tourette syndrome or Tourette syndrome/chronic tic disorder. Other previously reported exposures, including birth weight and prenatal maternal smoking, were not associated with Tourette syndrome/chronic tic disorder.
This study supports previously reported relationships between Tourette syndrome/chronic tic disorder and prenatal alcohol exposure, and identifies additional previously unexplored potential prenatal risk factors.
Individual participant time-to-event data from multiple prospective epidemiologic studies enable detailed investigation into the predictive ability of risk models. Here we address the challenges in appropriately combining such information across studies. Methods are exemplified by analyses of log C-reactive protein and conventional risk factors for coronary heart disease in the Emerging Risk Factors Collaboration, a collation of individual data from multiple prospective studies with an average follow-up duration of 9.8 years (dates varied). We derive risk prediction models using Cox proportional hazards regression analysis stratified by study and obtain estimates of risk discrimination, Harrell's concordance index, and Royston's discrimination measure within each study; we then combine the estimates across studies using a weighted meta-analysis. Various weighting approaches are compared and lead us to recommend using the number of events in each study. We also discuss the calculation of measures of reclassification for multiple studies. We further show that comparison of differences in predictive ability across subgroups should be based only on within-study information and that combining measures of risk discrimination from case-control studies and prospective studies is problematic. The concordance index and discrimination measure gave qualitatively similar results throughout. While the concordance index was very heterogeneous between studies, principally because of differing age ranges, the increments in the concordance index from adding log C-reactive protein to conventional risk factors were more homogeneous.
C index; coronary heart disease; D measure; individual participant data; inverse variance; meta-analysis; risk prediction; weighting
While the number of established genetic variants associated with adult body mass index (BMI) is growing, the relationships between these variants and growth during childhood are yet to be fully characterised. We examined the association between validated adult BMI associated single nucleotide polymorphisms (SNPs) and growth trajectories across childhood. We investigated the timing of onset of the genetic effect and whether it was sex specific.
Children from the ALSPAC and Raine birth cohorts were used for analysis (n = 9,328). Genotype data from 32 adult BMI associated SNPs were investigated individually and as an allelic score. Linear mixed effects models with smoothing splines were used for longitudinal modelling of the growth parameters and measures of adiposity peak and rebound were derived.
The allelic score was associated with BMI growth throughout childhood, explaining 0.58% of the total variance in BMI in females and 0.44% in males. The allelic score was associated with higher BMI at the adiposity peak (females = 0.0163 kg/m2 per allele, males = 0.0123 kg/m2 per allele) and earlier age (-0.0362 years per allele in males and females) and higher BMI (0.0332 kg/m2 per allele in females and 0.0364 kg/m2 per allele in males) at the adiposity rebound. No gene:sex interactions were detected for BMI growth.
This study suggests that known adult genetic determinants of BMI have observable effects on growth from early childhood, and is consistent with the hypothesis that genetic determinants of adult susceptibility to obesity act from early childhood and develop over the life course.
It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.
The standard approach in genome-wide association studies is to analyse the relationship between genetic variants and disease one marker at a time. Significant associations between markers and disease are then used as evidence to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically only explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates than single markers, and then use these scores to data mine genome-wide association studies. We show how allelic scores derived from known variants as well as allelic scores derived from hundreds of thousands of genetic markers across the genome explain significant portions of the variance in body mass index, levels of C-reactive protein, and LDLc cholesterol, and many of these scores show expected correlations with disease. Power calculations confirm the feasibility of scaling our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. Our method represents a simple way in which tens of thousands of molecular phenotypes could be screened for potential causal relationships with disease.
Background The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.
Methods We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual–participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.
Results For people born between 1900 and 1960, mean adult height increased 0.5–1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96–0.99) for death from any cause, 0.94 (0.93–0.96) for death from vascular causes, 1.04 (1.03–1.06) for death from cancer and 0.92 (0.90–0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12–1.42) for risk of melanoma death to 0.84 (0.80–0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.
Conclusion Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
Height; cardiovascular disease; cancer; cause-specific mortality; epidemiological study; meta-analysis
Pregnancy interventions to limit gestational weight gain (GWG) have been proposed as a means of preventing hypertensive disorders of pregnancy (HDP); however, it is currently unclear whether GWG has a causal influence on the development of HDP. Thus, we aimed to determine whether GWG in early pregnancy is a risk factor for preeclampsia and gestational hypertension and whether GWG precedes the increases in blood pressure in normotensive women across pregnancy.
We examined repeat antenatal clinic measurements of weight and blood pressure (median of 12 and 14 per woman, respectively) of 12,522 women in the Avon Longitudinal Study of Parents and Children.
Greater prepregnancy weight was associated with an increased risk of gestational hypertension and preeclampsia per 10 kg of prepregnancy weight: odds ratio (OR), 1.80; 95% confidence interval (CI), 1.70–1.91 and OR, 1.71; 95% CI, 1.49–1.95, respectively, for women weighing 90 kg or less before pregnancy; OR, 1.24; 95% CI, 1.03–1.49 and OR, 1.61; 95% CI, 1.18–2.19 for women weighing more than 90 kg. Fully adjusted odds ratios for gestational hypertension and preeclampsia per 200 g per week GWG up to 18 weeks were OR, 1.26; 95% CI, 1.16–1.38 and OR, 1.31; 95% CI, 1.07–1.62. In normotensive women, GWG in early pregnancy was associated positively with blood pressure change in midpregnancy and negatively with blood pressure change in late pregnancy. In all gestational periods, GWG was positively associated with concurrent blood pressure change. However, there was no evidence that blood pressure changes in any period were associated with subsequent GWG.
These findings suggest that GWG in early pregnancy may be a potential target for interventions aimed at reducing the risk of HDP.
Avon Longitudinal Study of Parents and Children; blood pressure; gestational weight gain; hypertensive disorder of pregnancy; preeclampsia
The long-term consequences of maternal physical activity during pregnancy for offspring cardiovascular health are unknown. We examined the association of maternal self-reported physical activity in pregnancy (18 weeks gestation) with offspring cardiovascular risk factors at age 15.
Prospective cohort study.
The Avon Longitudinal Study of Parents and Children (ALSPAC).
4665 maternal-offspring pairs (based on a sample with multiple imputation to deal with missing data) from the ALSPAC, a prospective cohort based in the South West of England with mothers recruited in pregnancy in 1991–1992.
Primary and secondary outcome measures
Offspring cardiovascular risk factors at age 15; body mass index (BMI), waist circumference, systolic blood pressure, diastolic blood pressure, glucose, insulin, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides.
Greater maternal physical activity was associated with lower BMI, waist circumference, glucose and insulin in unadjusted analyses. The magnitude of associations was generally small with wide CIs, and most associations attenuated towards the null after adjusting for confounders. The strongest evidence of association after adjustment for confounders was for glucose, although the 95% CI for this association includes the null; a one SD greater physical activity during pregnancy was associated with a −0.013 mmol/L difference in offspring glucose levels (equivalent to approximately one-third of a SD; 95% CI −0.027 to 0.001 mmol/L).
Our results suggest that maternal physical activity in pregnancy, measured at 18 weeks gestation, is unlikely to be an important determinant of later offspring cardiovascular health. There was some suggestion of association with offspring glucose, but given that all other associations (including insulin) were null after adjustment for confounders, this result should be interpreted with caution.
Paediatric cardiology < Paediatrics; Paediatrics; Epidemiology
The aim of this study was to investigate the association between maternal diabetes in pregnancy and offspring cognitive ability and also to assess whether the association was due to intrauterine mechanisms or shared familial characteristics.
We linked national registers and conducted a prospective cohort study of singleton Swedish-born men to explore associations between maternal pregnancy diabetes and educational achievement at age 16 years, the age of completing compulsory education in Sweden (n = 391,545 men from 337,174 families, graduating in 1988–1997 and n = 326,033 men from 282,079 families, graduating in 1998–2009), and intelligence quotient (IQ) at the mandatory conscription examination at 18 years of age (n = 664,871 from 543,203 families).
Among non-siblings, maternal diabetes in pregnancy was associated with lower offspring cognitive ability even after adjustment for maternal age at birth, parity, education, early-pregnancy BMI, offspring birth year, gestational age and birthweight. For example, in non-siblings, the IQ of men whose mothers had diabetes in their pregnancy was on average 1.36 points lower (95% CI −2.12, −0.60) than men whose mothers did not have diabetes. In comparison, we found no such association within sibships (mean difference 1.70; 95% CI −1.80, 5.21).
The association between maternal diabetes in pregnancy and offspring cognitive outcomes is likely explained by shared familial characteristics and not by an intrauterine mechanism.
Cognition; Diabetes; IQ; Pregnancy; Sibling comparison; Swedish registers
Given that the primordial ovarian follicular pool is established in utero, it may be influenced by parental characteristics and the intrauterine environment. Anti-Müllerian hormone (AMH) levels are increasingly recognized as a biomarker of ovarian reserve in females in adulthood and adolescence. We examined and compared associations of maternal and paternal prenatal exposures with AMH levels in adolescent (mean age, 15.4 years) female offspring (n = 1,399) using data from the Avon Longitudinal Study of Parents and Children, a United Kingdom birth cohort study that originated in 1991 and is still ongoing (data are from 1991–2008). The median AMH level was 3.67 ng/mL (interquartile range: 2.46–5.57). Paternal but not maternal smoking prior to and during pregnancy were inversely associated with AMH levels. No or irregular maternal menstrual cycles before pregnancy were associated with higher AMH levels in daughter during adolescence. High maternal gestational weight gain (top fifth versus the rest of the distribution) was associated with lower AMH levels in daughters. Parental age, body mass index, and alcohol intake during pregnancy, child's birth weight, and maternal parity and time to conception were not associated with daughters' AMH levels. Our results suggest that some parental preconceptual characteristics and environmental exposures while the child is in utero may influence the long-term ovarian development and function in female offspring.
anti-Müllerian hormone; maternal-paternal comparisons; prenatal risk factors
To investigate characteristics associated with wearing an accelerometer for the required and requested time among 8-year-old to 10-year-old children.
60 Bristol and North Somerset primary schools taking part in the ‘Active for Life Year 5’ randomised controlled trial (RCT) in 2011.
2048 children, aged 8–10 years, invited to wear an accelerometer for 5 days of recording.
Primary outcome measure
Numbers meeting required wear-time for inclusion in main RCT analysis (≥8 h/day ≥3 days) and numbers meeting requested wear-time (≥8 h/day for all 5 days).
817 (40%) of the children wore the accelerometer for the requested time and 1629 (80%) for the required time. In adjusted multivariable analyses the odds of wearing the accelerometer for the required time were greater in females as compared with males (OR 1.76 (1.42–2.18)), those with higher scores for reporting their mother restricted time on sedentary behaviours (1.26 (1.04–1.52) per increase of 1 on a 1–4 scale) and in children from schools with larger year group sizes (1.01 (1.00–1.02) per additional child). Living in a neighbourhood with higher levels of deprivation (0.49 (0.33–0.72) comparing highest to lowest third of the deprivation score) or reporting higher levels of weekday outdoor play (0.97 (0.94, 1.00) per 30 min more) were associated with reduced odds of meeting required time. Results were essentially the same for requested wear-time. Other characteristics, including child body mass index, were not associated with required or requested wear-time.
Only 40% of children wore the accelerometer for the requested time but 80% fulfilled the required criteria to be included in the main study analyses. Knowing which characteristics are associated with accelerometer wear could help target interventions to increase wear-time.
Epidemiology; Public Health; Sports MEdicine
Chronic kidney disease (CKD), the result of permanent loss of kidney function, is a major global problem. We identify common genetic variants at chr2p12-p13, chr6q26, chr17q23 and chr19q13 associated with serum creatinine, a marker of kidney function (P=10−10 to 10−15). SNPs rs10206899 (near NAT8, chr2p12-p13) and rs4805834 (near SLC7A9, chr19q13) were also associated with CKD. Our findings provide new insight into metabolic, solute and drug-transport pathways underlying susceptibility to CKD.
Substantial advances have been made in identifying common genetic variants influencing cardiometabolic traits and disease outcomes through genome wide association studies. Nevertheless, gaps in knowledge remain and new questions have arisen regarding the population relevance, mechanisms, and applications for healthcare. Using a new high-resolution custom single nucleotide polymorphism (SNP) array (Metabochip) incorporating dense coverage of genomic regions linked to cardiometabolic disease, the University College-London School-Edinburgh-Bristol (UCLEB) consortium of highly-phenotyped population-based prospective studies, aims to: (1) fine map functionally relevant SNPs; (2) precisely estimate individual absolute and population attributable risks based on individual SNPs and their combination; (3) investigate mechanisms leading to altered risk factor profiles and CVD events; and (4) use Mendelian randomisation to undertake studies of the causal role in CVD of a range of cardiovascular biomarkers to inform public health policy and help develop new preventative therapies.
The Active For Life Year 5 (AFLY5) randomised controlled trial protocol was published in this journal in 2011. It provided a summary analysis plan. This publication is an update of that protocol and provides a detailed analysis plan.
This update provides a detailed analysis plan of the effectiveness and cost-effectiveness of the AFLY5 intervention. The plan includes details of how variables will be quality control checked and the criteria used to define derived variables. Details of four key analyses are provided: (a) effectiveness analysis 1 (the effect of the AFLY5 intervention on primary and secondary outcomes at the end of the school year in which the intervention is delivered); (b) mediation analyses (secondary analyses examining the extent to which any effects of the intervention are mediated via self-efficacy, parental support and knowledge, through which the intervention is theoretically believed to act); (c) effectiveness analysis 2 (the effect of the AFLY5 intervention on primary and secondary outcomes 12 months after the end of the intervention) and (d) cost effectiveness analysis (the cost-effectiveness of the AFLY5 intervention). The details include how the intention to treat and per-protocol analyses were defined and planned sensitivity analyses for dealing with missing data. A set of dummy tables are provided in Additional file 1.
This detailed analysis plan was written prior to any analyst having access to any data and was approved by the AFLY5 Trial Steering Committee. Its publication will ensure that analyses are in accordance with an a priori plan related to the trial objectives and not driven by knowledge of the data.
Lower socioeconomic position is associated with shorter stature, in particular shorter leg length, but the magnitude of these associations in non-Western countries has received little attention.
To examine socioeconomic differentials in height, leg and trunk length in 6.5 year olds from the Republic of Belarus and compare these to differentials in parental height.
Multivariable linear regression was used to examine associations in a cohort of 13 889 children.
Children from non-manual households were 1.0 cm (95% confidence interval: 0.7–1.3 cm) taller than those from manual households. Mothers and fathers from non-manual backgrounds were 0.7 cm (0.5–0.8) and 1.8 cm (1.6–2.0) taller than those from manual backgrounds, respectively. Associations with higher parental educational attainment were similar. The magnitudes of the associations of socioeconomic position with leg length were similar to those with trunk length. Adjusting for mid-parental height and number of older siblings attenuated associations markedly.
In Belarus, similar socioeconomic differentials in height were observed in both children and their parents. Among children, height differentials were partly explained by mid-parental height and number of older siblings. Leg length was not a more sensitive indicator of childhood socioeconomic conditions than trunk length.
Height; leg length; trunk length; socioeconomic factors
In the present study, the authors investigated the role of the intrauterine environment in childhood adiposity by comparing the maternal-offspring body mass index (BMI) association with the paternal-offspring BMI association when the offspring were 3 years of age, using parental prepregnancy BMI (measured as weight in kilograms divided by height in meters squared). The parent-offspring trios (n = 29,216) were recruited during pregnancy from 2001 to 2008 into the Norwegian Mother and Child Cohort Study conducted by The Norwegian Institute of Public Health. Data from self-administered questionnaires were used in linear regression analyses. Crude analyses showed similar parental-offspring BMI associations; the mean difference in offspring BMI was 0.15 (95% confidence interval: 0.13, 0.16) per each 1-standard-deviation increase in maternal BMI and 0.15 (95% confidence interval: 0.13, 0.17) per each 1-standard-deviation increase in paternal BMI. After all adjustments, the mean difference in offspring BMI per each 1-standard-deviation increment of maternal BMI was 0.12, and the mean difference in offspring BMI per each 1-standard-deviation increment of paternal BMI was 0.13. There was no strong support for heterogeneity between the associations (P > 0.6). In conclusion, results from the present large population-based study showed similar parental-offspring BMI associations when the offspring were 3 years of age, which indicates that the maternal-offspring association may be explained by shared familial (environmental and genetic) risk factors rather than by the intrauterine environment.
adiposity; body mass index; child, preschool; fathers; infant; mothers; overweight; pregnancy
► Associations of exposures with mortality may be confounded by existing ill health. ► We used a son's height as an instrument for parents’ height to avoid confounding. ► Parents of taller sons had lower cardiovascular and respiratory disease mortality. ► Parents of taller sons had higher mortality from cancer. ► Previous studies of height are not substantially confounded by existing ill health.
Height is associated with mortality from many diseases, but it remains unclear whether the association is causal or due to confounding by social factors, genetic pleiotropy,1 or existing ill-health. The authors investigated whether the association of height with mortality is causal by using a son's height as an instrumental variable (IV) for parents’ height among the parents of a cohort of 1,036,963 Swedish men born between 1951 and 1980 who had their height measured at military conscription, aged around 18, between 1969 and 2001. In a two-sample IV analysis adjusting for son's age at examination and secular trends in height, as well as parental age, and socioeconomic position, the hazard ratio (HR) for all-cause paternal mortality per standard deviation (SD, 6.49 cm) of height was 0.96 (95% confidence interval (CI): 0.95, 0.96). The results of IV analyses of mortality from all causes, cardiovascular disease (CVD), respiratory disease, cancer, external causes and suicide were comparable to those obtained using son's height as a simple proxy for own height and to conventional analyses of own height in the present data and elsewhere, suggesting that such conventional analyses are not substantially confounded by existing ill-health.
IV, instrumental variable; HR, hazard ratio; SD, standard deviation; CI, confidence interval; CVD, cardiovascular disease; BMI, body mass index; SEP, socioeconomic position; CHD, coronary heart disease; Body height; Mortality; Confounding factor; Causality; Cohort studies
Maternal vitamin D status in pregnancy is a suggested determinant of bone-mineral content (BMC) in offspring, but has been assessed in small studies. We investigated this association in a large prospective study.
Eligible participants were mother-and-singleton-offspring pairs who had participated in the Avon Longitudinal Study of Parents and Children, and in which the mother had recorded measurements of 25(OH)D concentration in pregnancy and the offspring had undergone dual-energy x-ray absorptiometry at age 9–10 years. 25(OH)D concentrations in pregnancy were assessed per 10·0 nmol/L and classified as sufficient (more than 50·00 nmol/L), insufficient (49·99–27·50 nmol/L), or deficient (lower than 27·50 nmol/L). Associations between maternal serum 25(OH)D concentrations and offspring total body less head (TBLH) and spinal BMC were assessed by trimester.
3960 mother-and-offspring pairs, mainly of white European origin, were assessed (TBLH BMC n=3960, spinal BMC n=3196). Mean offspring age was 9·9 years. 2644 (67%) mothers had sufficient, 1096 (28%) insufficient, and 220 (6%) deficient 25(OH)D concentrations in pregnancy, but TBLH and spinal BMC did not differ between offspring of mothers in the lower two groups versus sufficient 25(OH)D concentration. No associations with offspring BMC were found for any trimester, including the third trimester, which is thought to be most relevant (TBLH BMC confounder-adjusted mean difference −0·03 g per 10·0 nmol/L, 95% CI −1·71 to 1·65; spinal BMC 0·04 g per 10·0 nmol/L, 95% CI −0·12 to 0·21).
We found no relevant association between maternal vitamin D status in pregnancy and offspring BMC in late childhood.
UK Medical Research Council, Wellcome Trust, and University of Bristol.
Epidemiological evidence for associations of Anti-Müllerian hormone (AMH) with cardiometabolic risk factors is lacking. Existing evidence comes from small studies in select adult populations, and findings are conflicting. We aimed to assess whether AMH is associated with cardiometabolic risk factors in a general population of adolescent females.
AMH, fasting insulin, glucose, HDLc, LDLc, triglycerides and C-reactive protein (CRP) were measured at a mean age 15.5 years in 1,308 female participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Multivariable linear regression was used to examine associations of AMH with these cardiometabolic outcomes.
AMH values ranged from 0.16–35.84 ng/ml and median AMH was 3.57 ng/ml (IQR: 2.41, 5.49). For females classified as post-pubertal (n = 848) at the time of assessment median (IQR) AMH was 3.81 ng/ml (2.55, 5.82) compared with 3.25 ng/ml (2.23, 5.05) in those classed as early pubertal (n = 460, P≤0.001). After adjusting for birth weight, gestational age, pubertal stage, age, ethnicity, socioeconomic position, adiposity and use of hormonal contraceptives, there were no associations with any of the cardiometabolic outcomes. For example fasting insulin changed by 0% per doubling of AMH (95%CI: −3%,+2%) p = 0.70, with identical results if HOMA-IR was used. Results were similar after additional adjustment for smoking, physical activity and age at menarche, after exclusion of 3% of females with the highest AMH values, after excluding those that had not started menarche and after excluding those using hormonal contraceptives.
Our results suggest that in healthy adolescent females, AMH is not associated with cardiometabolic risk factors.
To determine whether facial morphology is associated with fasting insulin, glucose and lipids independent of body mass index (BMI) in adolescents.
Population-based cross-sectional study.
Avon Longitudinal Study of Parents and Children (ALSPAC), South West of England.
From the ALSPAC database of 4747 three-dimensional facial laser scans, collected during a follow-up clinic at the age of 15, 2348 white British adolescents (1127 males and 1221 females) were selected on the basis of complete data on cardiometabolic parameters, BMI and Tanner's pubertal stage.
Main outcome measures
Fasting insulin, glucose and lipids (triglycerides, high-density lipoprotein cholesterol (HDLc) and low-density lipoprotein cholesterol (LDLc)).
On the basis of the collection of 63 x, y and z coordinates of 21 anthropometric landmarks, 14 facial principal components (PCs) were identified. These components explained 82% of the variation in facial morphology and were used as exposure variables. With adjustment for age, gender and pubertal stage, seven PCs were associated with fasting insulin, none with glucose, three with triglycerides, three with HDLc and four with LDLc. After additional adjustment for BMI, four PCs remained associated with fasting insulin, one with triglycerides and two with LDLc. None of these associations withstood adjustment for multiple comparisons.
These initial hypotheses generating analyses provide no evidence that facial morphology is importantly related to cardiometabolic outcomes. Further examination might be warranted. Facial morphology assessment may have value in identifying other areas of disease risk.
Epidemiology; Preventive Medicine; Statistics & Research Methods
Obesity is now a leading cause of preventable death in the industrialised world. Understanding its genetic influences can enhance insight into molecular pathogenesis and potential therapeutic targets. A non-synonymous polymorphism (rs35859249, p.Arg125Trp) in the N-terminal TBC1D1 phosphotyrosine-binding (PTB) domain has shown a replicated association with familial obesity in women. We investigated these findings in the Avon Longitudinal Study of Parents and Children (ALSPAC), a large European birth cohort of mothers and offspring, and by generating a predicted model of the structure of this domain. Structural prediction involved the use of three separate algorithms; Robetta, HHpred/MODELLER and I-TASSER. We used the transmission disequilibrium test (TDT) to investigate familial association in the ALSPAC study cohort (N = 2,292 mother-offspring pairs). Linear regression models were used to examine the association of genotype with mean measurements of adiposity (Body Mass Index (BMI), waist circumference and Dual-energy X-ray absorptiometry (DXA) assessed fat mass), and logistic regression was used to examine the association with odds of obesity. Modelling showed that the R125W mutation occurs in a location of the TBC1D1 PTB domain that is predicted to have a function in a putative protein:protein interaction. We did not detect an association between R125W and BMI (mean per allele difference 0.27 kg/m2 (95% Confidence Interval: 0.00, 0.53) P = 0.05) or obesity (odds ratio 1.01 (95% Confidence Interval: 0.77, 1.31, P = 0.96) in offspring after adjusting for multiple comparisons. Furthermore, there was no evidence to suggest that there was familial association between R125W and obesity (χ2 = 0.06, P = 0.80). Our analysis suggests that R125W in TBC1D1 plays a role in the binding of an effector protein, but we find no evidence that the R125W variant is related to mean BMI or odds of obesity in a general population sample.
Alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT) are widely used markers of liver disease. Several population-based cohort studies have found associations of these liver enzymes with all-cause mortality. None of these studies controlled for genetic variation as well as fetal and early life exposure, whether environmental or genetic.
We studied the associations of ALT and GGT with all-cause mortality using data for 686 twins (73–94 years old) included in the Longitudinal Study of Aging Danish Twins.
An increase in 1 logged U/L of GGT was associated with a 15% increase in the hazard ratio (HR) for mortality [95% confidence interval (CI) 0.99, 1.32] but there was no strong evidence of an association of ALT with all-cause mortality (HR = 1.07, 95% CI 0.82, 1.40) when controlling for potential confounders. In this analysis, the study population was treated as individuals, with similarities between twins accounted for by using robust standard errors. However, an intrapair analysis in which the proportion of twin pairs in which the twin with the higher level of ALT or GGT died first was compared with 50% (expected under the null hypothesis), found no strong evidence that higher ALT or GGT was associated with earlier death within twin pairs; the results were consistent in both monozygotic and dizygotic twins.
γ-glutamyltransferase but not ALT predicts mortality among older Danish twins when using traditional methods for controlling for potential confounders and existing diabetes and cardiovascular disease. Environmental developmental origins may explain the association, but larger twin studies are required to replicate our findings.
alanine aminotransferase; γ glutamyltransferase; mortality; twin studies
To explore associations of maternal prenatal smoking and child psychological problems and determine the role of causal intrauterine mechanisms.
Patients and Methods
Maternal smoking and child psychological problems were explored in 2 birth cohorts in Pelotas, Brazil (n=509; random sub-sample) and Avon Longitudinal Study of Parents and Children (ALSPAC), Britain (n=6,735). Four approaches for exploring causal mechanisms were applied: 1) cross-population comparisons between a high-income and a middle-income country, 2) multiple adjustment for socioeconomic and parental psychological factors, 3) maternal-paternal comparisons as a test of putative intrauterine effects; and 4) search for specific effects on different behavioural subscales.
Socioeconomic patterning of maternal prenatal smoking was stronger in the ALSPAC compared with the Pelotas cohort. Despite this difference in a key confounder, consistency in observed associations was found between these cohorts. In both cohorts, unadjusted, maternal smoking was associated with greater offspring hyperactivity, conduct/externalizing problems, and peer problems, but not with emotional/internalizing problems. After adjusting for confounders and paternal prenatal smoking, only the association with conduct/externalizing problems persisted in both cohorts (conduct problems in the ALSPAC cohort, odds ratio OR: 1.24 [95% confidence interval (CI): 1.07–1.46], p= .005; externalizing problems in the Pelotas cohort, OR:1.82 [95% CI:1.19–2.78], p=.005; ORs reflect ordinal ORs of maternal smokers having offspring with higher scores). Maternal smoking associations were stronger than paternal smoking associations, although statistical evidence for differences was weak in 1 cohort.
Evidence from 4 approaches suggests a possible intrauterine effect of maternal smoking on offspring conduct/externalizing problems.
ALSPAC; Pelotas; prenatal smoking; child; behavioral problems; developmental origins