Age at birth of first child and coronary heart disease risk factors at age 53 years in men and women: British birth cohort study

OBJECTIVE: To assess the associations between parental age at birth of first child and coronary heart disease (CHD) risk factors in men and women. To investigate whether the associations are explained by childhood predictors of age at parenthood or adult lifestyle factors related to child rearing. METHODS: Data from 2540 men and women, with CHD risk factors measured at age 53 years, from a birth cohort study of individuals born in Britain in 1946 (Medical Research Council National Survey of Health and Development) and followed up regularly throughout life, were analysed. RESULTS: Younger age at birth of first child in both men and women was associated with poorer mean body mass index (BMI), waist-hip ratio, blood pressure (BP), high-density lipoprotein cholesterol, triglyceride and glycated haemoglobin levels. Mean BMI decreased from 28.0 kg/m(2) (95% CI 27.2 to 28.8) in the teenage motherhood group to 26.8 kg/m(2) (25.9 to 27.7) in the oldest motherhood group (> or =30 years). For men, the equivalent mean values were 28.5 kg/m(2) (27.3 to 29.8) and 27.1 kg/m(2) (26.7 to 27.6). Associations with adiposity, lipid measures and glycated haemoglobin were largely explained by childhood antecedents and adult social and lifestyle variables. Associations with BP remained robust to adjustment: systolic blood pressure remained highest in teenage parents (7.5 mmHg (1.0 to 13.9) difference in women and 8.6 mmHg (0.4 to 16.8) difference in men between the youngest and the oldest parenthood groups) CONCLUSIONS: Lifestyle factors, rather than the biological impact of pregnancy, explain the relationship between age at motherhood and CHD risk factors. Family-based lifestyle interventions targeted at young parents may improve their future CHD risk

Maternal thyroid function and child educational attainment: prospective cohort study

Objective: To determine if first trimester maternal thyroid dysfunction is a critical determinant of child scholastic performance and overall educational attainment. Design: Prospective cohort study. Setting: Avon Longitudinal Study of Parents and Children cohort in the UK. Participants: 4615 mother-child pairs with an available first trimester sample (median 10 weeks gestation, interquartile range 8-12). Exposures: Free thyroxine, thyroid stimulating hormone, and thyroid peroxidase antibodies assessed as continuous measures and the seven clinical categories of maternal thyroid function. Main outcome measures: Five age-specific national curriculum assessments in 3580 children at entry stage assessment at 54 months, increasing up to 4461 children at their final school assessment at age 15. Results: No strong evidence of clinically meaningful associations of first trimester free thyroxine and thyroid stimulating hormone levels with entry stage assessment score or Standard Assessment Test scores at any of the key stages was found. Associations of maternal free thyroxine or thyroid stimulating hormone with the total number of General Certificates of Secondary Education (GCSEs) passed (range 0-16) were all close to the null: free thyroxine, rate ratio per pmol/L 1.00 (95% confidence interval 1.00 to 1.01); and thyroid stimulating hormone, rate ratio 0.98 (0.94 to 1.02). No important relationship was observed when more detailed capped scores of GCSEs allowing for both the number and grade of pass or when language, mathematics, and science performance were examined individually or when all educational assessments undertaken by an individual from school entry to leaving were considered. 200 (4.3%) mothers were newly identified as having hypothyroidism or subclinical hypothyroidism and 97 (2.1%) subclinical hyperthyroidism or hyperthyroidism. Children of mothers with thyroid dysfunction attained an equivalent number of GCSEs and equivalent grades as children of mothers with euthyroidism. Conclusions: Maternal thyroid dysfunction in early pregnancy does not have a clinically important association with impaired child performance at school or educational achievement

Behavioural early-life exposures and body composition at age 15 years

BACKGROUND/OBJECTIVES: Previous studies have demonstrated associations between some early-life exposures and later obesity, but most have used body mass index in childhood or adulthood as the outcome. The objective of this study was to investigate whether early-life exposures were associated with directly measured fat and lean mass in adolescence. SUBJECTS/METHODS: This study used data on 4750 mother–offspring pairs, collected as a part of the Avon Longitudinal Study of Parents and Children, Bristol, UK between 1991 and 1992; associations between behavioural exposures occurring from conception up to 5 years of age (maternal and paternal smoking during pregnancy, breastfeeding, age at introduction to solids, dietary patterns and physical inactivity during early childhood) and offspring body composition measured by dual-energy X-ray absorptiometry at ~ 15 years were assessed. RESULTS: After full adjustment for potential confounders, maternal smoking during pregnancy, having a junk food diet and spending more time watching television in early childhood were all associated with higher fat mass at age 15, whereas maternal smoking, having a healthy diet and playing computer games more frequently in early childhood were all associated with a higher lean mass at age 15. Associations with paternal smoking were generally weaker for both fat and lean mass, but as there was no strong statistical evidence for maternal vs paternal differences, confounding by social factors rather than a direct effect of maternal smoking cannot be ruled out. Early feeding was not associated with fat or lean mass at age 15. CONCLUSIONS: This study does not provide compelling evidence for associations between most early-life factors and body composition in adolescence. However, possible associations with dietary patterns and physical inactivity in early childhood require further investigation in other cohorts that have direct measurements of adolescent body composition.SD Leary, DA Lawlor, G Davey Smith, MJ Brion and AR Nes

Complexity of a complex trait locus: HP, HPR, haemoglobin and cholesterol

HP and HPR are related and contiguous genes in strong linkage disequilibrium (LD), encoding haptoglobin and haptoglobin-related protein. These bind and chaperone free Hb for recycling, protecting against oxidation. A copy number variation (CNV) within HP (Hp1/Hp2) results in different possible haptoglobin complexes which have differing properties. HPR rs2000999 (G/A), identified in meta-GWAS, influences total cholesterol (TC) and LDL-cholesterol (LDL-C). We examined the relationship between HP CNV, HPR rs2000999, Hb, red cell count (RCC), LDL-C and TC in the British Women's Heart and Health Study (n=2779 for samples having CNV, rs2000999, and phenotypes). Analysing single markers by linear regression, rs2000999 was associated with LDL-C (β=0.040 mmol/L, p=0.023), TC (β=-0.040 mmol/L, p=0.019), Hb (β=-0.044 g/dL, p=0.028) and borderline with RCC (β=-0.032 × 10(12)/L, p=0.066). Analysis of CNV by linear regression revealed an association with Hb (Hp1 vs Hp2, β=0.057 g/dL, p=0.004), RCC (β=0.045 × 10(12)/L, p=0.014), and showed a trend with LDL-C and TC. There were 3 principal haplotypes (Hp1-G 36%; Hp2-G 45%; Hp2-A 18%). Haplotype comparisons showed that LDL-C and TC associations were from rs2000999; Hb and RCC associations derived largely from the CNV. Distinct genotype-phenotype effects are evident at the genetic epidemiological level once LD has been analysed, perhaps reflecting HP-HPR functional biology and evolutionary history. The derived Hp2 allele of the HP gene has apparently been subject to malaria-driven positive selection. Haptoglobin-related protein binds Hb and apolipoprotein-L, i.e. linking HPR to the cholesterol system; and the HPR/apo-L complex is specifically trypanolytic. Our analysis illustrates the complex interplay between functions and haplotypes of adjacent genes, environmental context and natural selection, and offers insights into potential use of haptoglobin or haptoglobin-related protein as therapeutic agents.Philip A.I. Guthrie, Santiago Rodriguez, Tom R. Gaunt, Debbie A. Lawlor George Davey Smith, Ian N.M. Da

Descending aortic calcification increases renal dysfunction and in-hospital mortality in cardiac surgery patients with intraaortic balloon pump counterpulsation placed perioperatively : a case control study

Introduction: Acute kidney injury (AKI) after cardiac surgery increases length of hospital stay and in-hospital mortality. A significant number of patients undergoing cardiac surgical procedures require perioperative intra-aortic balloon pump (IABP) support. Use of an IABP has been linked to an increased incidence of perioperative renal dysfunction and death. This might be due to dislodgement of atherosclerotic material in the descending thoracic aorta (DTA). Therefore, we retrospectively studied the correlation between DTA atheroma, AKI and in-hospital mortality. Methods: A total of 454 patients were retrospectively matched to one of four groups: -IABP/-DTA atheroma, +IABP/-DTA atheroma, -IABP/+DTA atheroma, +IABP/+DTA atheroma. Patients were then matched according to presence/absence of DTA atheroma, presence/absence of IABP, performed surgical procedure, age, gender and left ventricular ejection fraction (LVEF). DTA atheroma was assessed through standard transesophageal echocardiography (TEE) imaging studies of the descending thoracic aorta. Results: Basic patient characteristics, except for age and gender, did not differ between groups. Perioperative AKI in patients with -DTA atheroma/+IABP was 5.1% versus 1.7% in patients with -DTA atheroma/-IABP. In patients with +DTA atheroma/+IABP the incidence of AKI was 12.6% versus 5.1% in patients with +DTA atheroma/-IABP. In-hospital mortality in patients with +DTA atheroma/-IABP was 3.4% versus 8.4% with +DTA atheroma/+IABP. In patients with +DTA atheroma/+IABP in hospital mortality was 20.2% versus 6.4% with +DTA atheroma/-IABP. Multivariate logistic regression identified DTA atheroma > 1 mm (P = *0.002, odds ratio (OR) = 4.13, confidence interval (CI) = 1.66 to 10.30), as well as IABP support (P = *0.015, OR = 3.04, CI = 1.24 to 7.45) as independent predictors of perioperative AKI and increased in-hospital mortality. DTA atheroma in conjunction with IABP significantly increased the risk of developing acute kidney injury (P = 0.0016) and in-hospital mortality (P = 0.0001) when compared to control subjects without IABP and without DTA atheroma. Conclusions: Perioperative IABP and DTA atheroma are independent predictors of perioperative AKI and in-hospital mortality. Whether adding an IABP in patients with severe DTA calcification increases their risk of developing AKI and mortality postoperatively cannot be clearly answered in this study. Nevertheless, when IABP and DTA are combined, patients are more likely to develop AKI and to die postoperatively in comparison to patients without IABP and DTA atheroma

Hyperglycaemia and risk of adverse perinatal outcomes: Systematic review and meta-analysis

Objectives: To assess the association between maternal glucose concentrations and adverse perinatal outcomes in women without gestational or existing diabetes and to determine whether clear thresholds for identifying women at risk of perinatal outcomes can be identified. Design: Systematic review and meta-analysis of prospective cohort studies and control arms of randomised trials. Data sources: Databases including Medline and Embase were searched up to October 2014 and combined with individual participant data from two additional birth cohorts. Eligibility criteria for selecting studies: Studies including pregnant women with oral glucose tolerance (OGTT) or challenge (OGCT) test results, with data on at least one adverse perinatal outcome. Appraisal and data extraction: Glucose test results were extracted for OGCT (50 g) and OGTT (75 g and 100 g) at fasting and one and two hour post-load timings. Data were extracted on induction of labour; caesarean and instrumental delivery; pregnancy induced hypertension; pre-eclampsia; macrosomia; large for gestational age; preterm birth; birth injury; and neonatal hypoglycaemia. Risk of bias was assessed with a modified version of the critical appraisal skills programme and quality in prognostic studies tools. Results: 25 reports from 23 published studies and two individual participant data cohorts were included, with up to 207 172 women (numbers varied by the test and outcome analysed in the meta-analyses). Overall most studies were judged as having a low risk of bias. There were positive linear associations with caesarean section, induction of labour, large for gestational age, macrosomia, and shoulder dystocia for all glucose exposures across the distribution of glucose concentrations. There was no clear evidence of a threshold effect. In general, associations were stronger for fasting concentration than for post-load concentration. For example, the odds ratios for large for gestational age per 1 mmol/L increase of fasting and two hour post-load glucose concentrations (after a 75 g OGTT) were 2.15 (95% confidence interval 1.60 to 2.91) and 1.20 (1.13 to 1.28), respectively. Heterogeneity was low between studies in all analyses. Conclusions: This review and meta-analysis identified a large number of studies in various countries. There was a graded linear association between fasting and post-load glucose concentration across the whole glucose distribution and most adverse perinatal outcomes in women without pre-existing or gestational diabetes. The lack of a clear threshold at which risk increases means that decisions regarding thresholds for diagnosing gestational diabetes are somewhat arbitrary. Research should now investigate the clinical and cost-effectiveness of applying different glucose thresholds for diagnosis of gestational diabetes on perinatal and longer term outcomes

Genetic markers as instrumental variables: an application to child fat mass and academic achievement

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Cohort profile: the avon longitudinal study of parents and children: ALSPAC mothers cohort

The Avon Longitudinal Study of Children and Parents (ALSPAC) was established to understand how genetic and environmental characteristics influence health and development in parents and children. All pregnant women resident in a defined area in the South West of England, with an expected date of delivery between 1st April 1991 and 31st December 1992, were eligible and 13 761 women (contributing 13 867 pregnancies) were recruited. These women have been followed over the last 19–22 years and have completed up to 20 questionnaires, have had detailed data abstracted from their medical records and have information on any cancer diagnoses and deaths through record linkage. A follow-up assessment was completed 17–18 years postnatal at which anthropometry, blood pressure, fat, lean and bone mass and carotid intima media thickness were assessed, and a fasting blood sample taken. The second follow-up clinic, which additionally measures cognitive function, physical capability, physical activity (with accelerometer) and wrist bone architecture, is underway and two further assessments with similar measurements will take place over the next 5 years. There is a detailed biobank that includes DNA, with genome-wide data available on >10 000, stored serum and plasma taken repeatedly since pregnancy and other samples; a wide range of data on completed biospecimen assays are available. Details of how to access these data are provided in this cohort profile

Studies of Caenorhabditis elegans DAF-2/insulin signaling reveal targets for pharmacological manipulation of lifespan

Much excitement has arisen from the observation that decrements in insulin-like signaling can dramatically extend lifespan in the nematode, Caenorhabditis elegans, and fruitfly, Drosophila melanogaster. In addition, there are tantalizing hints that the IGF-I pathway in mice may have similar effects. In addition to dramatic effects on lifespan, invertebrate insulin-like signaling also promotes changes in stress resistance, metabolism and development. Which, if any, of the various phenotypes of insulin pathway mutants are relevant to longevity? What are the genes that function in collaboration with insulin to prolong lifespan? These questions are at the heart of current research in C. elegans longevity. Two main theories exist as to the mechanism behind insulin's effects on invertebrate longevity. One theory is that insulin programs metabolic parameters that prolong or reduce lifespan. The other theory is that insulin determines the cell's ability to endure oxidative stress from respiration, thereby determining the rate of aging. However, these mechanisms are not mutually exclusive and several studies seem to support a role for both. Here, we review recently published reports investigating the mechanisms behind insulin's dramatic effect on longevity. We also spotlight several C. elegans genes that are now known to interact with insulin signaling to determine lifespan. These insights into pathways affecting invertebrate lifespan may provide a basis for developing strategies for pharmacological manipulation of human lifespan