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1.  Is there an intrauterine influence on obesity? Evidence from parent–child associations in the Avon Longitudinal Study of Parents and Children (ALSPAC) 
Archives of Disease in Childhood  2007;92(10):876-880.
Background
It has been suggested that increasing obesity levels in young women lead to intrauterine environments that, in turn, stimulate increased obesity among their offspring, generating an intergenerational acceleration of obesity levels. If this mechanism is important, the association of maternal body mass index (BMI) with offspring BMI should be stronger than the association of paternal with offspring BMI.
Objective
To compare the relative strengths of association of maternal and paternal BMI with offspring BMI at age 7.5, taking into account the possible effect of non‐paternity.
Methods
We compared strength of association for maternal–offspring and paternal–offspring BMI for 4654 complete parent–offspring trios in the Avon Longitudinal Study of Parents and Children (ALSPAC), using unstandardised and standardised regression analysis. We carried out a sensitivity analysis to investigate the influence of non‐paternity on these associations.
Results
The strength of association between parental BMI and offspring BMI at age 7.5 was similar for both parents. Taking into account correlations between maternal and paternal BMI, performing standardised rather than unstandardised regression and carrying out a sensitivity analysis for non‐paternity emphasised the robustness of the general similarity of the associations. The associations between high parental BMI (top decile) and offspring BMI are also similar for both parents.
Conclusion
Comparison of mother–offspring and father–offspring associations for BMI suggests that intergenerational acceleration mechanisms do not make an important contribution to levels of childhood BMI within the population. Associations at later ages and for different components of body composition now require study.
doi:10.1136/adc.2006.104869
PMCID: PMC2083247  PMID: 17595200
2.  Is chronic fatigue syndrome (CFS/ME) heritable in children, and if so, why does it matter? 
Archives of Disease in Childhood  2007;92(12):1058-1061.
We need a clear definition of CFS/ME in children and sample sizes for genetic studies need to be much larger
doi:10.1136/adc.2006.110502
PMCID: PMC2066085  PMID: 17804594
3.  Childhood and adulthood socioeconomic position across 20 causes of death: a prospective cohort study of 800 000 Norwegian men and women 
Objective
To assess the impact of childhood and adulthood socioeconomic position (SEP) across 20 causes of death in a large population‐wide sample of Norwegian men and women.
Methods
Census data on parental occupational class from 1960 and data from the tax register on household income in 1990 were linked to the death register for 1990–2001, and 20 causes of death were studied. Relative indices of inequalities were computed. Norwegians in the age group 0–20 years in 1960 and still alive in 1990 were followed for deaths in 1990 to 2001. This follow up involved 795 324 individuals (78%) and 20 887 deaths.
Main results
In men most support for an effect of childhood socioeconomic position was found for stomach cancer, lung cancer, coronary heart disease, “other violent death”, and all causes of death. In women similar effects were found for lung cancer, cervical cancer, coronary heart disease, chronic obstructive pulmonary disease, and all causes of death.
Conclusions
The effect of childhood socioeconomic position relative to adulthood varies by cause of death. Although there are some exceptions, the patterns in men and women are generally similar.
doi:10.1136/jech.2006.052811
PMCID: PMC2465604  PMID: 17933960
life course epidemiology; social inequality; cause‐specific mortality
4.  Associations between tooth loss and mortality patterns in the Glasgow Alumni Cohort 
Heart  2006;93(9):1098-1103.
Objective
To use data from the Glasgow Alumni Cohort to investigate whether oral health in young adulthood is independently associated with later life cardiovascular disease (CVD) and cancer mortality.
Methods and results
Of the original cohort (n = 15 322), 12 631 subjects were traced through the National Health Service Central Register. Of these, 9569 men and 2654 women were 30 years or younger at baseline. During up to 57 years of follow‐up, 1432 deaths occurred among subjects with complete data, including 509 deaths from CVD and 549 from cancer. After adjusting for potential confounders, no substantial association was found between the number of missing teeth (as a continuous variable) and all‐cause mortality (hazard ratio (HR) for each extra missing tooth  = 1.01; 95% confidence interval (CI) 1.00 to 1.02), CVD mortality (HR = 1.01; 95% CI 0.99 to 1.03) or cancer mortality (HR = 1.00; 95% CI 0.98 to 1.02). When the number of missing teeth was treated as a categorical variable, there was evidence that students with nine or more missing teeth at baseline had an increased risk of CVD (HR = 1.35; 95% CI 1.03 to 1.77) compared with those with fewer than five missing teeth. When the number of missing teeth was transformed using fractional polynomials, there seemed to be a non‐linear relation between missing teeth and CVD mortality.
Conclusions
Although some evidence was found to support the relation between tooth loss and CVD mortality, causal mechanisms underlying this association remain uncertain.
doi:10.1136/hrt.2006.097410
PMCID: PMC1955024  PMID: 17164486
tooth loss; cardiovascular diseases; stroke; coronary heart diseases; mortality
6.  Does consideration of either psychological or material disadvantage improve coronary risk prediction? Prospective observational study of Scottish men 
Objective
To assess the value of psychosocial risk factors in discriminating between individuals at higher and lower risk of coronary heart disease, using risk prediction equations.
Design
Prospective observational study.
Setting
Scotland.
Participants
5191 employed men aged 35 to 64 years and free of coronary heart disease at study enrolment
Main outcome measures
Area under receiver operating characteristic (ROC) curves for risk prediction equations including different risk factors for coronary heart disease.
Results
During the first 10 years of follow up, 203 men died of coronary heart disease and a further 200 were admitted to hospital with this diagnosis. Area under the ROC curve for the standard Framingham coronary risk factors was 74.5%. Addition of “vital exhaustion” and psychological stress led to areas under the ROC curve of 74.5% and 74.6%, respectively. Addition of current social class and lifetime social class to the standard Framingham equation gave areas under the ROC curve of 74.6% and 74.9%, respectively. In no case was there strong evidence for improved discrimination of the model containing the novel risk factor over the standard model.
Conclusions
Consideration of psychosocial risk factors, including those that are strong independent predictors of heart disease, does not substantially influence the ability of risk prediction tools to discriminate between individuals at higher and lower risk of coronary heart disease.
doi:10.1136/jech.2006.055921
PMCID: PMC2660009  PMID: 17699540
cardiovascular disease; risk assessment; Framingham risk score; primary prevention; psychosocial factors
7.  Influence of common genetic variation on blood lipid levels, cardiovascular risk, and coronary events in two British prospective cohort studies 
European Heart Journal  2012;34(13):972-981.
Aims
The aim of this study was to quantify the collective effect of common lipid-associated single nucleotide polymorphisms (SNPs) on blood lipid levels, cardiovascular risk, use of lipid-lowering medication, and risk of coronary heart disease (CHD) events.
Methods and results
Analysis was performed in two prospective cohorts: Whitehall II (WHII; N = 5059) and the British Women’s Heart and Health Study (BWHHS; N = 3414). For each participant, scores were calculated based on the cumulative effect of multiple genetic variants influencing total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Compared with the bottom quintile, individuals in the top quintile of the LDL-C genetic score distribution had higher LDL-C {mean difference of 0.85 [95% confidence interval, (CI) = 0.76–0.94] and 0.63 [95% CI = 0.50–0.76] mmol/l in WHII and BWHHS, respectively}. They also tended to have greater odds of having ‘high-risk’ status (Framingham 10-year cardiovascular disease risk >20%) [WHII: odds ratio (OR) = 1.36 (0.93–1.98), BWHHS: OR = 1.49 (1.14–1.94)]; receiving lipid-lowering treatment [WHII: OR = 2.38 (1.57–3.59), BWHHS: OR = 2.24 (1.52–3.29)]; and CHD events [WHII: OR = 1.43 (1.02–2.00), BWHHS: OR = 1.31 (0.99–1.72)]. Similar associations were observed for the TC score in both studies. The TG score was associated with high-risk status and medication use in both studies. Neither HDL nor TG scores were associated with the risk of coronary events. The genetic scores did not improve discrimination over the Framingham risk score.
Conclusion
At the population level, common SNPs associated with LDL-C and TC contribute to blood lipid variation, cardiovascular risk, use of lipid-lowering medications and coronary events. However, their effects are too small to discriminate future lipid-lowering medication requirements or coronary events.
doi:10.1093/eurheartj/ehs243
PMCID: PMC3612774  PMID: 22977227
Lipid genetic score; Lipid medication; Framingham
8.  Use of Folic Acid Supplements in Early Pregnancy in Relation to Maternal Plasma Levels in Week 18 of Pregnancy 
Molecular nutrition & food research  2012;57(4):10.1002/mnfr.201200116.
We compared plasma-folate at week 18 of gestation with self-reported use of supplements containing folic acid from before pregnancy to 17 weeks gestation. Birth cohorts typically measure plasma-folate in mid-gestation, but effects of folic acid supplementation are sometimes specific to the periconceptional period. The relationship between mid-gestation plasma-folate and periconceptional supplementation is not known.
The sample comprised 2911 women from The Norwegian Mother and Child Cohort Study. For women reporting continuous supplementation from gestational week -4-17 (N=238), median plasma-folate was 15.72 at week 18 (in nmol/L). This was about threefold higher than the median plasma-folate of 5.67 for women reporting no supplementation from week -4-17 (N=844), but only slightly higher than the median plasma-folate of 13.34 for all women reporting supplementation in week 13-17 (N=1158). Reported supplementation before week 8 was not associated with plasma-folate at week 18, in an analysis that adjusted for continued supplementation after week 8.
Overall we found a strong and coherent relationship between self-reported folic acid use and plasma-folate at week 18. We also found that plasma-folate at week 18 did not reflect self-reported supplementation before 8 weeks. For periconceptional supplementation per se, self-report data may offer a better measure.
doi:10.1002/mnfr.201200116
PMCID: PMC3882014  PMID: 23065724
Folic acid; maternal report; periconceptional; plasma; pregnancy cohort
9.  Prenatal nutrition, epigenetics and schizophrenia risk: can we test causal effects? 
Epigenomics  2012;4(3):303-315.
We posit that maternal prenatal nutrition can influence offspring schizophrenia risk via epigenetic effects. In this article, we consider evidence that prenatal nutrition is linked to epigenetic outcomes in offspring and schizophrenia in offspring, and that schizophrenia is associated with epigenetic changes. We focus upon one-carbon metabolism as a mediator of the pathway between perturbed prenatal nutrition and the subsequent risk of schizophrenia. Although post-mortem human studies demonstrate DNA methylation changes in brains of people with schizophrenia, such studies cannot establish causality. We suggest a testable hypothesis that utilizes a novel two-step Mendelian randomization approach, to test the component parts of the proposed causal pathway leading from prenatal nutritional exposure to schizophrenia. Applied here to a specific example, such an approach is applicable for wider use to strengthen causal inference of the mediating role of epigenetic factors linking exposures to health outcomes in population-based studies.
doi:10.2217/epi.12.20
PMCID: PMC3970193  PMID: 22690666
Agouti; DNA methylation; epigenetic epidemiology; folate; Mendelian randomization; one-carbon metabolism; prenatal nutrition; psychosis; Reelin; schizophrenia
10.  Reproducibility measures and their effect on diet–cancer associations in the Boyd Orr cohort 
Objectives
To quantify measurement error in the estimation of family diet intakes using 7‐day household food inventories and to investigate the effect of measurement‐error adjustment on diet–disease associations.
Design and setting
Historical cohort study in 16 districts in England and Scotland, between 1937 and 1939.
Subjects
4999 children from 1352 families in the Carnegie Survey of Diet and Health. 86.6% of these children were traced as adults and form the Boyd Orr cohort. The reproducibility analysis was based on 195 families with two assessments of family diet recorded 3–15 months apart.
Methods
Intraclass correlation coefficients (ICCs) were calculated for a variety of nutrients and food groups. Diet–cancer associations reported previously in the Boyd Orr cohort were reassessed using two methods: (a) the ICC and (b) the regression calibration.
Main results
The ICCs for the dietary intakes ranged from 0.44 (β carotene) to 0.85 (milk and milk products). The crude fully adjusted hazard ratio (HR) for cancer mortality per 1 MJ/day increase in energy intake was 1.15 (95% CI 1.06 to 1.24). After adjustment using the ICC for energy (0.80) the HR (95% CI) increased to 1.19 (1.08 to 1.31), and the estimate from regression calibration was 1.14 (0.98 to 1.32). The crude fully adjusted odds ratio (OR) for cancer incidence per 40 g/day increase in fruit intake was 0.84 (95% CI 0.73 to 0.97). After adjustment using the fruit ICC (0.78) it became 0.81 (0.67 to 0.96) and the OR derived from regression calibration was 0.81 (0.59 to 1.10).
Conclusions
The diet–disease relationships for the dietary intakes with low measurement error were robust to adjustment for measurement error.
doi:10.1136/jech.2006.046524
PMCID: PMC2465690  PMID: 17435211
11.  Effect of conjugal bereavement on mortality of the bereaved spouse in participants of the Renfrew/Paisley Study 
Objectives
To investigate how loss of a spouse affects mortality risk in the bereaved partner.
Design and setting
Prospective cohort study in Renfrew and Paisley in Scotland.
Participants
4395 married couples aged 45–64 years when the study was carried out between 1972 and 1976.
Methods
The date of bereavement for the bereaved spouse was the date of death of his or her spouse. Bereavement could occur at any time during the follow‐up period, so it was considered as a time‐dependent exposure variable and the Cox proportional hazards model for time‐dependent variables was used. The relative rate (RR) of mortality was calculated for bereaved versus non‐bereaved spouses and adjusted for confounding variables.
Main outcome measures
Causes of death to 31 March 2004.
Results
Bereaved participants were at higher risk than non‐bereaved participants of dying from any cause (RR 1.27; 95% CI 1.2 to 1.35). These risks remained but were attenuated after adjustment for confounding variables. There were raised RRs for bereaved participants dying of cardiovascular disease, coronary heart disease, stroke, all cancer, lung cancer, smoking‐related cancer, and accidents or violence. After adjustment for confounding variables, RRs remained higher for bereaved participants for all these causes except for mortality from lung cancer. There was no strong statistical evidence that the increased risks of death associated with bereavement changed with time after bereavement.
Conclusions
Conjugal bereavement, in addition to existing risk factors, is related to mortality risk for major causes of death.
doi:10.1136/jech.2006.052043
PMCID: PMC2465697  PMID: 17435215
12.  Breast feeding in infancy and social mobility: 60‐year follow‐up of the Boyd Orr cohort 
Archives of Disease in Childhood  2007;92(4):317-321.
Objective
To assess the association of having been breast fed with social class mobility between childhood and adulthood.
Design
Historical cohort study with a 60‐year follow‐up from childhood into adulthood.
Setting
16 urban and rural centres in England and Scotland.
Participants
3182 original participants in the Boyd Orr Survey of Diet and Health in Pre‐War Britain (1937–39) were sent follow‐up questionnaires between 1997 and 1998. Analyses are based on 1414 (44%) responders with data on breast feeding measured in childhood and occupational social class in both childhood and adulthood.
Main outcome
Odds of moving from a lower to a higher social class between childhood and adulthood in those who were ever breast fed versus those who were bottle fed.
Results
The prevalence of breast feeding varied by survey district (range 45–86%) but not with household income (p = 0.7), expenditure on food (p = 0.3), number of siblings (p = 0.7), birth order (p = 0.5) or social class (p = 0.4) in childhood. Participants who had been breast fed were 41% (95% CI 10% to 82%) more likely to move up a social class in adulthood (p = 0.007) than bottle‐fed infants. Longer breastfeeding duration was associated with greater odds of upward social mobility in fully adjusted models (p for trend = 0.003). Additionally controlling for survey district, household income and food expenditure in childhood, childhood height, birth order or number of siblings did not attenuate these associations. In an analysis comparing social mobility among children within families with discordant breastfeeding histories, the association was somewhat attenuated (OR 1.16; 95% CI 0.74 to 1.8).
Conclusions
Breast feeding was associated with upward social mobility. Confounding by other measured childhood predictors of social class in adulthood did not explain this effect, but we cannot exclude the possibility of residual or unmeasured confounding.
doi:10.1136/adc.2006.105494
PMCID: PMC2083668  PMID: 17301108
13.  Differentials and income-related inequalities in maternal depression during the first two years after childbirth: birth cohort studies from Brazil and the UK 
Background
Depression is a prevalent health problem among women during the childbearing years. To obtain a more accurate global picture of maternal postnatal depression, studies that explore maternal depression with comparable measurements are needed. The aims of the study are: (1) to compare the prevalence of maternal depression in the first and second year postpartum between a UK and Brazilian birth cohort study; (2) to explore the extent to which variations in the rates were explained by maternal and infant characteristics, and (3) to investigate income-related inequalities in maternal depression after childbirth in both settings.
Methods
Population-based birth cohort studies were carried out in Avon, UK in 1991 (ALSPAC) and in the city of Pelotas, Brazil in 2004, where 13 798 and 4109 women were analysed, respectively. Self-completion questionnaires were used in the ALSPAC study while questionnaires completed by interviewers were used in the Pelotas cohort study. Three repeated measures of maternal depression were obtained using the Edinburgh Postnatal Depression Scale in the first and second year after delivery in each cohort. Unadjusted and adjusted analyses were carried out. The Relative index of Inequality was used for the analysis of income-relate inequalities so that results were comparable between cohorts.
Results
At both the second and third time assessments, the likelihood of being depressed was higher among women from the Pelotas cohort study. These differences were not completely explained by differences in maternal and infant characteristics. Income-related inequalities in maternal depression after childbirth were high and of similar magnitude in both cohort studies at the three time assessments.
Conclusion
The burden of maternal depression after childbirth varies between and within populations. Strategies to reduce income-related inequalities in maternal depression should be targeted to low-income women in both developed and developing countries.
doi:10.1186/1745-0179-5-12
PMCID: PMC2698823  PMID: 19500361
14.  Socioeconomic position and overweight among adolescents: data from birth cohort studies in Brazil and the UK 
BMC Public Health  2009;9:105.
Background
Developed and developing countries are facing rapid increases in overweight and obesity among children and adolescents. The patterns of overweight/obesity differ by age, sex, rural or urban residence and socioeconomic position (SEP) and vary between and within countries.
Methods
We investigated patterns of SEP – overweight status association among adolescents from the UK (ALSPAC) and Brazil (the 1982 and 1993 Pelotas birth cohort studies).
All analyses were performed separately for males and females. Logistic regression analysis was used to examine the relationships between overweight status and two SEP indicators – family income and maternal education.
Results
A strong positive association was observed in 11-year-old boys from the 1993 Pelotas cohort, with higher prevalence of overweight among the least poor and among those whose mothers had more years of schooling (x2 for linear trend p < 0.001). In ALSPAC study higher prevalence of overweight was seen among boys whose mothers had lower educational achievement (x2 for linear trend p = 0.006). Among 11 year-old girls from 1993 Pelotas cohort study there was a positive association (higher prevalence of overweight in the higher socioeconomic and educational strata, x2 for linear trend p < 0.001 and p = 0.01, respectively) while an inverse association was found in the ALSPAC study (x2 for linear trend p < 0.001). Among males from the 1982 cohort study, overweight at 18 years of age showed a positive association with both SEP indicators while among females, the reverse association was found.
Conclusion
The results of this study demonstrate that the social patterning of overweight varies between and within populations over time. Specific approaches should be developed within populations in order to contain the obesity epidemic and reduce disparities.
doi:10.1186/1471-2458-9-105
PMCID: PMC2673220  PMID: 19368733
15.  The applicability of measures of socioeconomic position to different ethnic groups within the UK 
Background
In this paper we seek to tease out differences in socioeconomic position between ethnic groups. There are 3 main reasons why conventional socioeconomic indicators and asset based measures may not be equally applicable to all ethnic groups:
1) Differences in response rate to conventional socioeconomic indicators
2) Cultural and social differences in economic priorities/opportunities
3) Differences in housing quality, assets and debt within socioeconomic strata
Methods
The sample consisted of White (n = 227), African-Caribbean (n = 213) and Indian and Pakistani (n = 233) adults aged between 18 and 59 years living in Leeds as measured in a stratified population survey. Measures included income, education, employment, car ownership, home ownership, housing quality, household assets, investments, debt, perceived ability to obtain various sums and perceived level of financial support given and received.
Results
Response rates to education and income questions were similar for the different ethnic groups. Overall response rates for income were much lower than those for education and biased towards wealthier people. There were differences between ethnic groups in economic priorities/opportunities particularly in relation to car ownership, home ownership, investment and debt. Differences in living conditions, household assets and debt between ethnic groups were dependent on differences in education; however differences in car ownership, home ownership, ability to obtain £10 000, and loaning money to family/friends and income from employment/self employment persisted after adjustment for education.
Conclusion
In the UK, education appears to be an effective variable for measuring variation in SEP across ethnic groups but the ability to account for SEP differences may be improved by the addition of car and home ownership, ability to obtain £10 000, loaning money to family/friends and income from employment/self employment. Further research is required to establish the degree to which results of this study are generalisable.
doi:10.1186/1475-9276-8-4
PMCID: PMC2657895  PMID: 19250528
16.  Job insecurity and incident coronary heart disease: the Whitehall II prospective cohort study 
Atherosclerosis  2013;227(1):178-181.
Objective
This study uses a prospective design to examine the association between self-reported job insecurity and incident coronary heart disease; an association which has been little investigated previously.
Methods
Participants were 4174 British civil servants (1236 women and 2938 men), aged 42 to 56 with self-reported data on job insecurity and free from coronary heart disease at baseline (1995-6). These participants were followed until 2002-4, an average of 8.6 years, for incident fatal coronary heart disease, clinically verified incident non-fatal myocardial infarction, or definite angina (a total of 168 events).
Results
Cox proportional hazard models adjusted for socio-demographic characteristics showed job insecurity to be associated with a 1.42-fold (95% CI, 1.05-1.93) risk of incident coronary heart disease compared with secure employment. Adjustment for physiological and behavioral cardiovascular risk factors had little effect on this estimate; 1.38 (1.01-1.88).
Conclusion
This study suggests that job insecurity may adversely affect coronary health.
doi:10.1016/j.atherosclerosis.2012.12.027
PMCID: PMC3940189  PMID: 23332775
job insecurity; stress; incident coronary heart disease; angina; middle-aged; prospective
17.  Associations of childhood 25-hydroxyvitamin D2 and D3 and cardiovascular risk factors in adolescence: prospective findings from the Avon Longitudinal Study of Parents and Children 
Background
Studies of the associations of circulating total 25-hydroxyvitamin D (25(OH)D) with cardiovascular disease risk factors in adults have reported inconsistent findings. We aimed to compare prospective associations of two analogues of childhood 25(OH)D (25(OH)D2 and 25(OH)D3) with cardiovascular risk factors measured in adolescence.
Methods and results
We examined associations of childhood (ages 7–12 years) 25(OH)D2 and 25-25(OH)D3 with a range of cardiovascular risk factors (blood pressure, fasting lipids, glucose, insulin and C-reactive protein (CRP)) determined in adolescence (mean age 15.4 years). Data were from 2470 participants of the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective population-based cohort. After adjustments for age, gender, socioeconomic position and BMI, there were no associations of 25(OH)D2 with cardiovascular risk factors. There was a positive association of season-adjusted (and unadjusted) 25(OH)D3 with high-density lipoprotein cholesterol (HDL-C) (mean change per doubling of 25(OH)D3: 0.03 mmol/l; 95% confidence interval (CI): 0.001 to 0.05, p = 0.02) and an inverse association with fasting insulin (relative difference of −4.59% per doubling; 95% CI: −8.37 to −0.59, p = 0.03). Participants with total 25(OH)D concentration <50 nmol/l had 0.04 mmol/l lower HDL-C (95% CI: −0.07 to −0.01) and 5.54% higher fasting insulin (95% CI: 0.82 to 10.47) compared with participants with total 25(OH)D ≥72 nmol/l.
Conclusions
In the first prospective study of children/adolescents, we have shown that higher 25(OH)D3 concentrations in childhood are associated with higher levels of HDL-C and lower fasting insulin in adolescence.
doi:10.1177/2047487312465688
PMCID: PMC3931583  PMID: 23185083
Vitamin D; cardiovascular diseases; paediatrics; ALSPAC
18.  Associations of 25-Hydroxyvitamin D2 and D3 with Cardiovascular Risk Factors in Childhood: Cross-Sectional Findings from the Avon Longitudinal Study of Parents and Children 
Context
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)].
Objective
The objective of the study was to compare associations of 25(OH)D2 and 25(OH)D3 with cardiovascular risk factors in children.
Design/Setting
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.
Main Outcomes
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.
Results
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).
Conclusions
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.
doi:10.1210/jc.2011-2335
PMCID: PMC3927053  PMID: 22344194
19.  ASSOCIATION BETWEEN MATERNAL USE OF FOLIC ACID SUPPLEMENTS AND RISK OF AUTISM IN CHILDREN 
Context
Prenatal folic acid supplements reduce the risk of neural tube defects in children, but it has not been determined whether they protect against other neurodevelopmental disorders.
Objective
To examine the association between maternal use of prenatal folic acid supplements and the subsequent risk of autistic disorder in children.
Design, Setting, and Patients
The study sample of 85,176 was derived from the population-based, prospective Norwegian Mother and Child Cohort Study (MoBa). The children were born in 2002–08. By the end of follow-up on March 31st, 2012, the age range was 3.3–10.2 years and the mean age 6.4 years. The exposure of primary interest was use of folic acid from 4 weeks before to 8 weeks after the start of pregnancy. The start of pregnancy was defined as the first day of the last menstrual period before conception. Relative risks of ASD were estimated by odds ratios (ORs) with 95% confidence intervals (CIs) in a logistic regression analysis. Analyses were adjusted for maternal education level, year of birth, and parity.
Main Outcome Measure
Specialist-confirmed diagnosis of autistic disorder.
Results
To date, 114 children in the study sample have been diagnosed with autistic disorder. In children whose mothers took folic acid, 0.10% (64/61,042) had autistic disorder, compared with 0.21% (50/24,134) in those unexposed to folic acid. The adjusted OR for autistic disorder in children of folic acid users was 0.61 (95% CI, 0.41–0.90). Similar analyses for prenatal fish oil supplements showed no such association with autistic disorder, even though fish oil use was associated with the same maternal characteristics as folic acid use.
Conclusion
Prenatal folic acid supplements around the time of conception were associated with a lower risk of autistic disorder in the MoBa cohort.
doi:10.1001/jama.2012.155925
PMCID: PMC3908544  PMID: 23403681
20.  Using genetic proxies for lifecourse sun exposure to assess the causal relationship of sun exposure with circulating vitamin D and prostate cancer risk 
Background
Ecological and epidemiological studies have identified an inverse association of intensity and duration of sunlight exposure with prostate cancer, which may be explained by a reduction in vitamin D synthesis. Pigmentation traits influence sun exposure and therefore may affect prostate cancer risk. Because observational studies are vulnerable to confounding and measurement error, we used Mendelian randomization to examine the relationship of sun exposure with both prostate cancer risk and the intermediate phenotype, plasma levels of vitamin D.
Methods
We created a tanning, a skin color and a freckling score as combinations of SNPs that have been previously associated with these phenotypes. A higher score indicates propensity to burn, have a lighter skin color and freckles. The scores were tested for association with vitamin D levels (25-hydroxyvitamin-D and 1,25-dihydroxyvitamin-D) and PSA-detected prostate cancer in 3123 white British individuals enrolled in the Prostate Testing for cancer and Treatment (ProtecT) study.
Results
The freckling score was inversely associated with 25(OH)D levels (change in 25(OH)D per score unit −0.27; 95%CI: −0.52, −0.01), and the tanning score was positively associated with prostate cancer risk (OR 1.05; 95%CI: 1.02,1.09), after adjustment for population stratification and potential confounders.
Conclusions
Individuals who tend to burn are more likely to spend less time in the sun and consequently have lower plasma vitamin D levels and higher susceptibility to prostate cancer.
Impact
The use of pigmentation related genetic scores is valuable for the assessment of the potential benefits of sun exposure with respect to prostate cancer risk.
doi:10.1158/1055-9965.EPI-12-1248
PMCID: PMC3616836  PMID: 23441100
pigmentation; tanning; sun exposure; vitamin D; prostate cancer
21.  Alcohol consumption and PSA-detected prostate cancer risk—A case-control nested in the ProtecT study 
Alcohol is an established carcinogen but not an established risk factor for prostate cancer, despite some recent prospective studies suggesting increased risk among heavy drinkers. The aim of this study was to investigate the role of alcohol on prostate-specific antigen (PSA) levels and prostate cancer risk. Two thousand four hundred PSA detected prostate cancer cases and 12,700 controls matched on age and general practice were identified through a case-control study nested in the PSA-testing phase of a large UK-based randomized controlled trial for prostate cancer treatment (ProtecT). Linear and multinomial logistic regression models were used to estimate ratios of geometric means (RGMs) of PSA and relative risk ratios (RRRs) of prostate cancer by stage and grade, with 95% confidence intervals (CIs), associated with weekly alcohol intake and drinking patterns. We found evidence of lower PSA (RGM 0.98, 95% CI: 0.98–0.99) and decreased risk of low Gleason-grade (RRR 0.96; 95%CI 0.93–0.99) but increased risk of high-grade prostate cancer (RRR 1.04; 95%CI 0.99–1.08; pdifference=0.004) per 10 units/week increase in alcohol consumption, not explained by current BMI, blood pressure, comorbidities, or reverse causation. This is the first large population-based study to find evidence of lower PSA levels for increasing alcohol consumption, with potential public health implications for the detection of prostate cancer. Our results also support a modestly higher risk of high-grade disease for heavy drinkers, but require independent replication to establish the nature of the association of alcohol with low-grade disease, preferably in cohorts with a heterogeneous case-mix.
What's new?
Alcohol is not an established risk factor for prostate cancer; however, the current work suggests that heavy drinking could cause a small increase in risk of the more aggressive forms. If the results are confirmed to be causal, prostate cancer risk will be added to the many long-term health risks of heavy drinking, and public health strategies will then also reduce high-risk, poorer prognosis prostate cancer. The authors also found that heavy drinkers have lower PSA levels, suggesting that heavy alcohol consumption could be used as a marker to identify men in whom some cancers might be missed.
doi:10.1002/ijc.27877
PMCID: PMC3786564  PMID: 23024014
alcohol; prostate cancer; prostate specific antigen; ProtecT, nested case–control
22.  Area-Level Deprivation and Overall and Cause-Specific Mortality: 12 Years’ Observation on British Women and Systematic Review of Prospective Studies 
PLoS ONE  2013;8(9):e72656.
Background
Prospective studies have suggested a negative impact of area deprivation on overall mortality, but its effect on cause-specific mortality and the mechanisms that account for this association remain unclear. We investigate the association of area deprivation, using Index of Multiple deprivation (IMD), with overall and cause-specific mortality, contextualising findings within a systematic review.
Methods And Findings
We used data from 4,286 women from the British Women’s Heart Health Study (BWHHS) recruited at 1999-2001 to examine the association of IMD with overall and cause-specific mortality using Cox regression models. One standard deviation (SD) increase in the IMD score had a hazard ratio (HR) of 1.21 (95% CI: 1.13-1.30) for overall mortality after adjustment for age and lifecourse individual deprivation, which was attenuated to 1.15 (95% CI: 1.04-1.26) after further inclusion of mediators (health behaviours, biological factors and use of statins and blood pressure-lowering medications). A more pronounced association was observed for respiratory disease and vascular deaths. The meta-analysis, based on 20 published studies plus the BWHHS (n=21), yielded a summary relative risk (RR) of 1.15 (95% CI: 1.11-1.19) for area deprivation (top [least deprived; reference] vs. bottom tertile) with overall mortality in an age and sex adjusted model, which reduced to 1.06 (95% CI: 1.04-1.08) in a fully adjusted model.
Conclusions
Health behaviours mediate the association between area deprivation and cause-specific mortality. Efforts to modify health behaviours may be more successful if they are combined with measures that tackle area deprivation.
doi:10.1371/journal.pone.0072656
PMCID: PMC3782490  PMID: 24086262
23.  Folic Acid Supplements in Pregnancy and Severe Language Delay in Children 
Context
Prenatal folic acid supplements reduce the risk of neural tube defects and may have beneficial effects on other aspects of neurodevelopment.
Objective
To examine associations between mothers' use of prenatal folic acid supplements and risk of severe language delay in their children at age 3 years.
Design, Setting, and Patients
The prospective observational Norwegian Mother and Child Cohort Study recruited pregnant women between 1999 and December 2008. Data on children born before 2008 whose mothers returned the 3-year follow-up questionnaire by June 16, 2010, were used. Maternal use of folic acid supplements within the interval from 4 weeks before to 8 weeks after conception was the exposure. Relative risks were approximated by estimating odds ratios (ORs) with 95% CIs in a logistic regression analysis.
Main Outcome Measure
Children's language competency at age 3 years measured by maternal report on a 6-point ordinal language grammar scale. Children with minimal expressive language (only 1-word or unintelligible utterances) were rated as having severe language delay.
Results
Among 38 954 children, 204 (0.5%) had severe language delay. Children whose mothers took no dietary supplements in the specified exposure interval were the reference group (n=9052 [24.0%], with severe language delay in 81 children [0.9%]). Adjusted ORs for 3 patterns of exposure to maternal dietary supplements were (1) other supplements, but no folic acid (n=2480 [6.6%], with severe language delay in 22 children [0.9%]; OR, 1.04; 95% CI, 0.62-1.74); (2) folic acid only (n=7127 [18.9%], with severe language delay in 28 children [0.4%]; OR, 0.55; 95% CI, 0.35-0.86); and (3) folic acid in combination with other supplements (n=19005 [50.5%], with severe language delay in 73 children [0.4%]; OR, 0.55; 95% CI, 0.39-0.78).
Conclusion
Among this Norwegian cohort of mothers and children, maternal use of folic acid supplements in early pregnancy was associated with a reduced risk of severe language delay in children at age 3 years.
doi:10.1001/jama.2011.1433
PMCID: PMC3780384  PMID: 21990300
24.  Common Variants in Left/Right Asymmetry Genes and Pathways Are Associated with Relative Hand Skill 
PLoS Genetics  2013;9(9):e1003751.
Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728). The most strongly associated variant, rs7182874 (P = 8.68×10−9), is located in PCSK6, further supporting an association we previously reported. We also confirmed the specificity of this association in individuals with RD; the same locus was not associated with relative hand skill in a general population cohort (n = 2,666). As PCSK6 is known to regulate NODAL in the development of left/right (LR) asymmetry in mice, we developed a novel approach to GWAS pathway analysis, using gene-set enrichment to test for an over-representation of highly associated variants within the orthologs of genes whose disruption in mice yields LR asymmetry phenotypes. Four out of 15 LR asymmetry phenotypes showed an over-representation (FDR≤5%). We replicated three of these phenotypes; situs inversus, heterotaxia, and double outlet right ventricle, in the general population cohort (FDR≤5%). Our findings lead us to propose that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development.
Author Summary
Humans have developed a population level bias towards right-handedness for tool-use. Understanding the genetic basis of handedness can help explain why this bias exists and may offer clues into the evolution of handedness and brain asymmetry. We have tested for correlation between relative hand skill and hundreds of thousands of genetic variants in a cohort of individuals with reading disability. The strongest associated variant is in the gene PCSK6, an enzyme that cleaves NODAL into an active form. NODAL plays a key role during the establishment of left/right (LR) asymmetry in diverse species, from snails to mammals. Pcsk6 knock-out mice display LR asymmetry defects like heterotaxia (abnormal organ positioning). We uncovered further variants associated with relative hand skill in the human versions of genes that also cause the LR asymmetry phenotypes heterotaxia, and situs inversus (reversal of organ asymmetry) when knocked out in mice. These results replicate in an independent general population cohort without reading disability. We propose that handedness is under the control of many variants, some of which are in genes that also contribute to the determination of body LR asymmetry.
doi:10.1371/journal.pgen.1003751
PMCID: PMC3772043  PMID: 24068947
25.  Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins and risk of prostate cancer: a case-control study, systematic review and meta-analysis 
Background
Disturbed folate metabolism is associated with an increased risk of some cancers. Our objective was to determine whether blood levels of folate, vitamin B12 and related metabolites were associated with prostate cancer risk.
Methods
Matched case-control study nested within the UK population-based ProtecT study of PSA-detected prostate cancer in men aged 50–69 years. Plasma concentrations of folate, B12 (cobalamin), holo-haptocorrin, holo- and total-transcobalamin, and total homocysteine (tHcy) were measured in 1,461 cases and 1,507 controls. ProtecT study estimates for associations of folate, B12, and tHcy with prostate cancer risk were included in a meta-analysis, based on a systematic review.
Results
In the ProtecT study, increased B12 and holo-haptocorrin concentrations showed positive associations with prostate cancer risk (highest vs lowest quartile of B12 odds ratio (OR)=1.17 (95% CI 0.95–1.43), P-for-trend=0.06; highest vs lowest quartile of holo-haptocorrin OR=1.27 (1.04–1.56), P-for-trend=0.01); folate, holo-transcobalamin and tHcy were not associated with prostate cancer risk. In the meta-analysis, circulating B12 levels were associated with an increased prostate cancer risk (pooled OR=1.10 (1.01–1.19) per 100 pmol/L increase in B12, P=0.002); the pooled OR for the association of folate with prostate cancer was positive (OR=1.11 (0.96–1.28) per 10 nmol/L, P=0.2) and conventionally statistically significant if ProtecT (the only case-control study) was excluded (OR=1.18 (1.00–1.40) per 10 nmol/L, P=0.02).
Conclusion
Vitamin B12 and (in cohort studies) folate were associated with increased prostate cancer risk.
Impact
Given current controversies over mandatory fortification, further research is needed to determine whether these are causal associations.
doi:10.1158/1055-9965.EPI-10-0180
PMCID: PMC3759018  PMID: 20501771
folate; vitamin B12; cobalamin; transcobalamin; haptocorrin; homocysteine; folate-mediated one-carbon metabolism; prostate cancer

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