Showing papers by "Debbie A Lawlor published in 2008"

Mendelian randomization: using genes as instruments for making causal inferences in epidemiology.

Abstract: Observational epidemiological studies suffer from many potential biases, from confounding and from reverse causation, and this limits their ability to robustly identify causal associations. Several high-profile situations exist in which randomized controlled trials of precisely the same intervention that has been examined in observational studies have produced markedly different findings. In other observational sciences, the use of instrumental variable (IV) approaches has been one approach to strengthening causal inferences in non-experimental situations. The use of germline genetic variants that proxy for environmentally modifiable exposures as instruments for these exposures is one form of IV analysis that can be implemented within observational epidemiological studies. The method has been referred to as 'Mendelian randomization', and can be considered as analogous to randomized controlled trials. This paper outlines Mendelian randomization, draws parallels with IV methods, provides examples of implementation of the approach and discusses limitations of the approach and some methods for dealing with these.

Newly identified loci that influence lipid concentrations and risk of coronary artery disease

Abstract: To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.

Birth Weight and Risk of Type 2 Diabetes: A Systematic Review

Abstract: Context Low birth weight is implicated as a risk factor for type 2 diabetes. However, the strength, consistency, independence, and shape of the association have not been systematically examined. Objective To conduct a quantitative systematic review examining published evidence on the association of birth weight and type 2 diabetes in adults. Data Sources and Study Selection Relevant studies published by June 2008 were identified through literature searches using EMBASE (from 1980), MEDLINE (from 1950), and Web of Science (from 1980), with a combination of text words and Medical Subject Headings. Studies with either quantitative or qualitative estimates of the association between birth weight and type 2 diabetes were included. Data Extraction Estimates of association (odds ratio [OR] per kilogram of increase in birth weight) were obtained from authors or from published reports in models that allowed the effects of adjustment (for body mass index and socioeconomic status) and the effects of exclusion (for macrosomia and maternal diabetes) to be examined. Estimates were pooled using random-effects models, allowing for the possibility that true associations differed between populations. Data Synthesis Of 327 reports identified, 31 were found to be relevant. Data were obtained from 30 of these reports (31 populations; 6090 diabetes cases; 152 084 individuals). Inverse birth weight–type 2 diabetes associations were observed in 23 populations (9 of which were statistically significant) and positive associations were found in 8 (2 of which were statistically significant). Appreciable heterogeneity between populations (I 2 = 66%; 95% confidence interval [CI], 51%-77%) was largely explained by positive associations in 2 native North American populations with high prevalences of maternal diabetes and in 1 other population of young adults. In the remaining 28 populations, the pooled OR of type 2 diabetes, adjusted for age and sex, was 0.75 (95% CI, 0.70-0.81) per kilogram. The shape of the birth weight–type 2 diabetes association was strongly graded, particularly at birth weights of 3 kg or less. Adjustment for current body mass index slightly strengthened the association (OR, 0.76 [95% CI, 0.70-0.82] before adjustment and 0.70 [95% CI, 0.65-0.76] after adjustment). Adjustment for socioeconomic status did not materially affect the association (OR, 0.77 [95% CI, 0.70-0.84] before adjustment and 0.78 [95% CI, 0.72-0.84] after adjustment). There was no strong evidence of publication or small study bias. Conclusion In most populations studied, birth weight was inversely related to type 2 diabetes risk.

Common variants in the GDF5-UQCC region are associated with variation in human height

Abstract: Identifying genetic variants that influence human height will advance our understanding of skeletal growth and development. Several rare genetic variants have been convincingly and reproducibly associated with height in mendelian syndromes, and common variants in the transcription factor gene HMGA2 are associated with variation in height in the general population. Here we report genome-wide association analyses, using genotyped and imputed markers, of 6,669 individuals from Finland and Sardinia, and follow-up analyses in an additional 28,801 individuals. We show that common variants in the osteoarthritis-associated locus GDF5-UQCC contribute to variation in height with an estimated additive effect of 0.44 cm (overall P < 10(-15)). Our results indicate that there may be a link between the genetic basis of height and osteoarthritis, potentially mediated through alterations in bone growth and development.

Common Variation in the FTO Gene Alters Diabetes-Related Metabolic Traits to the Extent Expected Given Its Effect on BMI

Abstract: Objective: Common variation in the FTO gene is associated with body mass index (BMI) and type 2 diabetes. Increased BMI is associated with diabetes risk factors including raised insulin, glucose and triglycerides. We aimed to test whether FTO genotype is associated with variation in these metabolic traits. Research design and methods: We tested the association between FTO genotype and ten metabolic traits using data from 17,037 white European individuals. We compared the observed effect of FTO genotype on each trait to that expected given the FTO -BMI and BMI-trait associations. Results: Each copy of the FTO rs9939609 A allele was associated with higher fasting insulin (0.039SD [95%CI:0.013-0.064]; P =0.003), glucose (0.024SD [0.001-0.048]; P =0.044), and triglycerides (0.028SD [0.003-0.052]; P =0.025), and lower HDL-cholesterol (0.032SD [0.008-0.057]; P =0.009). There was no evidence of these associations when adjusting for BMI. Associations with fasting alanine-aminotransferase, gamma-glutamyl-transferase and LDL-cholesterol, HbA1c and systolic and diastolic blood pressure were in the expected direction but did not reach P FTO genotype was associated with a higher odds of metabolic syndrome (odds ratio:1.17 [95%CI:1.10-1.25]; P =3×10 −6 ). Conclusions: FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI. Sample sizes of greater than 12,000 individuals were needed to detect associations at P

Obesity in children. Part 1: Epidemiology, measurement, risk factors, and screening

Abstract: #### Summary points Obesity was first included in the international classification of diseases in 1948. Since then, an epidemic has developed internationally, affecting all age groups. This article describes the prevalence of obesity in children, its underlying risk factors, its consequences, and how it can be measured; it also discusses whether children should be screened for obesity. In a second article to be published next week we will discuss the prevention and management of obesity in children.1 The terms used are defined in box 1 (where authors of cited papers use terms differently we use the authors’ own words). #### Sources and selection criteria This review draws on the Foresight report, guidance from the National Institute of Health and Clinical Excellence, and a Cochrane review of preventing obesity. In April 2008 we searched the Cochrane Library database of reviews and the Centre for Reviews and Dissemination databases using the search term “obesity”. We also conducted a Medline search ((Child$ or paediatric or pediatric or adolescent) and (Obes$ or overweight)) limited to 1 January 2005 to 6 May 2008 and “review articles”; this identified 1105 articles. We read the abstracts …

Exploring the developmental overnutrition hypothesis using parental-offspring associations and FTO as an instrumental variable

Abstract: Background The developmental overnutrition hypothesis suggests that greater maternal obesity during pregnancy results in increased offspring adiposity in later life. If true, this would result in the obesity epidemic progressing across generations irrespective of environmental or genetic changes. It is therefore important to robustly test this hypothesis.

Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels.

Abstract: Identifying the genetic variants that regulate fasting glucose concentrations may further our understanding of the pathogenesis of diabetes. We therefore investigated the association of fasting glucose levels with SNPs in 2 genome-wide scans including a total of 5,088 nondiabetic individuals from Finland and Sardinia. We found a significant association between the SNP rs563694 and fasting glucose concentrations (P = 3.5 x 10(-7)). This association was further investigated in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies. The combined P value for association in these follow-up samples was 6.9 x 10(-26), and combining results from all studies resulted in an overall P value for association of 6.4 x 10(-33). Across these studies, fasting glucose concentrations increased 0.01-0.16 mM with each copy of the major allele, accounting for approximately 1% of the total variation in fasting glucose. The rs563694 SNP is located between the genes glucose-6-phosphatase catalytic subunit 2 (G6PC2) and ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11). Our results in combination with data reported in the literature suggest that G6PC2, a glucose-6-phosphatase almost exclusively expressed in pancreatic islet cells, may underlie variation in fasting glucose, though it is possible that ABCB11, which is expressed primarily in liver, may also contribute to such variation.

Inflammation, insulin resistance, and diabetes : mendelian randomization using CRP haplotypes points upstream

Abstract: Background Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables.

Association of age at menarche with cardiovascular risk factors, vascular structure, and function in adulthood: the Cardiovascular

Abstract: Background: It is unclear whether age at menarche is an independent determinant of future cardiovascular risk. Objective: We aimed to determine whether menarcheal age is an independentpredictorofbodymassindex(BMI)andawiderangeof cardiovascular risk factors in adolescence and adulthood. Design:WeexaminedtheassociationsofmenarchealagewithBMI (in kg/m 2 ) and other cardiovascular risk factors in adolescence and adulthood in a population-based sample of 794 female adolescents aged 9–18 y at baseline. Their age at first menstruation was requested at baseline and again 3 and 6 y later. Cardiovascular risk factors were assessed at baseline and at age 30–39 y. Results:A1-ydecreaseinmenarchealagewasassociatedwith0.81 (95% CI: 0.53, 1.08) higher adult BMI as well as greater waist circumference and waist-to-hip ratio, elevated systolic blood pressure, higher insulin resistance, and greater risk of metabolic syndrome (P 0.05 for all). In multivariable analysis in which these adult risk factors were mutually adjusted for, only the inverse associationbetweenageatmenarcheandadultBMIremained.However, this inverse association was lost after adjustment for premenarcheal BMI (: 0.16; 95% CI 0.55, 0.23; P 0.42). Higher premenarcheal BMI predicted earlier menarche, and the strong association between premenarcheal BMI and adult BMI was robust to adjustment for age at menarche. Conclusions: These findings suggest that early menarche is only a risk marker. Greater childhood BMI seems to contribute to earlier age at menarche and, because of tracking, greater adult BMI and associated cardiovascular risk. An independent effect of early menarche on adult adiposity cannot be excluded, but it is likely to be small at best. Am J Clin Nutr 2008;87:1876–82.

The Association of C-Reactive Protein and CRP Genotype with Coronary Heart Disease: Findings from Five Studies with 4,610 Cases amongst 18,637 Participants

Abstract: Background: It is unclear whether C-reactive protein (CRP) is causally related to coronary heart disease (CHD). Genetic variants that are known to be associated with CRP levels can be used to provide causal inference of the effect of CRP on CHD. Our objective was to examine the association between CRP genetic variant +1444C.T (rs1130864) and CHD risk in the largest study to date of this association. Methods and Results: We estimated the association of CRP genetic variant +1444C.T (rs1130864) with CRP levels and with CHD in five studies and then pooled these analyses (N=18,637 participants amongst whom there were 4,610 cases). CRP was associated with potential confounding factors (socioeconomic position, physical activity, smoking and body mass) whereas genotype (rs1130864) was not associated with these confounders. The pooled odds ratio of CHD per doubling of circulating CRP level after adjustment for age and sex was 1.13 (95%CI: 1.06, 1.21), and after further adjustment for confounding factors it was1.07 (95%CI: 1.02, 1.13).Genotype (rs1130864) wasassociated with circulating CRP;the pooledratio of geometric means of CRP level among individuals with the TT genotype compared to those with the CT/CC genotype was 1.21 (95%CI: 1.15, 1.28) and the pooled ratio of geometric means of CRP level per additional T allele was 1.14 (95%CI: 1.11, 1.18), with no strong evidence in either analyses of between study heterogeneity (I 2 =0%, p.0.9 for both analyses). There was no association of genotype (rs1130864) with CHD: pooled odds ratio 1.01 (95%CI: 0.88, 1.16) comparing individuals with TT genotype to those with CT/CC genotype and 0.96 (95%CI: 0.90, 1.03) per additional T allele (I 2 ,7.5%, p.0.6 for both meta-analyses). An instrumental variables analysis (in which the proportion of CRP levels explained by rs1130864 was related to CHD) suggested that circulating CRP was not associated with CHD: the odds ratio for a doubling of CRP level was 1.04 (95%CI: 0.61, 1.80). Conclusions: We found no association of a genetic variant, which is known to be related to CRP levels, (rs1130864) and having CHD. These findings do not support a causal association between circulating CRP and CHD risk, but very large, extended, genetic association studies would be required to rule this out.

Modifiable Maternal Exposures and Offspring Blood Pressure: A Review of Epidemiological Studies of Maternal Age, Diet, and Smoking

Abstract: Prenatal programming of adult disease is well established in animals. In humans the impact of common in utero exposures on long-term offspring health is less clear. We reviewed epidemiology studies of modifiable maternal exposures and offspring blood pressure (BP). Three maternal exposures were identified for review and meta-analyzed where possible: smoking during pregnancy, diet, and age at childbirth. Meta-analysis suggested there was a modest association between higher offspring BP and prenatal exposure to smoke (confounder-adjusted β = 0.62 mm Hg, 95% confidence interval: 0.19–1.05, I2 = 16.4%). However, the level of confounder adjustment varied between studies, which in some studies attenuated the association to the null. There was no strong evidence that any component of maternal diet during pregnancy (maternal protein, energy, calcium, and various other nutrients) influences offspring BP. The results of studies of maternal age varied and there was strong evidence of heterogeneity in the pooled analysis. The association with maternal age, if present, was modest (confounder-adjusted β = 0.09 mm Hg/y, 95% confidence interval: −0.03 to 0.21, I2 = 89.8%). In sum, there is little empirical evidence that the maternal exposures reviewed program offspring BP. Other components of offspring health may be more susceptible to effects of programming in utero.

Genetic association study of BDNF in depression: finding from two cohort studies and a meta-analysis.

Abstract: Depression is common and a major cause of morbidity and mortality and is also known to have serious effects on quality of life. Both clinical and pharmacologic studies have implicated the role of brain-derived neurotrophic factor (BDNF) as a susceptibility locus for the development of mental illness, including depression, bipolar disorder, and schizophrenia. Population-based genetic studies have examined the association between BDNF and a variety of depression outcomes, but the results have not clearly established the role of BDNF in the development of this complex disorder. The aim of this study was to test for associations between two genetic variants in BDNF, Val66Met (rs6265) and -270 C > T, and depression measured in two independent samples. In this analysis we included 3,548 participants from British Women's Heart and Health Study (BWHHS) and 6,836 mothers from Avon Longitudinal Study of Parents and Children (ALSPAC) who had complete data on genotype and depression outcomes. We did not detect any strong evidence of associations between any of the two polymorphisms and indicators of depression in either BWHHS or ALSPAC samples. Further, we carried out a systematic review and meta-analysis of all association studies of these two BDNF polymorphisms and depression. The meta-analysis of Val66Met in depression obtained an overall summary OR of 1.06 (95% CI: 0.89-1.26, P = 0.537) comparing MM with VV genotypes and an OR of 0.97 (95% CI: 0.89-1.05, P = 0.403) comparing MV with VV genotypes. Our findings suggest that BDNF genotype does not exert a major influence on the development of depression.

Risk factors across the life course and dementia in a Brazilian population: results from the Sao Paulo Ageing & Health Study (SPAH)

Abstract: Background Several mechanisms have been suggested to explain the association between adversities across life and dementia. This study aimed to investigate the association between indicators of socioeconomic disadvantages throughout the life-course and dementia among older adults in Sao Paulo, Brazil and to explore possible causal pathways. Methods We used baseline data from the SPAH study which involved participants aged 65 years and older (n = 2005). The outcome of interest was prevalent dementia. Exposures included in the analyses were socioeconomic position (SEP) indicators in childhood (place of birth and literacy) and adulthood (occupation and income), anthropometric measurements as markers of intrauterine and childhood environment (head circumference and leg length), smoking, diabetes and hypertension. Logistic regression models were used to test the hypothesized pathways and to assess whether there was an association between cumulative adversities across the life course and prevalent dementia. Results Indicators of socioeconomic disadvantage in early life were associated with increased prevalence of dementia. This association was partially mediated through adulthood SEP. Head circumference and leg length were also clearly associated with dementia but there was no evidence that this association was mediated by early life socioeconomic disadvantage. There was an association between cumulative unfavourable conditions across the life course and dementia. Conclusions Early life disadvantages seem to operate through biological mechanisms associated with passive brain reserve and opportunities in life representing active cognitive reserve. Prevention of dementia should start early in life and continue through life span as seen with many other chronic diseases.

Physical activity and emotional problems amongst adolescents : a longitudinal study.

Abstract: Promotion of physical activity (PA) is at the top of the public health agenda. However, there are few longitudinal studies investigating the relationship between PA and children’s mental health. Therefore, we aimed to investigate the association between self-reported physical activity (PA) and emotional problems 1-year later in a cohort of schoolchildren. A total of 1,446 children aged 11–14 years from 39 schools in the North West of England completed a self-report questionnaire in class. Each child reported the total number of sessions of sporting activities (lasting more than 20 min) in which they participated during the previous week, including activities both in school and out of school. This total was averaged for the week in order to determine whether the child was physically active at recommended levels (1 h per day). Childhood emotional problems were measured using the Strengths and Difficulties Questionnaire (SDQ) (self-report) at baseline and 1-year later. Data on potential confounders were also collected by self-report questionnaire at baseline. In unadjusted analyses, children who, on average, participated in at least 1 h of sporting activity on a daily basis had fewer emotional problems at 1-year follow-up. This attenuated substantially after adjustment for gender (girls were less active but more likely to report emotional problems than boys). After adjustment for additional confounders including emotional problems at baseline, children who met recommended levels for PA had, on average, a score on the emotional problems sub-scale that was 0.29 units lower (−0.29 (95%CI: −0.61, 0.022)) at 1 year follow-up compared to children who did not undertake recommended levels of PA. Children who were physical activity also had higher scores on the hyperactivity sub-scale of the SDQ 1 year later, but there was no evidence to support an association between PA and other behavioural problems. Children who met recommended levels for PA had fewer emotional problems 1-year later, although the magnitude of this difference was reduced after adjustment for confounders, particularly gender. Future longitudinal studies need to record both PA and emotional problems at more frequent intervals in order to enable us to determine the effect of maintaining a physically active lifestyle on adolescent mental health outcomes.

Association of childhood intelligence with risk of coronary heart disease and stroke: findings from the Aberdeen Children of the 1950s cohort study.

Abstract: Objectives Associations of cognitive function assessed in adulthood with coronary heart disease (CHD) and stroke might reflect a causal effect or could be explained by residual confounding or a common underlying pathology (atherosclerosis) that links both declines in cognitive function and increased risk of cardiovascular disease (i.e. reverse causality). Our objective was to examine the association of childhood intelligence (assessed at an age when generalised atherosclerosis would be extremely unlikely) with risk of CHD and stroke in later life in a cohort of females and males on whom information on a wide range of potential confounding factors is available. Methods Cohort study of 11,125 individuals born in Aberdeen, Scotland, between 1950 and 1956, who had childhood intelligence measured at ages 7, 9, 11 and who have been followed up by linkage to hospital admissions and mortality data. Results The cohort contributed 264,672 person years of follow-up and over this time 93 females experienced CHD and 56 experienced a stroke; 264 males experienced CHD and 67 a stroke. There were inverse associations of childhood intelligence measured at all 3 ages (7, 9, 11 years) with both CHD and stroke, with some evidence that the association with intelligence assessed at age 11 was stronger than at younger ages. The magnitude of associations were similar for CHD and stroke. Adjustment for a range of potential confounding factors did not markedly attenuate the associations and there was evidence that the association was stronger in females than in males. For example, the age adjusted hazard ratio of a combined outcome of CHD and stroke per 1 standard deviation (SD; 1SD = 15 points) difference in intelligence score at age 11 in females was 0.52 (95% CI: 0.42, 0.64) and in males was 0.78 (95% CI: 0.68, 0.90), with adjustment for all potential confounding factors these became 0.60 (95% CI: 0.48, 0.76) and 0.84 (95% CI: 0.72, 0.98) respectively; P-value for interaction with gender in both models =0.002. Adjustment for educational attainment attenuated both associations to the null and removed evidence of a gender difference. Conclusions Our results suggest an association of intelligence in childhood with future CHD and stroke that is unlikely to be explained by reverse causality and was robust to adjustment for a wide range of confounding factors. This association appeared to be mediated by educational attainment. The gender difference seen in our study requires replication in other studies.

Physical activity in older women: associations with area deprivation and with socioeconomic position over the life course: observations in the British Women’s Heart and Health Study

Abstract: Objective: To assess the association between residential area-level deprivation, individual life-course socioeconomic position and adult levels of physical activity in older British women. Methods: A cross-sectional study of 4286 British women aged 60–79 years at baseline, who were randomly selected from general practitioner lists in 23 British towns between April 1999 and March 2001 (the British Women’s Heart and Health Study). Results: All three of childhood socioeconomic position, adult socioeconomic position and area of residence (in adulthood) deprivation were independently (of each other and potential confounders) associated with physical activity. There was a cumulative effect of life-course socioeconomic position on physical activity, with the proportion who undertook no moderate or vigorous activity per week increasing linearly with each additional indicator of life-course socioeconomic position (p Conclusion: Adverse socioeconomic position across the life-course is associated with an increased cumulative risk of low physical activity in older women. Reducing socioeconomic inequalities across the life course would thus be expected to improve levels of physical activity and the associated health benefits in later life.

Intrauterine Exposure to Alcohol and Tobacco Use and Childhood IQ: Findings from a Parental-Offspring Comparison within the Avon Longitudinal Study of Parents and Children

Abstract: This study aims to test the hypothesis that moderate maternal alcohol and tobacco use in pregnancy is associated with intelligent quotient (IQ) scores in childhood through intrauterine mechanisms. We conducted parental-offspring comparisons between the associations of tobacco and alcohol consumption with child's IQ in the Avon Longitudinal Study of Parents and Children. Analyses were conducted on 4332 participants with complete data on maternal and paternal use of alcohol and tobacco at 18 wk gestation, child's IQ and a range of confounders. IQ was measured at child age 8 with the Weschler Intelligence Scale for Children (WISC-III). We used multivariable linear and logistic regression to estimate mean differences and 95% confidence intervals in IQ scores across the exposure categories and computed f statistics to compare maternal and paternal associations. In fully adjusted models, there was no strong statistical evidence that maternal alcohol and tobacco consumption during pregnancy were associated with childhood IQ with any greater magnitude than paternal alcohol and tobacco consumption (also assessed during their partners' pregnancy). Our findings suggest that the relationship between maternal moderate alcohol and tobacco use in early pregnancy and childhood IQ may not be explained by intrauterine mechanisms.

A modified Mediterranean diet is associated with the greatest reduction in alanine aminotransferase levels in obese type 2 diabetes patients : results of a quasi-randomised controlled trial

Abstract: Aim The aim of the study was to compare the effect of different dietary interventions on alanine aminotransferase (ALT) in obese patients with diabetes.

Randomised controlled trial adapting US school obesity prevention to England.

Abstract: Objectives: To determine whether a school obesity prevention project developed in the United States can be adapted for use in England. Methods: A pilot cluster randomised controlled trial and interviews with teachers were carried out in 19 primary schools in South West England. Participants included 679 children in year 5 (age 9–10). Baseline and follow-up assessments were completed for 323 children (screen viewing) and 472 children (body mass index). Sixteen lessons on healthy eating, physical activity and reducing TV viewing were taught over 5 months by teachers. Main outcome measures were hours of screen activities, body mass index, mode of transport to school and teachers’ views of the intervention. Results: Children from intervention schools spent less time on screen-viewing activities after the intervention but these differences were imprecisely estimated: mean difference in minutes spent on screen viewing at the end of the intervention (intervention schools minus control schools) adjusted for baseline levels and clustering within schools was −11.6 (95% CI −42.7 to 19.4) for a week day and was −15.4 (95% CI −57.5 to 26.8) for a Saturday. There was no difference in mean body mass index or the odds of obesity. Conclusions: It is feasible to transfer this US school-based intervention to UK schools, and it may be effective in reducing the time children spend on screen-based activities. The study has provided information for a full-scale trial, which would require 50 schools (∼1250 pupils) to detect effects on screen viewing and body mass index over 2 years of follow-up.

Associations of birth size and duration of breast feeding with cardiorespiratory fitness in childhood: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC).

Abstract: Objectives: To explore the developmental origins of cardiorespiratory fitness. Methods: We examined the associations of birth size and duration of breast feeding with cardiorespiratory fitness assessed at the 9 year follow-up examination in 3612 participants of the Avon Longitudinal Study of Parents and Children (ALSPAC). We used physical work capacity at a heart rate of 170 beats per minute (PWC170) as our assessment of cardiorespiratory fitness. This was estimated using standard regression methods from parameters measured using an electronically braked cycle ergometer. Results: Birth weight, length and ponderal index were all positively associated with cardiorespiratory fitness in both sexes, with no strong evidence of a difference in effect between girls and boys. Work capacity increased by 1.12 W (95% CI: 0.83, 1.40) on average per 1 standard deviation (SD) greater birth weight. This association was not affected by adjustment for socioeconomic position and maternal smoking during pregnancy; there was some attenuation with adjustment for both maternal and paternal height and body mass index and more marked attenuation with adjustment for the child’s height and body mass index. In the fully adjusted model work capacity increased by 0.51 W (95% CI: 0.21, 0.81) per SD birth weight. Whether an individual had been breastfed and duration of breastfeeding were not associated with cardiorespiratory fitness in any models. Conclusion: Our results provide some support for a role of intrauterine factors in determining cardiorespiratory fitness in childhood.

Lifetime body mass index and later atherosclerosis risk in young adults: examining causal links using Mendelian randomization in the Cardiovascular Risk in Young Finns study

Abstract: Aims Mendelian randomization uses genetic variants related to environmentally modifiable risk factors in an attempt to improve causal inference from observational data. We examined the effect of lifetime body mass index (BMI) on adult carotid intima-media thickness (CIMT) and various atherosclerotic risk factors by using both Mendelian randomization and conventional analyses. Methods and results A total of 2230 individuals (1218 women), aged 3–18 at study induction, took part in clinical examinations in 1980, 1983, 1986, and, most recently, 2001 when they were aged 24–39. In these analyses we utilized the known relation between FTO polymorphism rs9939609 and BMI. The dose–response association between the number of A alleles in FTO and higher mean BMI from childhood to adulthood was confirmed, but no associations with potential confounding factors were observed. In standard regression models, lifetime BMI was associated with adult CIMT, lifetime systolic blood pressure, adult fasting glucose, and adult HOMA-index. When variation in FTO was used as an instrument for unconfounded BMI levels, similar or larger effects of lifetime BMI on all these phenotypes were found, although with wider confidence intervals. Conclusion Mutually supportive results from Mendelian randomization and standard regression models strengthen the evidence of the effect of lifetime BMI on atherosclerosis risk in young adults.

High molecular weight adiponectin is not associated with incident coronary heart disease in older women: a nested prospective case-control study.

Abstract: Context: Adiponectin levels appear weakly linked to incident vascular disease, but the high molecular weight (HMW) fraction may be more relevant. Objective: Our objective was to test whether HMW adiponectin, the key biologically active fraction, is linked to incident coronary heart disease (CHD) events. Design, Participants, and Main Outcome Measures: We assessed the association between HMW adiponectin (measured by ELISA) and CHD risk in a prospective (4-yr) case-control study nested within the British Women's Heart and Health Study. All women were postmenopausal. Setting: Women were seen in a primary care setting. Results: Among both cases (n = 167) and controls (n = 333), HMW adiponectin positively correlated with age and high-density lipoprotein cholesterol and inversely correlated with waist to hip ratio, fasting insulin, fasting glucose, homeostasis model assessment for insulin resistance scores, C-reactive protein, and triglycerides, in similar fashion to total adiponectin. The age-adjusted relative...

Sodium intake in infancy and blood pressure at 7 years: Findings from the Avon Longitudinal Study of Parents and Children

Abstract: Sodium intake in infancy and blood pressure at 7 years: findings from the Avon Longitudinal Study of Parents and Children

Does High C-reactive Protein Concentration Increase Atherosclerosis? The Whitehall II Study

Abstract: Background: C-reactive protein (CRP), a marker of systemic inflammation, is associated with risk of coronary events and subclinical measures of atherosclerosis. Evidence in support of this link being causal would include an association robust to adjustments for confounders (multivariable standard regression analysis) and the association of CRP gene polymorphisms with atherosclerosis (Mendelian randomization analysis).Methodology/Principal Findings: We genotyped 3 tag single nucleotide polymorphisms (SNPs) [+ 1444T>C (rs1130864); +2303G>A (rs1205) and +4899T>G (rs 3093077)] in the CRP gene and assessed CRP and carotid intima-media thickness (CIMT), a structural marker of atherosclerosis, in 4941 men and women aged 50-74 (mean 61) years (the Whitehall II Study). The 4 major haplotypes from the SNPs were consistently associated with CRP level, but not with other risk factors that might confound the association between CRP and CIMT. CRP, assessed both at mean age 49 and at mean age 61, was associated both with CIMT in age and sex adjusted standard regression analyses and with potential confounding factors. However, the association of CRP with CIMT attenuated to the null with adjustment for confounding factors in both prospective and cross-sectional analyses. When examined using genetic variants as the instrument for serum CRP, there was no inferred association between CRP and CIMT.Conclusions/Significance: Both multivariable standard regression analysis and Mendelian randomization analysis suggest that the association of CRP with carotid atheroma indexed by CIMT may not be causal.

Obesity in children. Part 2: Prevention and management

Abstract: #### Summary points In the first part of this article we described how obesity in children is measured, its prevalence, whether children should be screened, and the risk factors for and consequences of obesity.1 In this part we review the current evidence on the prevention and management of childhood obesity. #### Sources and selection criteria This review draws on the Foresight report, guidance from the National Institute for Health and Clinical Excellence and the Australian National Health Medical Research Council, and Cochrane review. In April 2008 we searched the Cochrane Library database of reviews and the Centre for Reviews and Dissemination databases using the search term “obesity”. We also conducted a Medline search ((Child$ or paediatric or pediatric or adolescent) and (Obes$ or overweight)) limited to 1 January 2005 to 6 May 2008 and “review articles”; this identified 1105 articles. We read the abstracts of these articles and retrieved relevant papers. We also used articles from our own bibliographies collected over the past 10 years. The evidence to support the measurement, prevention, and management of obesity in children is still relatively weak, with few randomised controlled trials or systematic reviews. The strength of evidence is developing and the updated Cochrane review that will be published in 2009 …

The methylenetetrahydrofolate reductase C677T genotype and the risk of obesity in three large population-based cohorts.

Abstract: Objective: Epidemiological studies have shown that low folate levels are associated with a high body mass index (BMI). These findings have potentially important health implications and warrant further investigation to determine whether a causal relationship exists and the direction of this relationship. The methylenetetrahydrofolate reductase (MTHFR) C677T TT genotype is associated with reduced folate availability and may be a surrogate for measuring folate levels. We sought to determine whether MTHFR C677T genotype was associated with obesity. Design: We carried out our study on four populations from three longitudinal studies based in the UK and Denmark in which DNA for genotyping was obtained along with measures of obesity. Methods: Our subjects were taken from the British Women’s Heart and Health Study (BWHHS), the Avon Longitudinal Study of Parents and Children (two populations: mothers and children) and the Copenhagen City Heart Study. We performed analyses separately by population, and then carried out a meta-analysis, combining similar populations. Results: Initial findings in the BWHHS suggested that the TT genotype may be associated with an increased risk of obesity BMIR30, however, no association was found with BMI or central adiposity in this cohort. This genotype was not associated with obesity in our other cohorts. Conclusions: Our results suggest that the initial positive finding with obesity in the BWHHS was a chance finding. Our findings do not support a causal effect of low folate on obesity.

Life‐course socio‐economic position, area deprivation and Type 2 diabetes: findings from the British Women's Heart and Health Study

Abstract: Objectives We examined whether area deprivation influenced risk of Type 2 diabetes, fasting blood glucose and insulin resistance over and above the effect of individual socio-economic position (SEP) measured across the life course. Methods A cross-sectional analysis of 4286 women aged 60 to 79 years from 457 British electoral wards in 23 towns. Results Area deprivation was positively associated with diagnosed [odds ratio (OR) 1.32, 95% confidence interval (CI) 1.13, 1.53, per quintile of area deprivation, n = 2895], but not undiagnosed Type 2 diabetes after adjustment for individual life-course SEP. This association was robust to adjustment for adult health behaviours and physiological risk factors. Insulin resistance [homeostasis model assessment (HOMA) score] increased by 1.90% (95% CI 0.01, 3.82, n = 2526) per quintile of area deprivation after adjustment for individual SEP, while fasting blood glucose increased by 0.69% (95% CI 0.16, 1.22, n = 2875) after adjustment for individual SEP. Conclusions Area level deprivation independently influences diagnosed Type 2 diabetes, insulin resistance and fasting blood glucose. Examination of more specific characteristics of places is needed to understand the mechanisms by which these effects arise.