Showing papers by "Debbie A Lawlor published in 2010"

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Abstract: Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Abstract: Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Abstract: Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and approximately 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-)(8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Abstract: Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

Genome-wide association study identifies five loci associated with lung function.

Abstract: Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n < or = 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n < or = 883). We confirmed the reported locus at 4q31 and identified associations with FEV(1) or FEV(1)/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.

Association of maternal weight gain in pregnancy with offspring obesity and metabolic and vascular traits in childhood.

Abstract: Background— We sought to examine the association of gestational weight gain (GWG) and prepregnancy weight with offspring adiposity and cardiovascular risk factors. Methods and Results— Data from 5154 (for adiposity and blood pressure) and 3457 (for blood assays) mother-offspring pairs from a UK prospective pregnancy cohort were used. Random-effects multilevel models were used to assess incremental GWG (median and range of repeat weight measures per woman: 10 [1, 17]). Women who exceeded the 2009 Institute of Medicine–recommended GWG were more likely to have offspring with greater body mass index, waist, fat mass, leptin, systolic blood pressure, C-reactive protein, and interleukin-6 levels and lower high-density lipoprotein cholesterol and apolipoprotein A1 levels. Children of women who gained less than the recommended amounts had lower levels of adiposity, but other cardiovascular risk factors tended to be similar in this group to those of offspring of women gaining recommended amounts. When examined in ...

Association between general and central adiposity in childhood, and change in these, with cardiovascular risk factors in adolescence: prospective cohort study

Abstract: Objectives To examine the prospective associations between body mass index (BMI), waist circumference, and fat mass in childhood and cardiovascular risk factors at age 15-16. Design Prospective cohort study. Setting Avon Longitudinal Study of Parents and Children. Participants 5235 children aged 9-12 at start of study. Main exposures BMI, waist circumference, and fat mass determined by dual energy x ray absorptiometry, assessed at age 9-12 and at age 15-16. Main outcome measures Systolic and diastolic blood pressure and concentrations of fasting glucose, insulin, triglycerides, low density lipoprotein cholesterol, and high density lipoprotein cholesterol assessed at age 15-16. Results In girls a 1 SD greater BMI at age 9-12 was associated with cardiovascular risk factors at age 15-16 in fully adjusted models: odds ratio 1.23 (95% confidence interval 1.10 to 1.38) for high systolic blood pressure (≥130 mm Hg); 1.19 (1.03 to 1.38) for high concentration of low density lipoprotein cholesterol (≥2.79 mmol/l); 1.43 (1.06 to 1.92) for high concentration of triglycerides (≥1.7 mmol/l); 1.25 (1.08 to 1.46) for low concentration of high density lipoprotein cholesterol ( 0.2 for heterogeneity). When waist circumference or fat mass or both were added to models including BMI they did not increase the variation in cardiovascular risk factors already explained by BMI and confounders alone. Girls who were overweight/obese at age 9-12 but were normal weight by 15-16 had similar odds of adverse levels of risk factors to those who were normal weight at both ages. In boys odds of high systolic blood pressure, high concentrations of triglycerides and insulin, and low concentrations of high density lipoprotein cholesterol remained higher in this group compared with those who were normal weight at both ages but were lower than in those who remained overweight/obese at both ages. Conclusions Measurements of waist circumference or directly assessed fat mass in childhood do not seem to be associated with cardiovascular risk factors in adolescence any more strongly than BMI. Girls who favourably alter their overweight status between childhood and adolescence have cardiovascular risk profiles broadly similar to those who were normal weight at both time points, but boys who change from overweight to normal show risk factor profiles intermediate between those seen in boys who are normal weight at both ages or overweight at both ages.

Genetic loci influencing kidney function and chronic kidney disease

Abstract: Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10(-10) to 10(-15)). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 x 10(-5) and P = 3.6 x 10(-4), respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease.

Association of existing diabetes, gestational diabetes and glycosuria in pregnancy with macrosomia and offspring body mass index, waist and fat mass in later childhood: findings from a prospective pregnancy cohort

Abstract: The aim of the study was to examine the association of existing diabetes (i.e. already diagnosed prior to pregnancy), gestational diabetes and glycosuria (both diagnosed and ascertained during pregnancy) with birthweight and future offspring BMI, waist circumference and fat mass (assessed by dual x-ray emission absorptiometry). A prospective pregnancy/birth cohort study was performed using data from the Avon Longitudinal Study of Parents and Children. Among 10,591 mother–offspring pairs included in analyses with birth size, women with existing diabetes (n = 40), those diagnosed with gestational diabetes (n = 53) and those with at least two episodes of ++ glycosuria (n = 372) had greater mean birthweight and odds for macrosomia (birthweight > 4,000 g) than women with none of these. Adjusted odds ratios for macrosomia were 3.56 (95% CI 1.53–8.28), 5.50 (95% CI 1.18–10.30) and 1.58 (95% CI 1.18–2.12) for existing diabetes, gestational diabetes and glycosuria, respectively. Among 6,842 mother–offspring pairs with anthropometric measurements at age 9–11 years, maternal gestational diabetes and glycosuria (but not existing diabetes) were associated with increased offspring odds of general or central overweight/obesity. For gestational diabetes, these associations attenuated towards the null with adjustment for maternal prepregnancy BMI, but independent associations remained for glycosuria. The adjusted odds ratio for general overweight/obesity when comparing women with at least two episodes of ++ glycosuria with those with no evidence of diabetes or glycosuria was 1.35 (95% CI 1.00–1.82) and that for central obesity (top 10% waist circumference vs all others) was 1.31 (95% CI 1.00–1.72). These results provide some evidence for a long-term effect of maternal glycaemia in pregnancy on offspring obesity risk.

Preeclampsia and Gestational Hypertension Are Associated With Childhood Blood Pressure Independently of Family Adiposity Measures The Avon Longitudinal Study of Parents and Children

Abstract: Background—Offspring of women with hypertensive disorders of pregnancy are at increased risk of cardiovascular complications later in life, but the mechanisms underlying these associations are unclear. Our aim was to examine whether adjusting for birth weight and familial adiposity changed the association of hypertensive disorders of pregnancy with offspring blood pressure. Methods and Results—Using data from 6343 nine-year-old participants in the Avon Longitudinal Study of Parents and Children, we examined the association between hypertensive disorders of pregnancy (preeclampsia and gestational hypertension) and offspring blood pressure. Both preeclampsia and gestational hypertension were associated with systolic and diastolic blood pressures in the 9-year-old offspring; after adjustment for parental and own adiposity and for other potential confounders, the mean difference in systolic blood pressure was 2.05 mm Hg (95 confidence interval, 0.72 to 3.38) and 2.04 mm Hg (95 confidence interval, 1.42 to 2.6...

Adiposity and cardiovascular risk factors in a large contemporary population of pre-pubertal children

Abstract: Aims To examine the associations of several markers of adiposity and a wide range of cardiovascular risk factors and biomarkers in pre-pubertal children. Methods and results Four measures of adiposity,body mass index (BMI), waist circumference, dual-energy X-ray absorptiometry (DXA)-determined fat mass, and leptin concentration, were available in up to 7589 children aged 8.8–11.7 (9.9 mean) years from the Avon Longitudinal Study of Parents and Children (ALSPAC). Thirteen per cent of boys and 18.8% of girls were overweight, and 5.3% of boys and 5% of girls were obese. Body mass index was highly correlated with waist circumference ( r = 0.91), DXA fat mass ( r = 0.87), and leptin concentration ( r = 0.75), and all had similar associations with cardiovascular risk factors. A 1 kg/m2 greater BMI was associated with 1.4mmHg (95% CI 1.25–1.44) higher systolic blood pressure (BP). In 5002 children, a 1 kg/m2 greater BMI was associated with a 0.05 mmol/L (95% CI 0.036–0.055) higher non-high-density lipoprotein (HDL) cholesterol and 0.03 mmol/L (95% CI −0.034 to −0.025) lower HDL cholesterol. There were also graded associations with apolipoproteins A1 and B, interleukin-6, and C-reactive protein. Comparing children who were obese with those who were normal weight, the odds ratio for hypertension was 10.7 (95% CI 7.2–15.9) for boys and 13.5 (95% CI 9.4–19.5) for girls. Conclusion In pre-pubertal UK children, overweight/obesity is common and has broadly similar associations with BP, HDL cholesterol, and non-HDL cholesterol to those observed in adults. Future research should evaluate whether effective interventions to maintain healthy weight in childhood could have important benefits for adult cardiovascular risk.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Abstract: Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Maternal Smoking and Child Psychological Problems: Disentangling Causal and Noncausal Effects

Abstract: OBJECTIVE: To explore associations of maternal prenatal smoking and child psychological problems and determine the role of causal intrauterine mechanisms. PATIENTS AND METHODS: Maternal smoking and child psychological problems were explored in 2 birth cohorts in Pelotas, Brazil ( n = 509, random subsample), and the Avon Longitudinal Study of Parents and Children (ALSPAC) in Britain ( n = 6735). Four approaches for exploring causal mechanisms were applied: (1) cross-population comparisons between a high-income and a middle-income country; (2) multiple adjustment for socioeconomic and parental psychological factors; (3) maternal-paternal comparisons as a test of putative intrauterine effects; and (4) searching for specific effects on different behavioral subscales. RESULTS: Socioeconomic patterning of maternal prenatal smoking was stronger in the ALSPAC compared with the Pelotas cohort. Despite this difference in a key confounder, consistency in observed associations was found between these cohorts. In both cohorts, unadjusted maternal smoking was associated with greater offspring hyperactivity, conduct/externalizing problems, and peer problems but not with emotional/internalizing problems. After adjusting for confounders and paternal prenatal smoking, only the association with conduct/externalizing problems persisted in both cohorts (conduct problems in the ALSPAC cohort, odds ratio [OR]: 1.24 [95% confidence interval (CI): 1.07–1.46], P = .005; externalizing problems in the Pelotas cohort, OR: 1.82 [95% CI: 1.19–2.78], P = .005; ORs reflect ordinal odds ratios of maternal smokers having offspring with higher scores). Maternal smoking associations were stronger than paternal smoking associations, although statistical evidence that these associations differed was weak in 1 cohort. CONCLUSION: Evidence from 4 approaches suggests a possible intrauterine effect of maternal smoking on offspring conduct/externalizing problems.

Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms

Abstract: Background-Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target. Methods and Results-We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI -0.28 to 0.60 mm Hg) and diastolic blood pressure (-0.04 mm Hg, 95% CI -0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib. Conclusions-Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans. (Circulation. 2010; 121: 52-62.)

Changes in ponderal index and body mass index across childhood and their associations with fat mass and cardiovascular risk factors at age 15.

Abstract: Background: Little is known about whether associations between childhood adiposity and later adverse cardiovascular health outcomes are driven by tracking of overweight from childhood to adulthood and/or by vascular and metabolic changes from childhood overweight that persist into adulthood. Our objective is to characterise associations between trajectories of adiposity across childhood and a wide range of cardiovascular risk factors measured in adolescence, and explore the extent to which these are mediated by fat mass at age 15. Methods and Findings: Using data from the Avon Longitudinal Study of Parents and Children, we estimated individual trajectories of ponderal index (PI) from 0–2 years and BMI from 2–10 years using random-effects linear spline models (N=4601). We explored associations between PI/BMI trajectories and DXA-determined total-body fat-mass and cardiovascular risk factors at 15 years (systolic and diastolic blood pressure, fasting LDL- and HDL-cholesterol, triglycerides, C-reactive protein, glucose, insulin) with and without adjustment for confounders. Changes in PI/BMI during all periods of infancy and childhood were associated with greater DXA-determined fat-mass at age 15. BMI changes in childhood, but not PI changes from 0–2 years, were associated with most cardiovascular risk factors in adolescence; associations tended to be strongest for BMI changes in later childhood (ages 8.5–10), and were largely mediated by fat mass at age 15. Conclusion: Changes in PI/BMI from 0–10 years were associated with greater fat-mass at age 15. Greater increases in BMI from age 8.5–10 years are most strongly associated with cardiovascular risk factors at age 15, with much of these associations mediated by fat-mass at this age. We found little evidence supporting previous reports that rapid PI changes in infancy are associated with future cardiovascular risk. This study suggests that associations between early overweight and subsequent adverse cardiovascular health are largely due to overweight children tending to remain overweight.

Associations of serum 25-hydroxyvitamin D, parathyroid hormone and calcium with cardiovascular risk factors: analysis of 3 NHANES cycles (2001-2006).

Abstract: Background Increasing evidence suggests a role for mineral metabolism in cardiovascular disease risk 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH), and calcium may be directly associated with cardiovascular risk factors or mediated by each other Methodology/Principal Findings We combined data for adult participants in three cycles of the National Health and Nutrition Examination Survey (2001–2, 2003–4, 2005–6), a representative sample of the civilian, non-institutionalized US population (N = 3,958) Using this data we examined joint associations of 25(OH)D, PTH and calcium with a range of cardiovascular risk factors 25(OH)D was inversely associated with fasting insulin (mean difference in insulin per 1 standard deviation 25(OH)D: −0053 (95%CI: −0091, −0015)), glucose (−0046 95%CI: −0081, −0012) and systolic blood pressure (SBP) (−0032 95%CI: −0062, −0001), and positively associated with high density lipoprotein cholesterol HDL-c (0088 95%CI: 0044, 0148), after adjustment for ethnicity, smoking, socio-economic status and waist circumference PTH was positively associated with diastolic blood pressure (0110, 95%CI: 0055, 0164) in confounder adjusted models, but was not associated with other cardiovascular risk factors Albumin adjusted calcium was associated with triglycerides (0102 95%CI: 0063, 0141), postload glucose (0078, 95%CI: 0025, 0130), fasting insulin (0074, 95%CI: 0044, 0104), HbA1c (0070, 95%CI: 0036, 0105), SBP (0064, 95%CI: 0028, 0100), fasting glucose (0055, 95%CI: 0018, 0092) and low density lipoprotein cholesterol (0052, 95%CI: 0014, 0091) With mutual adjustment for each other, these associations remained essentially unchanged Conclusions/Significance Lower levels of 25(OH)D and higher levels of calcium and PTH appear to be associated with different cardiovascular risk factors and may therefore affect cardiovascular disease risk through different mechanisms

Determinants of vascular phenotype in a large childhood population: the Avon Longitudinal Study of Parents and Children (ALSPAC)

Abstract: Aims: To assess the feasibility and reproducibility of non-invasive vascular assessment in a childhood population setting and identify the determinants of vascular phenotype in early life. Methods and results: We studied 7557 children (age 9.8–12.3 years) participating in the Avon Longitudinal Study of Parents and Children (ALSPAC). Six research technicians underwent a 5-month training protocol to enable study of brachial artery endothelial function by flow-mediated dilatation (FMD) and arterial stiffness by carotid to radial pulse wave velocity (PWV) and brachial distensibility [distensibility coefficient (DC)]. Reproducibility studies were performed at the beginning, the middle, and the end of the study. A blinded repeat evaluation of a random selection of 3% of the cohort was also undertaken throughout the study. The effect of anthropometric and environmental factors on each measure was examined. Successful measures were obtained in 88, 95, and 87% of the studied children for FMD, PWV, and DC, respectively. The coefficients of variation between technicians for FMD, PWV, and DC were 10.5, 4.6, and 6.6% at the beginning of the study and reached 7.7, 4.1, and 10% at the end. Baseline vessel diameter and gender were important determinants of all the vascular measures, with a small effect of room and skin temperatures on FMD and PWV. Boys consistently had lower FMD and DC and higher PWV measures (P < 0.01 for all). Conclusion: Reproducible, high-quality assessments of vascular structure and function in children can be made on a large scale in field studies by suitably trained non-specialist operators. This study provides an invaluable resource for assessing the impact of early influences, genetic, and environmental factors on arterial phenotype.

Assessing prediction of diabetes in older adults using different adiposity measures: a 7 year prospective study in 6,923 older men and women

Abstract: Aims/hypothesis The aim of this study was to examine whether waist circumference (WC) or WHR improve diabetes prediction beyond body mass index in older men and women, and to define optimal cut-off points.

Cotinine-assessed second-hand smoke exposure and risk of cardiovascular disease in older adults

Abstract: Objectives To examine whether second-hand smoke (SHS) exposure measured by serum cotinine is associated with increased coronary heart disease (CHD) and stroke risk among contemporary older British adults. Design Prospective population-based study with selfreported medical history and health behaviours. Fasting blood samples were analysed for serum cotinine and cardiovascular disease (CVD) risk markers. Setting Primary care centres in 25 British towns in 1998e2001. Patients 8512 60e79-year-old men and women selected from primary care registers. Main outcome measures Fatal and non-fatal myocardial infarction (MI; n¼445) and stroke (n¼386) during median 7.8-year follow-up. Main exposure Observational study of serum cotinine assayed from fasting blood sample using liquid chromatography tandem mass spectrometry method, and self-reported smoking history. Results Among 5374 non-smokers without pre-existing CVD, geometric mean cotinine was 0.15 ng/ml (IQR 0.05e0.30). Compared with non-smokers with cotinine #0.05 ng/ml, higher cotinine levels (0.06e0.19, 0.2e0.7 and 0.71e15.0 ng/ml) showed little association with MI; adjusted HRs were 0.92 (95% CI 0.63 to 1.35), 1.07 (0.73 to 1.55) and 1.09 (0.69 to 1.72), p(trend)¼ 0.69. Equivalent HRs for stroke were 0.82 (0.55 to 1.23), 0.74 (0.48 to 1.13) and 0.69 (0.41 to 1.17), p(trend)¼ 0.065. The adjustment for sociodemographic, behavioural and CVD risk factors had little effect on the results. The HR of MI for smokers (1e9 cigarettes/day) compared with non-smokers with cotinine #0.05 ng/ml was 2.14 (1.39 to 3.52) and 1.03 (0.52 to 2.04) for stroke. Conclusions In contemporary older men and women, SHS exposure (predominantly at low levels) was not related to CHD or stroke risks, but we cannot rule out the possibility of modest effects at higher exposure levels.

Are there socioeconomic inequalities in cardiovascular risk factors in childhood, and are they mediated by adiposity? Findings from a prospective cohort study.

Abstract: Socioeconomic gradients in adiposity were not present during childhood for previous generations, but have emerged in contemporary children. It is unknown whether this translates to socioeconomic gradients in associated cardiovascular risk factors in children, with consequent implications for inequalities in coronary heart disease (CHD) and diabetes when these children reach adulthood. Using data from 7772 participants aged 10-years from the Avon Longitudinal Study of Parents and Children, we examined the association between maternal education and a large number of cardiovascular risk factors (cholesterol, triglycerides, high-density lipoprotein, apolipoprotein, adiponectin, leptin, C-reactive protein (CRP), interleukin-6 (IL-6) and systolic and diastolic blood pressure), and examined whether inequalities were mediated by adiposity, measured by dual energy X-ray absorptiometry (DXA)-assessed total fat mass. There were socioeconomic differences in a number of the cardiovascular risk factors (apolipoprotein B, systolic and diastolic blood pressure, CRP, leptin and IL-6). Inequalities were greater in girls than boys. Inequalities in CRP and leptin were completely mediated by adiposity. Inequalities in other cardiovascular risk factors were partially mediated by adiposity. This study showed important socioeconomic inequalities in adiposity and associated cardiovascular risk factors in a contemporary UK population of 10-year-old children. Differences between contemporary children and previous generations in the socioeconomic patterning of cardiovascular risk factors suggest future adults may have greater inequalities in diabetes and CHD than current adults. These findings highlight the importance of interventions aimed at preventing obesity in childhood, particularly among those of lower socioeconomic position.