Showing papers by "George Davey Smith published in 2007"

A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity

Abstract: Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.

Measuring socioeconomic position in health research

Abstract: Objective: In this article we review different measures of socioeconomic position (SEP) and their uses in health-related research. Areas of agreement: Socioeconomic circumstances influence health. Areas of controversy: Generally, poorer socioeconomic circumstances lead to poorer health. This has generated a search for generic mechanisms that could explain such a general association. However, we propose that there is a greater variation in the association between SEP and health than is generally acknowledged when specific health outcomes are investigated. We propose that studying these variations provide a better understanding of the aetiological mechanisms relating specific diseases with specific exposures. Areas to develop research: Using different indicators of SEP in health research can better capture these variations and is important when evaluating the full contribution of confounding by socioeconomic conditions. We propose that using an array of SEP indicators within a life course framework also offers considerable opportunity to explore causal pathways in disease aetiology.

The Impact of Residual and Unmeasured Confounding in Epidemiologic Studies: A Simulation Study

Abstract: Measurement error in explanatory variables and unmeasured confounders can cause considerable problems in epidemiologic studies. It is well recognized that under certain conditions, nondifferential measurement error in the exposure variable produces bias towards the null. Measurement error in confounders will lead to residual confounding, but this is not a straightforward issue, and it is not clear in which direction the bias will point. Unmeasured confounders further complicate matters. There has been discussion about the amount of bias in exposure effect estimates that can plausibly occur due to residual or unmeasured confounding. In this paper, the authors use simulation studies and logistic regression analyses to investigate the size of the apparent exposure-outcome association that can occur when in truth the exposure has no causal effect on the outcome. The authors consider two cases with a normally distributed exposure and either two or four normally distributed confounders. When the confounders are uncorrelated, bias in the exposure effect estimate increases as the amount of residual and unmeasured confounding increases. Patterns are more complex for correlated confounders. With plausible assumptions, effect sizes of the magnitude frequently reported in observational epidemiologic studies can be generated by residual and/or unmeasured confounding alone.

Clustered environments and randomized genes: a fundamental distinction between conventional and genetic epidemiology.

Abstract: Background In conventional epidemiology confounding of the exposure of interest with lifestyle or socioeconomic factors, and reverse causation whereby disease status influences exposure rather than vice versa, may invalidate causal interpretations of observed associations. Conversely, genetic variants should not be related to the confounding factors that distort associations in conventional observational epidemiological studies. Furthermore, disease onset will not influence genotype. Therefore, it has been suggested that genetic variants that are known to be associated with a modifiable (nongenetic) risk factor can be used to help determine the causal effect of this modifiable risk factor on disease outcomes. This approach, mendelian randomization, is increasingly being applied within epidemiological studies. However, there is debate about the underlying premise that associations between genotypes and disease outcomes are not confounded by other risk factors. We examined the extent to which genetic variants, on the one hand, and nongenetic environmental exposures or phenotypic characteristics on the other, tend to be associated with each other, to assess the degree of confounding that would exist in conventional epidemiological studies compared with mendelian randomization studies. Methods and Findings We estimated pairwise correlations between nongenetic baseline variables and genetic variables in a cross-sectional study comparing the number of correlations that were statistically significant at the 5%, 1%, and 0.01% level (a ¼ 0.05, 0.01, and 0.0001, respectively) with the number expected by chance if all variables were in fact uncorrelated, using a two-sided binomial exact test. We demonstrate that behavioural, socioeconomic, and physiological factors are strongly interrelated, with 45% of all possible pairwise associations between 96 nongenetic characteristics (n ¼ 4,560 correlations) being significant at the p , 0.01 level (the ratio of observed to expected significant associations was 45; p-value for difference between observed and expected , 0.000001). Similar findings were observed for other levels of significance. In contrast, genetic variants showed no greater association with each other, or with the 96 behavioural, socioeconomic, and physiological factors, than would be expected by chance.

A common variant of HMGA2 is associated with adult and childhood height in the general population

Abstract: Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P= 4x10(-8)). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P= 3x10(-11), overall P= 4x10(-16), including the genome-wide association data). We also observed the association in children (P=1x 10(-6), N= 6,827) and a tall/short case-control study (P= 4x10(-6), N=3,207). We estimate that rs1042725 explains similar to 0.3% of population variation in height (similar to 0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitative traits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height.

Objectively Measured Physical Activity and Fat Mass in a Large Cohort of Children

Abstract: Previous studies have been unable to characterise the association between physical activity and obesity, possibly because most relied on inaccurate measures of physical activity and obesity. We carried out a cross sectional analysis on 5,500 12-year-old children enrolled in the Avon Longitudinal Study of Parents and Children. Total physical activity and minutes of moderate and vigorous physical activity (MVPA) were measured using the Actigraph accelerometer. Fat mass and obesity (defined as the top decile of fat mass) were measured using the Lunar Prodigy dual x-ray emission absorptiometry scanner. We found strong negative associations between MVPA and fat mass that were unaltered after adjustment for total physical activity. We found a strong negative dose-response association between MVPA and obesity. The odds ratio for obesity in adjusted models between top and the bottom quintiles of minutes of MVPA was 0.03 (95% confidence interval [CI] 0.01-0.13, p-value for trend <0.0001) in boys and 0.36 (95% CI 0.17-0.74, p-value for trend = 0.006) in girls. We demonstrated a strong graded inverse association between physical activity and obesity that was stronger in boys. Our data suggest that higher intensity physical activity may be more important than total activity.

Objectively Measured Physical Activity and Fat Mass in a Large Cohort of Children

Abstract: Previous studies have been unable to characterise the association between physical activity and obesity, possibly because most relied on inaccurate measures of physical activity and obesity. We carried out a cross sectional analysis on 5,500 12-year-old children enrolled in the Avon Longitudinal Study of Parents and Children. Total physical activity and minutes of moderate and vigorous physical activity (MVPA) were measured using the Actigraph accelerometer. Fat mass and obesity (defined as the top decile of fat mass) were measured using the Lunar Prodigy dual x-ray emission absorptiometry scanner. We found strong negative associations between MVPA and fat mass that were unaltered after adjustment for total physical activity. We found a strong negative dose-response association between MVPA and obesity. The odds ratio for obesity in adjusted models between top and the bottom quintiles of minutes of MVPA was 0.03 (95% confidence interval [CI] 0.01-0.13, p-value for trend <0.0001) in boys and 0.36 (95% CI 0.17-0.74, p-value for trend = 0.006) in girls. We demonstrated a strong graded inverse association between physical activity and obesity that was stronger in boys. Our data suggest that higher intensity physical activity may be more important than total activity.

Prepregnancy cardiovascular risk factors as predictors of pre-eclampsia: population based cohort study

Abstract: Objective To examine the effect of cardiovascular risk factors before pregnancy on risk of pre-eclampsia Design Population based prospective study Setting Linkage between a Norwegian population based study (Nord-Trondelag health study, HUNT-2) and Norway9s medical birth registry Participants 3494 women who gave birth after participating in the Nord-Trondelag health study at baseline; of whom 133 (38%) delivered after a pre-eclamptic pregnancy Main outcome measure Odds ratio of developing pre-eclampsia Results After adjustment for smoking; previous pre-eclampsia; parity; maternal age, education, and socioeconomic position; and duration between baseline measurements and delivery, positive associations were found between prepregnancy serum levels of triglycerides, cholesterol, low density lipoprotein cholesterol, non-high density lipoprotein cholesterol, and blood pressure and risk of pre-eclampsia The odds ratio of developing pre-eclampsia for women with baseline systolic blood pressures greater than 130 mm Hg (highest fifth) was 73 (95% confidence interval 31 to 172) compared with women with systolic blood pressures less than 111 mm Hg (lowest fifth) Similar results were found for nulliparous and parous women Women who used oral contraceptives at baseline had half the risk of pre-eclampsia compared with never or former users (05, 03 to 09) Conclusion Women with cardiovascular risk factors may be predisposed to pre-eclampsia

Gamma-Glutamyltransferase Is Associated With Incident Vascular Events Independently of Alcohol Intake: Analysis of the British Women’s Heart and Health Study and Meta-Analysis

Abstract: Objective—To investigate the association of -glutamyltransferase (GGT) with incident CHD and stroke. GGT is a marker of alcohol intake but may also reflect oxidative stress and nonalcoholic fatty liver disease. Alanine aminotransferase (ALT) is the enzyme most closely associated with liver fat content. Methods and Results—Associations of GGT and ALT with incident CHD, stroke, and a combined outcome of CHD or stroke were examined in the British Women’s Heart and Health study (n2961), and a meta-analysis of population based studies examining these associations was performed. In pooled analyses of fully adjusted results of 10 prospective studies, a change of 1 U/L of GGT was associated with a HR1.20 (95% CI: 1.02, 1.40) for CHD; a HR1.54 (95% CI: 1.20, 2.00) for stroke; and HR1.34 (95% CI: 1.22, 1.48) for CHD or stroke. Heterogeneity was substantially decreased when 2 studies in Asian populations were excluded. In a subgroup of nondrinkers results were similar to the main analysis. Meta analyses of the only 2 studies that examined the association of ALT with incident cardiovascular events found a HR1.18 (95% CI: 0.99, 1.41) for CHD and a HR1.10 (95% CI: 0.89, 1.36) for CHD or stroke (combined). Conclusion—GGT is associated with incident vascular events independently of alcohol intake. The mechanisms underlying this association remain unclear and require future study. (Arterioscler Thromb Vasc Biol. 2007;27:2729-2735.)

Socioeconomic Position, Co-Occurrence of Behavior-Related Risk Factors, and Coronary Heart Disease: the Finnish Public Sector Study

Abstract: Objectives. We examined the associations between socioeconomic position, co-occurrence of behavior-related risk factors, and the effect of these factors on the relative and absolute socioeconomic gradients in coronary heart disease.Methods. We obtained the socioeconomic position of 9337 men and 39 255 women who were local government employees aged 17–65 years from employers’ records (the Public Sector Study, Finland). A questionnaire survey in 2000–2002 was used to collect data about smoking, heavy alcohol consumption, physical inactivity, obesity, and prevalence of coronary heart disease (myocardial infarction or angina diagnosed by a doctor).Results. The age-adjusted odds of coronary heart disease were 2.1–2.2 times higher for low-income groups than high-income groups for both men and women, and adjustment for risk factors attenuated these associations by 13%–29%. There was no further attenuation with additional adjustment for the number of co-occurring risk factors, although socioeconomic disadvantage ...

Is there an intrauterine influence on obesity? Evidence from parent–child associations in the Avon Longitudinal Study of Parents and Children (ALSPAC)

Abstract: 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.

Income inequality and the double burden of under- and overnutrition in India

Abstract: Objectives: Developing countries are increasingly characterised by the simultaneous occurrence of under- and overnutrition. This study examined the association between contextual income inequality and the double burden of under- and overnutrition in India. Design: A population-based multilevel study of 77 220 ever married women, aged 15–49 years, from 26 Indian states, derived from the 1998–99 Indian National Family Health Survey data. The World Health Organization recommended categories of body mass index constituted the outcome, and the exposure was contextual measure of state income inequality based on the Gini coefficient of per capita consumption expenditure. Covariates included a range of individual demographic, socioeconomic, behavioural and morbidity measures and state-level economic development. Results: In adjusted models, for each standard deviation increase in income inequality, the odds ratio for being underweight increased by 19% (p = 0.02) and the odds ratio for being obese increased by 21% (p Conclusions: Rapidly developing economies, besides experiencing paradoxical health patterns, are typically characterised by increased levels of income inequality. This study suggests that the twin burden of undernutrition and overnutrition in India is more likely to occur in high-inequality states. Focusing on economic equity via redistribution policies may have a substantial impact in reducing the prevalence of both undernutrition and overnutrition.

Air pollution, social deprivation and mortality. A multilevel cohort study

Abstract: Background:It is becoming increasingly evident that exposure to air pollution and its adverse effects are not equitably distributed. Our goal was to investigate the role of social deprivation in explaining the effect of neighborhood differences in level of air pollution fine particulates (PM2.5) on

Birth weight; postnatal, infant, and childhood growth; and obesity in young adulthood: evidence from the Barry Caerphilly

Abstract: Background: Birth weight has been shown to be positively associatedwithadultobesity,butrelativelyfewstudieshaveexaminedthe associations with growth in specific periods of early childhood. Objective: The objective was to assess the association of measures of growth between birth an d5yo f agewith adult measures of adiposity. Design: We conducted a longitudinal study of young adults from Barry and Caerphilly, United Kingdom, who had previously taken partbetween1972and1974inarandomizedcontrolledtrialofmilk supplementation. We reexamined 679 men and women (72% of the target population) to measure body mass index (BMI; in kg/m 2 ), waist-to-hip ratio, sagittal abdominal diameter, and waist circumference. Results: An increase in weight velocity from 1 y and 9 mo t o5yo f age was the most important predictor of BMI, waist circumference, andsagittalabdominaldiameter.Az-scoreincreaseinweightgainin this period was associated with an increase in BMI of 1.13 (95% CI: 0.69,1.57;P0.001).Infantweightgainfrom5moto1yand9mo wasthestrongestpredictorofwaist-to-hipratio(0.51;95%CI:0.00, 1.02; P 0.05). Conclusions:Birthweightdoesnotpredictadiposityonthebasisof weight gain in childhood. The association between adult adiposity and weight gain in different periods is variable and depends on the measure of adiposity that is used. It remains unclear whether early childhood is the optimum period in the life course for the primary prevention of adult adiposity. Am J Clin Nutr 2007;86:907–13.

Social inequalities in antidepressant treatment and mortality: a longitudinal register study

Abstract: Background. Despite an increased prevalence of depression among people of low socio-economic position, it remains unclear whether their treatment with antidepressants appropriately matches their increased need compared with people from more affluent backgrounds. This study examined socio-economic differences in antidepressant prescriptions and mortality related to depressive dis- orders. Method. A longitudinal register study of 17 947 male and 47 458 female local government employees with linked information on socio-economic indicators (education and occupational status) and data on antidepressant use and mortality associated with depressive disorder (suicide, alcohol-related deaths) during the years 1994 to 2000. Results. In men, antidepressant treatment was less common among low educational groups than among high educational groups (OR 0 . 87, 95 % CI 0 . 76-0 . 99) and a corresponding difference was seen between occupational statuses (OR for manual v. upper non-manual 0 . 72, 95 % CI 0 . 62-0 . 84). In women, socio-economic position was not associated with antidepressant use. However, both among the men and women, employees with low socio-economic position had increased risk for mental-health-related mortality, as indicated by suicides, deaths from alcohol-related causes, and all-cause mortality. Conclusions. These data suggest a mismatch in the treatment of depression relative to apparent clinical need, with the lowest levels of treatment concentrated in the lower socio-economic groups, despite evidence of their increased prevalence of depression and suicide.

Associations between tooth loss and mortality patterns in the Glasgow Alumni Cohort

Abstract: 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.

Intrauterine Growth Retardation, Insulin Resistance, and Nonalcoholic Fatty Liver Disease in Children: Response to Nobili et al.

Abstract: We read with interest the article by Nobili et al. (1), who reported results of a case-control study that demonstrated an association between intrauterine growth retardation (defined as small for gestational age [SGA]) and pediatric nonalcoholic streatohepatitis (nonalcoholic fatty liver disease [NAFLD]). Nobili et al. (1) compared children with NAFLD with hospital control subjects. The choice of control subjects may result in an underestimate of the association between SGA and NAFLD if hospitalized children …

Lactase Persistence and Bitter Taste Response: Instrumental Variables and Mendelian Randomization in Epidemiologic Studies of Dietary Factors and Cancer Risk

Abstract: Consumption of dairy products seems to increase the risk of cancer at several sites, while intake of cruciferous vegetables could have protective effects. However, these dietary intakes are subject to measurement error, and associations with cancer could be due to confounders. Mendelian randomization has been suggested as a way to overcome confounding by exploiting the random allocation of alleles from parents to offspring. In mid-2006, the authors conducted a study of allele frequencies for the lactase (LCT) and taste receptor, type 2, member 38 (TAS2R38) genes, including 634 volunteers recruited (1992-1998) from the Italian branch of the European Prospective Investigation into Cancer and Nutrition. The authors hypothesized that there would be a lower milk intake among carriers of the LCT CC genotype and a different intake of cruciferous vegetables among carriers of the TAS2R38 variant. Overall, the frequency of the LCT T allele was higher in northern Italy than in southern Italy. Food intake was associated with gene variants. An association was evident for ice cream and LCT variants (p = 0.004); less so for milk intake. In addition, the TAS2R38 variant showed a geographic gradient and an association with cruciferous vegetable intake. These results suggest that the LCT and TAS2R38 variants are good candidates for Mendelian randomization studies of cancer and other health outcomes.

Offspring Birth Weight and Parental Mortality: Prospective Observational Study and Meta-Analysis

Abstract: The authors have investigated associations between offspring size at birth and parental cardiovascular disease mortality among 12,086 mothers and 6,936 fathers of participants in the British 1958 birth cohort. Birth weight was inversely associated with all-cause mortality and cardiovascular mortality in both mothers and fathers. The adjusted hazard ratio of cardiovascular disease mortality for a 1-standard deviation increase in offspring birth weight in mothers was 0.87 (95% confidence interval (CI): 0.82, 0.93) and in fathers was 0.94 (95% CI: 0.89, 0.99). The association was not specific for cardiovascular disease. In fathers, similar weak associations with violent and accidental deaths, stomach cancer, and alcohol- and smoking-related outcomes were found. Weak associations for these outcomes were also found for mothers, but the magnitude of the association with cardiovascular disease was greater than with any other outcomes. In a meta-analysis pooling results from this study with six others, the adjusted hazard ratio of cardiovascular disease mortality among mothers was 0.75 (95% CI: 0.67, 0.84) and that among fathers was 0.93 (95% CI: 0.91, 0.95), with evidence that the difference in effect between mothers and fathers was not due to chance (p < 0.001). The weak association of offspring birth weight with cardiovascular disease in fathers may be due to residual confounding by factors such as socioeconomic position and smoking that they share with the offspring's mother and that would therefore be associated with low offspring birth weight as well as adverse outcomes in the father. The stronger association in mothers is consistent with intergenerational effects on intrauterine growth and with the fetal origins hypothesis.

Similar Associations of Parental Prenatal Smoking Suggest Child Blood Pressure Is Not Influenced by Intrauterine Effects

Abstract: Maternal smoking in pregnancy may be associated with higher offspring blood pressure; however, results of previous studies have been inconsistent and included varying confounder adjustments. We studied the association between maternal smoking in pregnancy and offspring blood pressure at 7 years in the Avon Longitudinal Study of Parents and Children, accounting for important social and environmental confounders and using partner smoking to investigate intrauterine effects. Analysis was carried out in 6509 children with maternal smoking data and 7149 children with partner smoking data. In models adjusting for child age and sex, modest differences in systolic blood pressure were observed between children of mothers who did and did not smoke during pregnancy (β=0.64 mm Hg; 95% CI: 0.09 to 1.20; P =0.02). Adjusting for all of the confounders attenuated this difference toward the null (β=0.05 mm Hg; 95% CI: −0.59 to 0.68; P =0.9), mostly because of adjustment for breastfeeding, maternal education, and family social class. Associations were similar between maternal and partner smoking with offspring systolic blood pressure (for partner smoking: β=0.62 mm Hg; 95% CI: 0.17 to 1.07; P =0.07 minimally adjusted and β=0.26 mm Hg; 95% CI: −0.36 to 0.87; P =0.4 fully adjusted), providing further evidence that differences in child blood pressure observed in minimally adjusted models are not because of a biological influence of maternal smoking on the intrauterine environment.

Effect of conjugal bereavement on mortality of the bereaved spouse in participants of the Renfrew/Paisley Study

Abstract: 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.

Independent associations of fasting insulin, glucose, and glycated haemoglobin with stroke and coronary heart disease in older women

Abstract: BACKGROUND: Evidence suggests that variations in fasting glucose and insulin amongst those without frank type 2 diabetes mellitus are important determinants of cardiovascular disease. However, the relative importance of variations in fasting insulin, glucose, and glycated haemoglobin as risk factors for cardiovascular disease in women without diabetes is unclear. Our aim was to determine the independent associations of fasting insulin, glucose, and glycated haemoglobin with coronary heart disease and stroke in older women. METHODS AND FINDINGS: We undertook a prospective cohort study of 3,246 British women aged 60-79 y, all of whom were free of baseline coronary heart disease, stroke, and diabetes, and all of whom had fasting glucose levels below 7 mmol/l. Fasting insulin and homeostasis model assessment for insulin sensitivity (HOMA-S) were linearly associated with a combined outcome of coronary heart disease or stroke (n = 219 events), but there was no association of fasting glucose or glycated haemoglobin with these outcomes. Results were similar for coronary heart disease and stroke as separate outcomes. The age, life-course socioeconomic position, smoking, and physical activity adjusted hazard ratio for a combined outcome of incident coronary heart disease or stroke per one standard deviation of fasting insulin was 1.14 (95% CI 1.02-1.33). Additional adjustment for other components of metabolic syndrome, low-density lipoprotein cholesterol, fasting glucose, and glycated haemoglobin had little effect on this result. CONCLUSIONS: Our findings suggest that in women in the 60-79 y age range, insulin resistance, rather than insulin secretion or chronic hyperglycaemia, is a more important risk factor for coronary heart disease and stroke. Below currently used thresholds of fasting glucose for defining diabetes, neither fasting glucose nor glycated haemoglobin are associated with cardiovascular disease.

Prevalence and functionality of paucimorphic and private MC4R mutations in a large, unselected European British population, scanned by meltMADGE.

Abstract: Identification of unknown mutations has remained laborious, expensive, and only viable for studies of selected cases. Population-based "reference ranges" of rarer sequence diversity are not available. However, the research and diagnostic interpretation of sequence variants depends on such information. Additionally, this is the only way to determine prevalence of severe, moderate, and silent mutations and is also relevant to the development of screening programs. We previously described a system, meltMADGE, suitable for mutation scanning at the population level. Here we describe its application to a population-based study of MC4R (melanocortin 4 receptor) mutations, which are associated with obesity. We developed nine assays representing MC4R and examined a population sample of 1,100 subjects. Two "paucimorphisms" were identified (c.307G>A/p.Val103Ile in 27 subjects and c.-178A>C in 22 subjects). Neither exhibited any anthropometric effects, whereas there would have been >90% power to detect a body mass index (BMI) effect of 0.5 kg/m(2) at P=0.01. Two "private" variants were also identified. c.335C>T/p.Thr112Met has been previously described and appears to be silent. A novel variant, c.260C>A/p.Ala87Asp, was observed in a subject with a BMI of 31.5 kg/m(2) (i.e., clinically obese) but not on direct assay of a further 3,525 subjects. This mutation was predicted to be deleterious and analysis using a cyclic AMP (cAMP) responsive luciferase reporter assay showed substantial loss of function of the mutant receptor. This population-based mutation scan of MC4R suggests that there is no severe MC4R mutation with high prevalence in the United Kingdom, but that obesity-causing MC4R mutation at 1 in 1,100 might represent one of the commonest autosomal dominant disorders in man.

Associations of Gestational Age and Intrauterine Growth With Systolic Blood Pressure in a Family-Based Study of 386 485 Men in 331 089 Families

Abstract: Background— We conducted a family-based study to explore mechanisms underlying the associations of birth weight and gestational age with systolic blood pressure measured at 17 to 19 years of age. Methods and Results— A record linkage study of 386 485 singleton-born men from 331 089 families was undertaken. Birth weight was inversely associated with systolic blood pressure within siblings, with a mean difference (adjusted for age at examination, examination center, and year of examination) within siblings per 1-SD difference in birth weight of −0.21 mm Hg (95% CI, −0.33 to −0.08) and between nonsiblings of −0.12 (95% CI, −0.16 to −0.08). Gestational age was inversely associated with systolic blood pressure within siblings (−0.18 mm Hg; 95% CI, −0.25 to −0.11, per week of gestational age) and between nonsiblings (−0.26 mm Hg; 95% CI, −0.29 to −0.24). Adjustment for socioeconomic position and maternal characteristics did not alter these within- or between-family associations. Furthermore, the associations we...