Showing papers by "George Davey Smith 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.

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.

Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies

Abstract: To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.

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 ...

Effect of body mass index and alcohol consumption on liver disease: analysis of data from two prospective cohort studies

Abstract: Objective To investigate whether alcohol consumption and raised body mass index (BMI) act together to increase risk of liver disease. Design Analysis of data from prospective cohort studies. Setting Scotland. Participants Data were from two of the Midspan prospective cohort studies (9559 men): “Main” study 1965-8, participants from workplaces across central belt of Scotland, population of island of Tiree, and mainland relatives, and “Collaborative” study, 1970-3, participants from 27 workplaces in Glasgow, Clydebank, and Grangemouth. Follow-up was to 31 December 2007 (median 29 years, range 0.13-42). We divided participants into nine groups based on measures of body mass index (BMI) (underweight/normal weight Main outcome measures Liver disease morbidity and mortality. Results 80 (0.8%) men died with liver disease as the main cause and 146 (1.5%) with liver disease as any cause. In the Collaborative study, 196 men (3.3%) had liver disease defined by a death, admission, or cancer registration. BMI and alcohol consumption were strongly associated with liver disease mortality in analyses adjusted for other confounders (P=0.001 and P Conclusions Raised BMI and alcohol consumption are both related to liver disease, with evidence of a supra-additive interaction between the two. The occurrence of both factors in the same populations should inform health promotion and public health policies.

The Effect of Rural-to-Urban Migration on Obesity and Diabetes in India: A Cross-Sectional Study

Abstract: Background: Migration from rural areas of India contributes to urbanisation and may increase the risk of obesity and diabetes. We tested the hypotheses that rural-to-urban migrants have a higher prevalence of obesity and diabetes than rural nonmigrants, that migrants would have an intermediate prevalence of obesity and diabetes compared with life-long urban and rural dwellers, and that longer time since migration would be associated with a higher prevalence of obesity and of diabetes. Methods and Findings: The place of origin of people working in factories in north, central, and south India was identified. Migrants of rural origin, their rural dwelling sibs, and those of urban origin together with their urban dwelling sibs were assessed by interview, examination, and fasting blood samples. Obesity, diabetes, and other cardiovascular risk factors were compared. A total of 6,510 participants (42% women) were recruited. Among urban, migrant, and rural men the age- and factory-adjusted percentages classified as obese (body mass index [BMI] .25 kg/m 2 ) were 41.9% (95% confidence interval [CI] 39.1–44.7), 37.8% (95% CI 35.0–40.6), and 19.0% (95% CI 17.0–21.0), respectively, and as diabetic were 13.5% (95% CI 11.6–15.4), 14.3% (95% CI 12.2–16.4), and 6.2% (95% CI 5.0–7.4), respectively. Findings for women showed similar patterns. Rural men had lower blood pressure, lipids, and fasting blood glucose than urban and migrant men, whereas no differences were seen in women. Among migrant men, but not women, there was weak evidence for a lower prevalence of both diabetes and obesity among more recent (#10 y) migrants. Conclusions: Migration into urban areas is associated with increases in obesity, which drive other risk factor changes. Migrants have adopted modes of life that put them at similar risk to the urban population. Gender differences in some risk factors by place of origin are unexpected and require further exploration. Please see later in the article for the Editors’ Summary.

Hypertension in Pregnancy and Later Cardiovascular Risk Common Antecedents

Abstract: Background— Preeclampsia and gestational hypertension are associated with increased risk for cardiovascular disease later in life. We have assessed whether the effect can be attributed to factors that operate in pregnancy or to prepregnancy risk factors that are shared by both disorders. Methods and Results— Longitudinal data from 2 consecutive waves of a Norwegian population-based study (the Nord-Trondelag Health Study [HUNT]) were combined with data from the Medical Birth Registry of Norway. Among 24 865 women who had participated in both HUNT 1 and 2, we indentified 3225 women with a singleton birth between the 2 studies who had standardized measurements of blood pressure, serum lipids, and body mass index. The crude results showed that women who experienced preeclampsia or gestational hypertension in pregnancy had substantially higher levels of body mass index and systolic and diastolic blood pressures and unfavorable lipids compared with other women. However, after adjustment for prepregnancy measure...

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.

Epigenetic Epidemiology of Common Complex Disease: Prospects for Prediction, Prevention, and Treatment

Abstract: There is considerable anticipation of future improvements in disease prevention and treatment following recent advances in genomics [1]. One aspect of genomics that is receiving considerable interest is epigenetics—the regulatory processes that control the transcription of information encoded in the DNA sequence into RNA before their translation into proteins. Programmed developmental changes and the ability of the genome to register, signal, and perpetuate environmental cues are subsumed under the epigenetic banner [2]. Genes are packaged into chromatin and dynamic chromatin remodeling processes are required for the initial step in gene expression (transcription), achieved by altering the accessibility of gene promoters and regulatory regions [3]. Epigenetic factors are responsible for this regulatory process, the major components of which are DNA methylation, histone modifications, and the action of small non-coding RNAs (Figure 1). Unlike DNA sequence, which is largely fixed throughout the lifecourse, epigenetic patterns not only vary from tissue to tissue but alter with advancing age and are sensitive to environmental exposures [4]–[7]. It is this propensity for change that makes epigenetic processes the focus of such interest, as they lie at the interface of the environment and co-ordinated transcriptional control. Figure 1 Epigenetic modifications. In rare developmental disorders, the role of aberrant epigenetic processes is well established [8]. Our focus here, however, is on the potential role of epigenetic processes in the context of common complex disease. Tumor-specific changes in epigenetic patterns are a hallmark of numerous cancers, with analysis of the epigenetic machinery beginning to feature prominently in emerging cancer diagnostics and therapies [9]–[11]. There is an increasing body of evidence to demonstrate that epigenetic patterns are altered by environmental factors known to be associated with disease risk (e.g., diet, smoking, alcohol intake, environmental toxicants, stress) [7],[8]; however, an important question remains to be resolved in defining which epigenetic changes are a secondary outcome of either exposure or disease, and which lie on the causal pathway linking the two. Without proven causality, interventions to prevent or treat common complex diseases based upon epigenetic mechanisms will not be fruitful. Conversely, regardless of causality, defining a robust prospective relationship between epigenetic patterns and phenotypic traits may have application in diagnostics or in identifying high-risk individuals for non-epigenetic-based interventions.

Sociodemographic patterning of non-communicable disease risk factors in rural India: a cross sectional study

Abstract: Objectives To investigate the sociodemographic patterning of non-communicable disease risk factors in rural India. Design Cross sectional study. Setting About 1600 villages from 18 states in India. Most were from four large states due to a convenience sampling strategy. Participants 1983 (31% women) people aged 20–69 years (49% response rate). Main outcome measures Prevalence of tobacco use, alcohol use, low fruit and vegetable intake, low physical activity, obesity, central adiposity, hypertension, dyslipidaemia, diabetes, and underweight. Results Prevalence of most risk factors increased with age. Tobacco and alcohol use, low intake of fruit and vegetables, and underweight were more common in lower socioeconomic positions; whereas obesity, dyslipidaemia, and diabetes (men only) and hypertension (women only) were more prevalent in higher socioeconomic positions. For example, 37% (95% CI 30% to 44%) of men smoked tobacco in the lowest socioeconomic group compared with 15% (12% to 17%) in the highest, while 35% (30% to 40%) of women in the highest socioeconomic group were obese compared with 13% (7% to 19%) in the lowest. The age standardised prevalence of some risk factors was: tobacco use (40% (37% to 42%) men, 4% (3% to 6%) women); low fruit and vegetable intake (69% (66% to 71%) men, 75% (71% to 78%) women); obesity (19% (17% to 21%) men, 28% (24% to 31%) women); dyslipidaemia (33% (31% to 36%) men, 35% (31% to 38%) women); hypertension (20% (18% to 22%) men, 22% (19% to 25%) women); diabetes (6% (5% to 7%) men, 5% (4% to 7%) women); and underweight (21% (19% to 23%) men, 18% (15% to 21%) women). Risk factors were generally more prevalent in south Indians compared with north Indians. For example, the prevalence of dyslipidaemia was 21% (17% to 33%) in north Indian men compared with 33% (29% to 38%) in south Indian men, while the prevalence of obesity was 13% (9% to 17%) in north Indian women compared with 24% (19% to 30%) in south Indian women. Conclusions The prevalence of most risk factors was generally high across a range of sociodemographic groups in this sample of rural villagers in India; in particular, the prevalence of tobacco use in men and obesity in women was striking. However, given the limitations of the study (convenience sampling design and low response rate), cautious interpretation of the results is warranted. These data highlight the need for careful monitoring and control of non-communicable disease risk factors in rural areas of India.

Genetic Markers of Adult Obesity Risk Are Associated with Greater Early Infancy Weight Gain and Growth

Abstract: Background: Genome-wide studies have identified several common genetic variants that are robustly associated with adult obesity risk. Exploration of these genotype associations in children may provide insights into the timing of weight changes leading to adult obesity.Methods and Findings: Children from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were genotyped for ten genetic variants previously associated with adult BMI. Eight variants that showed individual associations with childhood BMI (in/near: FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, and ETV5) were used to derive an "obesity-risk-allele score'' comprising the total number of risk alleles (range: 2-15 alleles) in each child with complete genotype data (n = 7,146). Repeated measurements of weight, length/height, and body mass index from birth to age 11 years were expressed as standard deviation scores (SDS). Early infancy was defined as birth to age 6 weeks, and early infancy failure to thrive was defined as weight gain between below the 5th centile, adjusted for birth weight. The obesity-risk-allele score showed little association with birth weight (regression coefficient: 0.01 SDS per allele; 95% CI 0.00-0.02), but had an apparently much larger positive effect on early infancy weight gain (0.119 SDS/allele/year; 0.023-0.216) than on subsequent childhood weight gain (0.004 SDS/allele/year; 0.004-0.005). The obesity-risk-allele score was also positively associated with early infancy length gain (0.158 SDS/allele/year; 0.032-0.284) and with reduced risk of early infancy failure to thrive (odds ratio = 0.92 per allele; 0.86-0.98; p = 0.009).Conclusions: The use of robust genetic markers identified greater early infancy gains in weight and length as being on the pathway to adult obesity risk in a contemporary birth cohort.

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.

Circulating Folate, Vitamin B12, Homocysteine, Vitamin B12 Transport Proteins, and Risk of Prostate Cancer: a Case-Control Study, Systematic Review, and Meta-analysis

Abstract: Background: Disturbed folate metabolism is associated with an increased risk of some cancers. Our objective was to determine whether blood levels of folate, vitamin B12, and related metabolites were associated with prostate cancer risk. Methods: Matched case-control study nested within the U.K. population–based Prostate testing for cancer and Treatment (ProtecT) study of prostate-specific antigen–detected prostate cancer in men ages 50 to 69 years. Plasma concentrations of folate, B12 (cobalamin), holo-haptocorrin, holo-transcobalamin total transcobalamin, and total homocysteine (tHcy) were measured in 1,461 cases and 1,507 controls. ProtecT study estimates for associations of folate, B12, and tHcy with prostate cancer risk were included in a meta-analysis, based on a systematic review. Results: In the ProtecT study, increased B12 and holo-haptocorrin concentrations showed positive associations with prostate cancer risk [highest versus lowest quartile of B12 odds ratio (OR) = 1.17 (95% confidence interval, 0.95-1.43); Ptrend = 0.06; highest versus lowest quartile of holo-haptocorrin OR = 1.27 (1.04-1.56); Ptrend = 0.01]; folate, holo-transcobalamin, and tHcy were not associated with prostate cancer risk. In the meta-analysis, circulating B12 levels were associated with an increased prostate cancer risk [pooled OR = 1.10 (1.01-1.19) per 100 pmol/L increase in B12; P = 0.002]; the pooled OR for the association of folate with prostate cancer was positive [OR = 1.11 (0.96-1.28) per 10 nmol/L; P = 0.2) and conventionally statistically significant if ProtecT (the only case-control study) was excluded [OR = 1.18 (1.00-1.40) per 10 nmol/L; P = 0.02]. Conclusion: Vitamin B12 and (in cohort studies) folate were associated with increased prostate cancer risk. Impact: Given current controversies over mandatory fortification, further research is needed to determine whether these are causal associations. Cancer Epidemiol Biomarkers Prev; 19(6); 1632–42. ©2010 AACR.

Inequalities in premature mortality in Britain: observational study from 1921 to 2007

Abstract: Objective To report on the extent of inequality in premature mortality as measured between geographical areas in Britain. Design Observational study of routinely collected mortality data and public records. Population subdivided by age, sex, and geographical area (parliamentary constituencies from 1991 to2007, pre-1974 local authorities over a longer time span). Setting Great Britain. Participants Entire population aged under 75 from 1990 to 2007, and entire population aged under 65 in the periods 1921-39, 1950-3, 1959-63, 1969-73, and 1981-2007. Main outcome measure Relative index of inequality (RII) and ratios of inequality in age-sex standardised mortality ratios under ages 75 and 65. The relative index of inequality is the relative rate of mortality for the hypothetically worst-off compared with the hypothetically best-off person in the population, assuming a linear association between socioeconomic position and risk of mortality. The ratio of inequality is the ratio of the standardised mortality ratio of the most deprived 10% to the least deprived 10%. Results When measured by the relative index of inequality, geographical inequalities in age-sex standardised rates of mortality below age 75 have increased every two years from 1990-1 to 2006-7 without exception. Over this period the relative index of inequality increased from 1.61 (95% confidence interval 1.52 to 1.69) in 1990-1 to 2.14 (2.02 to 2.27) in 2006-7. Simple ratios indicated a brief period around 2001 when a small reduction in inequality was recorded, but this was quickly reversed and inequalities up to the age of 75 have now reached the highest levels reported since at least 1990. Similarly, inequalities in mortality ratios under the age of 65 improved slightly in the early years of this century but the latest figures surpass the most extreme previously reported. Comparison of crudely age-sex standardised rates for those below age 65 from historical records showed that geographical inequalities in mortality are higher in the most recent decade than in any similar time period for which records are available since at least 1921. Conclusions Inequalities in premature mortality between areas of Britain continued to rise steadily during the first decade of the 21st century. The last time in the long economic record that inequalities were almost as high was in the lead up to the economic crash of 1929 and the economic depression of the 1930s. The economic crash of 2008 might precede even greater inequalities in mortality between areas in Britain.

Mendelian Randomization for Strengthening Causal Inference in Observational Studies: Application to Gene × Environment Interactions.

Abstract: Identification of environmentally modifiable factors causally influencing disease risk is fundamental to public-health improvement strategies Unfortunately, observational epidemiological studies are limited in their ability to reliably identify such causal associations, reflected in the many cases in which conventional epidemiological studies have apparently identified associations that randomized controlled trials have failed to verify The use of genetic variants as proxy measures of exposure -an application of the Mendelian randomization principle-can contribute to strengthening causal inference Genetic variants are not subject to bias due to reverse causation (disease processes influencing exposure, rather than vice versa) or recall bias, and if simple precautions are applied, they are not influenced by confounding or attenuation by errors The principles of Mendelian randomization are illustrated with specific reference to studies of the effects of alcohol intake on various health-related outcomes through the utilization of genetic variants related to alcohol metabolism (in ALDH2 and ADH1B) Ways of incorporating Gene × Environment interactions into the Mendelian randomization framework are developed, and the strengths and limitations of the approach discussed

Functional Gene Group Analysis Reveals a Role of Synaptic Heterotrimeric G Proteins in Cognitive Ability

Abstract: Although cognitive ability is a highly heritable complex trait, only a few genes have been identified, explaining relatively low proportions of the observed trait variation. This implies that hundreds of genes of small effect may be of importance for cognitive ability. We applied an innovative method in which we tested for the effect of groups of genes defined according to cellular function (functional gene group analysis). Using an initial sample of 627 subjects, this functional gene group analysis detected that synaptic heterotrimeric guanine nucleotide binding proteins (G proteins) play an important role in cognitive ability (PEMP = 1.9 × 10−4). The association with heterotrimeric G proteins was validated in an independent population sample of 1507 subjects. Heterotrimeric G proteins are central relay factors between the activation of plasma membrane receptors by extracellular ligands and the cellular responses that these induce, and they can be considered a point of convergence, or a “signaling bottleneck.” Although alterations in synaptic signaling processes may not be the exclusive explanation for the association of heterotrimeric G proteins with cognitive ability, such alterations may prominently affect the properties of neuronal networks in the brain in such a manner that impaired cognitive ability and lower intelligence are observed. The reported association of synaptic heterotrimeric G proteins with cognitive ability clearly points to a new direction in the study of the genetic basis of cognitive ability.

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.

The combined effect of smoking tobacco and drinking alcohol on cause-specific mortality: a 30 year cohort study

Abstract: Smoking and consuming alcohol are both related to increased mortality risk. Their combined effects on cause-specific mortality were investigated in a prospective cohort study. Participants were 5771 men aged 35-64, recruited during 1970-73 from various workplaces in Scotland. Data were obtained from a questionnaire and a screening examination. Causes of death were all cause, coronary heart disease (CHD), stroke, alcohol-related, respiratory and smoking-related cancer. Participants were divided into nine groups according to their smoking status (never, ex or current) and reported weekly drinking (none, 1-14 units and 15 or more). Cox proportional hazards models were used to obtain relative rates of mortality, adjusted for age and other risk factors. In 30 years of follow-up, 3083 men (53.4%) died. Compared with never smokers who did not drink, men who both smoked and drank 15+ units/week had the highest all-cause mortality (relative rate = 2.71 (95% confidence interval 2.31-3.19)). Relative rates for CHD mortality were high for current smokers, with a possible protective effect of some alcohol consumption in never smokers. Stroke mortality increased with both smoking and alcohol consumption. Smoking affected respiratory mortality with little effect of alcohol. Adjusting for a wide range of confounders attenuated the relative rates but the effects of alcohol and smoking still remained. Premature mortality was particularly high in smokers who drank 15 or more units, with a quarter of the men not surviving to age 65. 30% of men with manual occupations both smoked and drank 15+ units/week compared with only 13% with non-manual ones. Smoking and drinking 15+ units/week was the riskiest behaviour for all causes of death.

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.