Common variants near MC4R are associated with fat mass, weight and risk of obesity.

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

Cost-effectiveness of a primary care based physical activity intervention in 45-74 year old men and women: a randomised controlled trial.

The article was first published in:British Journal of Sports Medicine 1998:32:236-241.OBJECTIVE: To assess the cost-effectiveness of a primary care based intervention aimed at increasing levels of physical activity in inactive people aged 45-74. METHODS: A total of 714 inactive people aged 45-74, taken from two west London general practices, were randomised into two groups. Intervention subjects were invited to a consultation with an exercise development officer, and offered a personalised 10 week programme to increase their level of regular physical activity, combining leisure centre and home based activities. Control subjects were sent information on local leisure centres. All subjects were followed up at eight months. RESULTS: There was a net 10.6% (95% confidence interval 4.5 to 16.9%) reduction in the proportion of people classified as sedentary in the intervention group compared with the control group, eight months after the intervention. The intervention group also reported an increase in the mean number of episodes of physical activity per week, as compared with the control group (an additional 1.52 episodes (95% confidence interval 1.14 to 1.95)). The cost of moving a person out of the sedentary group was shown to be less than 650 Pounds. The cost of moving someone to the now commonly recommended level was estimated at almost 2500 Pounds. CONCLUSIONS: Moderate physical activity can be successfully encouraged in previously sedentary men and women aged 45-74 through a primary care based intervention. The process of recruitment was the most important variable cost. A high uptake rate would maximise cost-effectiveness, and sensitivity analysis suggests that unit costs could be halved with a more effective recruitment strategy.This trial was supported by West London Health Promotion Agency through a grant awarded by North Thames NHS Executive Responsive Funding programme (RFG013

Prenatal and early life influences on epigenetic age in children: A study of mother-offspring pairs from two cohort studies.

DNA methylation based biomarkers of aging are highly correlated with actual age. Departures of methylation-estimated age from actual age can be used to define epigenetic measures of child development or age acceleration in adults. Very little is known about genetic or environmental determinants of these epigenetic measures of aging. We obtained DNA methylation profiles using Infinium HumanMethylation450 BeadChips across five time points in 1018 mother-child pairs from the Avon Longitudinal Study of Parents and Children. Using the Horvath age estimation method, we calculated epigenetic age for these samples. Age acceleration (AA) was defined as the residuals from regressing epigenetic age on actual age. AA was tested for associations with cross-sectional clinical variables in children. We identified associations between AA and sex, birth weight, birth by caesarean section and several maternal characteristics in pregnancy, namely smoking, weight, BMI, selenium and cholesterol level. Offspring of non-drinkers had higher AA on average but this difference appeared to resolve during childhood. The associations between sex, birth weight and AA found in ARIES were replicated in an independent cohort (GOYA). In children, epigenetic AA measures are associated with several clinically relevant variables, and early life exposures appear to be associated with changes in AA during adolescence. Further research into epigenetic aging, including the use of causal inference methods, is required to better our understanding of aging

Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility

Inflammatory bowel disease (IBD) typically manifests as either ulcerative colitis (UC) or Crohn's disease (CD). Systematic identification of susceptibility genes for IBD has thus far focused mainly on CD, and little is known about the genetic architecture of UC. Here we report a genome-wide association study with 440,794 SNPs genotyped in 1,167 individuals with UC and 777 healthy controls. Twenty of the most significantly associated SNPs were tested for replication in three independent European case-control panels comprising a total of 1,855 individuals with UC and 3,091 controls. Among the four consistently replicated markers, SNP rs3024505 immediately flanking the IL10 (interleukin 10) gene on chromosome 1q32.1 showed the most significant association in the combined verification samples (P = 1.35 × 10 -12; OR = 1.46 (1.31-1.62)). The other markers were located in ARPC2 and in the HLA-BTNL2 region. Association between rs3024505 and CD (1,848 cases, 1,804 controls) was weak (P = 0.013; OR = 1.17 (1.01-1.34)). IL10 is an immunosuppressive cytokine that has long been proposed to influence IBD pathophysiology. Our findings strongly suggest that defective IL10 function is central to the pathogenesis of the UC subtype of IBD. © 2008 Nature Publishing Group

Progressor but not regressor skin tumours inhibit Langerhans' cell migration from epidermis to local lymph nodes

Langerhans' cells (LC) are found in high numbers infiltrating skin tumours, the functional significance of which remains unknown. To study the mechanism by which tumours increase the number of LC we developed a procedure whereby supernatant from cultured T7 tumour cells applied topically increases the number of LC. Tumour factors increased the number of resident epidermal LC and did not attract LC precursors into parental murine skin grafted onto F1 hybrids. There was no evidence for increased LC division in response to the tumour-derived factors. LC migration from the epidermis to local lymph nodes, induced by topical fluorescein isothiocyanate (FITC), was inhibited by the tumour supernatant. To examine the functional significance of this, FITC-induced migration of LC from the epidermis overlying progressor tumours, which evade immunological destruction, and regressor tumours, which are immunologically destroyed, was examined. The progressor tumour T7 growing subcutaneously in syngeneic mice inhibited FITC-induced migration of LC from overlying epidermis. Furthermore, two progressor, but not two regressor murine skin tumour lines growing in BALB/c nu/nu mice inhibited LC migration from the epidermis. Our results demonstrate that progressor skin tumours produce factor(s) which inhibit LC migration from the epidermis to lymph nodes, leading to LC accumulation. Inhibition of LC migration by tumour-derived factors may enable tumours to evade the activation of protective immunity as regressor tumours do not interfere with the normal trafficking of LC