Genetic variation in the pleiotropic association between physical activity and body weight in mice

<p>Abstract</p> <p>Background</p> <p>A sedentary lifestyle is often assumed to lead to increases in body weight and potentially obesity and related diseases but in fact little is known about the genetic association between physical activity and body weight. We tested for such an association between body weight and the distance, duration, and speed voluntarily run by 310 mice from the F₂generation produced from an intercross of two inbred lines that differed dramatically in their physical activity levels.</p> <p>Methods</p> <p>We used a conventional interval mapping approach with SNP markers to search for QTLs that affected both body weight and activity traits. We also conducted a genome scan to search for relationship QTLs (<it>rel</it>QTLs), or chromosomal regions that affected an activity trait variably depending on the phenotypic value of body weight.</p> <p>Results</p> <p>We uncovered seven quantitative trait loci (QTLs) affecting body weight, but only one co-localized with another QTL previously found for activity traits. We discovered 19 <it>rel</it>QTLs that provided evidence for a genetic (pleiotropic) association of physical activity and body weight. The three genotypes at each of these loci typically exhibited a combination of negative, zero, and positive regressions of the activity traits on body weight, the net effect of which was to produce overall independence of body weight from physical activity. We also demonstrated that the <it>rel</it>QTLs produced these varying associations through differential epistatic interactions with a number of other epistatic QTLs throughout the genome.</p> <p>Conclusion</p> <p>It was concluded that individuals with specific combinations of genotypes at the <it>rel</it>QTLs and <it>epi</it>QTLs might account for some of the variation typically seen in plots of the association of physical activity with body weight.</p

A search for quantitative trait loci controlling within-individual variation of physical activity traits in mice

<p>Abstract</p> <p>Background</p> <p>In recent years it has become increasingly apparent that physical inactivity can predispose individuals to a host of health problems. While many studies have analyzed the effect of various environmental factors on activity, we know much less about the genetic control of physical activity. Some studies in mice have discovered quantitative trait loci (QTL) influencing various physical activity traits, but mostly have analyzed inter-individual variation rather than variation in activity within individuals over time. We conducted a genome scan to identify QTLs controlling the distance, duration, and time run by mice over seven consecutive three-day intervals in an F₂population created by crossing two inbred strains (C57L/J and C3H/HeJ) that differed widely (average of nearly 300%) in their activity levels. Our objectives were (a) to see if we would find QTLs not originally discovered in a previous investigation that assessed these traits over the entire 21-day period and (b) to see if some of these QTLs discovered might affect the activity traits only in the early or in the late time intervals.</p> <p>Results</p> <p>This analysis uncovered 39 different QTLs, over half of which were new. Some QTLs affected the activity traits only in the early time intervals and typically exhibited significant dominance effects whereas others affected activity only in the later age intervals and exhibited less dominance. We also analyzed the regression slopes of the activity traits over the intervals, and found several QTLs affecting these traits that generally mapped to unique genomic locations.</p> <p>Conclusions</p> <p>It was concluded that the genetic architecture of physical activity in mice is much more complicated than has previously been recognized, and may change considerably depending on the age at which various activity measures are assessed.</p

Interventions Delivered in Clinical Settings are Effective in Reducing Risk of HIV Transmission Among People Living with HIV: Results from the Health Resources and Services Administration (HRSA)’s Special Projects of National Significance Initiative

To support expanded prevention services for people living with HIV, the US Health Resources and Services Administration (HRSA) sponsored a 5-year initiative to test whether interventions delivered in clinical settings were effective in reducing HIV transmission risk among HIV-infected patients. Across 13 demonstration sites, patients were randomized to one of four conditions. All interventions were associated with reduced unprotected vaginal and/or anal intercourse with persons of HIV-uninfected or unknown status among the 3,556 participating patients. Compared to the standard of care, patients assigned to receive interventions from medical care providers reported a significant decrease in risk after 12 months of participation. Patients receiving prevention services from health educators, social workers or paraprofessional HIV-infected peers reported significant reduction in risk at 6 months, but not at 12 months. While clinics have a choice of effective models for implementing prevention programs for their HIV-infected patients, medical provider-delivered methods are comparatively robust

The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A

Genome-wide association studies (GWAS) have provided strong evidence for inherited predisposition to childhood acute lymphoblastic leukaemia (ALL) identifying a number of risk loci. We have previously shown common SNPs at 9p21.3 influence ALL risk. These SNP associations are generally not themselves candidates for causality, but simply act as markers for functional variants. By means of imputation of GWAS data and subsequent validation SNP genotyping totalling 2,177 ALL cases and 8,240 controls, we have shown that the 9p21.3 association can be ascribed to the rare highimpact CDKN2A p.Ala148Thr variant (rs3731249; Odds ratio=2.42, P=3.45×10−19). The association between rs3731249 genotype and risk was not specific to particular subtype of B-cell ALL. The rs3731249 variant is associated with predominant nuclear localisation of the CDKN2A transcript suggesting the functional effect of p.Ala148Thr on ALL risk may be through compromised ability to inhibit cyclin D within the cytoplasm

Human mass balance study of the novel anticancer agent ixabepilone using accelerator mass spectrometry

Ixabepilone (BMS-247550) is a semi-synthetic, microtubule stabilizing epothilone B analogue which is more potent than taxanes and has displayed activity in taxane-resistant patients. The human plasma pharmacokinetics of ixabepilone have been described. However, the excretory pathways and contribution of metabolism to ixabepilone elimination have not been determined. To investigate the elimination pathways of ixabepilone we initiated a mass balance study in cancer patients. Due to autoradiolysis, ixabepilone proved to be very unstable when labeled with conventional [14C]-levels (100 μCi in a typical human radio-tracer study). This necessitated the use of much lower levels of [14C]-labeling and an ultra-sensitive detection method, Accelerator Mass Spectrometry (AMS). Eight patients with advanced cancer (3 males, 5 females; median age 54.5 y; performance status 0–2) received an intravenous dose of 70 mg, 80 nCi of [14C]ixabepilone over 3 h. Plasma, urine and faeces were collected up to 7 days after administration and total radioactivity (TRA) was determined using AMS. Ixabepilone in plasma and urine was quantitated using a validated LC-MS/MS method. Mean recovery of ixabepilone-derived radioactivity was 77.3% of dose. Fecal excretion was 52.2% and urinary excretion was 25.1%. Only a minor part of TRA is accounted for by unchanged ixabepilone in both plasma and urine, which indicates that metabolism is a major elimination mechanism for this drug. Future studies should focus on structural elucidation of ixabepilone metabolites and characterization of their activities

A genome scan for quantitative trait loci affecting cyanogenic potential of cassava root in an outbred population

<p>Abstract</p> <p>Background</p> <p>Cassava (<it>Manihot esculenta </it>Crantz) can produce cyanide, a toxic compound, without self-injury. That ability was called the cyanogenic potential (CN). This project aimed to identify quantitative trait loci (QTL) associated with the CN in an outbred population derived from 'Hanatee' × 'Huay Bong 60', two contrasting cultivars. CN was evaluated in 2008 and in 2009 at Rayong province, and in 2009 at Lop Buri province, Thailand. CN was measured using a picrate paper kit. QTL analysis affecting CN was performed with 303 SSR markers.</p> <p>Results</p> <p>The phenotypic values showed continuous variation with transgressive segregation events with more (115 ppm) and less CN (15 ppm) than either parent ('Hanatee' had 33 ppm and 'Huay Bong 60' had 95 ppm). The linkage map consisted of 303 SSR markers, on 27 linkage groups with a map that encompassed 1,328 cM. The average marker interval was 5.8 cM. Five QTL underlying CN were detected. <it>CN08R1</it>from 2008 at Rayong, <it>CN09R1</it>and <it>CN09R2 </it>from 2009 at Rayong, and <it>CN09L1 </it>and <it>CN09L2 </it>from 2009 at Lop Buri were mapped on linkage group 2, 5, 10 and 11, respectively. Among all the identified QTL, <it>CN09R1 </it>was the most significantly associated with the CN trait with LOD score 5.75 and explained the greatest percentage of phenotypic variation (%Expl.) of 26%.</p> <p>Conclusions</p> <p>Five new QTL affecting CN were successfully identified from 4 linkage groups. Discovery of these QTL can provide useful markers to assist in cassava breeding and studying genes affecting the trait.</p

Consequences of epistasis on growth in an erhualian × white duroc pig cross

Epistasis describes an interaction between the effects of loci. We included epistasis in quantitative trait locus (QTL) mapping of growth at a series of ages in a cross of a Chinese pig breed, Erhualian, with a commercial line, White Duroc. Erhualian pigs have much lower growth rates than White Duroc. We improved a method for genomewide testing of epistasis and present a clear analysis workflow. We also suggest a new approach for interpreting epistasis results where significant additive and dominance effects of a locus in specific backgrounds are determined. In total, seventeen QTL were found and eleven showed epistasis. Loci on chromosomes 2, 3, 4 and 7 were highlighted as affecting growth at more than one age or forming an interaction network. Epistasis resulted in both the QTL on chromosomes 3 and 7 having effects in opposite directions. We believe it is the first time for the chromosome 7 locus that an allele from a Chinese breed has been found to decrease growth. The consequences of epistasis were diverse. Results were impacted by using growth rather than body weight as the phenotype and by correcting for an effect of mother. Epistasis made a considerable contribution to growth in this population and modelling epistasis was important for accurately determining QTL effects

Heritability of physical activity traits in Brazilian families: the Baependi Heart Study

<p>Abstract</p> <p>Background</p> <p>It is commonly recognized that physical activity has familial aggregation; however, the genetic influences on physical activity phenotypes are not well characterized. This study aimed to (1) estimate the heritability of physical activity traits in Brazilian families; and (2) investigate whether genetic and environmental variance components contribute differently to the expression of these phenotypes in males and females.</p> <p>Methods</p> <p>The sample that constitutes the Baependi Heart Study is comprised of 1,693 individuals in 95 Brazilian families. The phenotypes were self-reported in a questionnaire based on the WHO-MONICA instrument. Variance component approaches, implemented in the SOLAR (Sequential Oligogenic Linkage Analysis Routines) computer package, were applied to estimate the heritability and to evaluate the heterogeneity of variance components by gender on the studied phenotypes.</p> <p>Results</p> <p>The heritability estimates were intermediate (35%) for weekly physical activity among non-sedentary subjects (weekly PA_NS), and low (9-14%) for sedentarism, weekly physical activity (weekly PA), and level of daily physical activity (daily PA). Significant evidence for heterogeneity in variance components by gender was observed for the sedentarism and weekly PA phenotypes. No significant gender differences in genetic or environmental variance components were observed for the weekly PA_NS trait. The daily PA phenotype was predominantly influenced by environmental factors, with larger effects in males than in females.</p> <p>Conclusions</p> <p>Heritability estimates for physical activity phenotypes in this sample of the Brazilian population were significant in both males and females, and varied from low to intermediate magnitude. Significant evidence for heterogeneity in variance components by gender was observed. These data add to the knowledge of the physical activity traits in the Brazilian study population, and are concordant with the notion of significant biological determination in active behavior.</p

A study protocol for applying the co-creating knowledge translation framework to a population health study

BACKGROUND: Population health research can generate significant outcomes for communities, while Knowledge Translation (KT) aims to expressly maximize the outcomes of knowledge producing activity. Yet the two approaches are seldom explicitly combined as part of the research process. A population health study in Port Lincoln, South Australia offered the opportunity to develop and apply the co-KT Framework to the entire research process. This is a new framework to facilitate knowledge formation collaboratively between researchers and communities throughout a research to intervention implementation process. DESIGN: This study employs a five step framework (the co-KT Framework) that is formulated from engaged scholarship and action research principles. By following the steps a knowledge base will be cumulatively co-created with the study population that is useful to the research aims. Step 1 is the initiating of contact between the researcher and the study contexts, and the framing of the research issue, achieved through a systematic data collection tool. Step 2 refines the research issue and the knowledge base by building into it context specific details and conducting knowledge exchange events. Step 3 involves interpreting and analysing the knowledge base, and integrating evidence to inform intervention development. In Step 4 the intervention will be piloted and evaluated. Step 5 is the completion of the research process where outcomes for improvement will be instituted as regular practice with the facilitation of the community. In summary, the model uses an iterative knowledge construction mechanism that is complemented by external evidence to design interventions to address health priorities within the community. DISCUSSION: This is a systematic approach that operationalises the translational cycle using a framework for KT practice. It begins with the local context as its foundation for knowledge creation and ends with the development of contextually applicable interventions. It will be of interest to those involved in KT research, participatory action research, population health research and health care systems studies. The co-KT Framework is a method for embedding the principles of KT into all stages of a community-based research process, in which research questions are framed by emergent data from each previous stage.Kathryn Powell, Alison Kitson, Elizabeth Hoon, Jonathan Newbury, Anne Wilson and Justin Beilb