Jana Anderson

Probing the metabolic network in bloodstream-form Trypanosoma brucei using untargeted metabolomics with stable isotope labelled glucose

Metabolomics coupled with heavy-atom isotope-labelled glucose has been used to probe the metabolic pathways active in cultured bloodstream form trypomastigotes of Trypanosoma brucei, a parasite responsible for human African trypanosomiasis. Glucose enters many branches of metabolism beyond glycolysis, which has been widely held to be the sole route of glucose metabolism. Whilst pyruvate is the major end-product of glucose catabolism, its transamination product, alanine, is also produced in significant quantities. The oxidative branch of the pentose phosphate pathway is operative, although the non-oxidative branch is not. Ribose 5-phosphate generated through this pathway distributes widely into nucleotide synthesis and other branches of metabolism. Acetate, derived from glucose, is found associated with a range of acetylated amino acids and, to a lesser extent, fatty acids; while labelled glycerol is found in many glycerophospholipids. Glucose also enters inositol and several sugar nucleotides that serve as precursors to macromolecule biosynthesis. Although a Krebs cycle is not operative, malate, fumarate and succinate, primarily labelled in three carbons, were present, indicating an origin from phosphoenolpyruvate via oxaloacetate. Interestingly, the enzyme responsible for conversion of phosphoenolpyruvate to oxaloacetate, phosphoenolpyruvate carboxykinase, was shown to be essential to the bloodstream form trypanosomes, as demonstrated by the lethal phenotype induced by RNAi-mediated downregulation of its expression. In addition, glucose derivatives enter pyrimidine biosynthesis via oxaloacetate as a precursor to aspartate and orotate.

Association between active commuting and incident cardiovascular disease, cancer, and mortality: prospective cohort study

Objective To investigate the association between active commuting and incident cardiovascular disease (CVD), cancer, and all cause mortality. Design Prospective population based study. Setting UK Biobank. Participants 263 450 participants (106 674 (52%) women; mean age 52.6), recruited from 22 sites across the UK. The exposure variable was the mode of transport used (walking, cycling, mixed mode v non-active (car or public transport)) to commute to and from work on a typical day. Main outcome measures Incident (fatal and non-fatal) CVD and cancer, and deaths from CVD, cancer, or any causes. Results 2430 participants died (496 were related to CVD and 1126 to cancer) over a median of 5.0 years (interquartile range 4.3-5.5) follow-up. There were 3748 cancer and 1110 CVD events. In maximally adjusted models, commuting by cycle and by mixed mode including cycling were associated with lower risk of all cause mortality (cycling hazard ratio 0.59, 95% confidence interval 0.42 to 0.83, P=0.002; mixed mode cycling 0.76, 0.58 to 1.00, P<0.05), cancer incidence (cycling 0.55, 0.44 to 0.69, P<0.001; mixed mode cycling 0.64, 0.45 to 0.91, P=0.01), and cancer mortality (cycling 0.60, 0.40 to 0.90, P=0.01; mixed mode cycling 0.68, 0.57 to 0.81, P<0.001). Commuting by cycling and walking were associated with a lower risk of CVD incidence (cycling 0.54, 0.33 to 0.88, P=0.01; walking 0.73, 0.54 to 0.99, P=0.04) and CVD mortality (cycling 0.48, 0.25 to 0.92, P=0.03; walking 0.64, 0.45 to 0.91, P=0.01). No statistically significant associations were observed for walking commuting and all cause mortality or cancer outcomes. Mixed mode commuting including walking was not noticeably associated with any of the measured outcomes. Conclusions Cycle commuting was associated with a lower risk of CVD, cancer, and all cause mortality. Walking commuting was associated with a lower risk of CVD independent of major measured confounding factors. Initiatives to encourage and support active commuting could reduce risk of death and the burden of important chronic conditions.

Metabolomic analysis of trypanosomatid protozoa

Metabolomics aims to measure all low molecular weight chemicals within a given system in a manner analogous to transcriptomics, proteomics and genomics. In this review we highlight metabolomics approaches that are currently being applied to the kinetoplastid parasites, Trypanosoma brucei and Leishmania spp. The use of untargeted metabolomics approaches, made possible through advances in mass spectrometry and informatics, and stable isotope labelling has increased our understanding of the metabolism in these organisms beyond the views established using classical biochemical approaches. Set within the context of metabolic networks, predicted using genome-wide reconstructions of metabolism, new hypotheses on how to target aspects of metabolism to design new drugs against these protozoa are emerging.

The association between physical activity and risk of mortality is modulated by grip strength and cardiorespiratory fitness: evidence from 498 135 UK-Biobank participants

Aims It is unclear whether the potential benefits of physical activity differ according to level of cardiorespiratory fitness (CRF) or strength. The aim of this study was to determine whether the association between physical activity and mortality is moderated by CRF and grip strength sufficiently to inform health promotion strategies. Methods and results 498 135 participants (54.7% women) from the UK Biobank were included (CRF data available in 67 702 participants). Exposure variables were grip strength, CRF, and physical activity. All-cause mortality and cardiovascular disease (CVD) events were the outcomes. 8591 died over median 4.9 years [IQR 4.3–5.5] follow-up. There was a significant interaction between total physical activity and grip strength (P < 0.0001) whereby the higher hazard of mortality associated with lower physical activity was greatest among participants in the lowest tertile for grip strength (hazard ratio, HR:1.11 [95% CI 1.09–1.14]) and lowest among those in the highest grip strength tertile (HR:1.04 [1.01–1.08]). The interaction with CRF did not reach statistical significance but the pattern was similar. The association between physical activity and mortality was larger among those in the lowest tertile of CRF (HR:1.13 [1.02–1.26]) than those in the highest (HR:1.03 [0.91–1.16]). The pattern for CVD events was similar. Conclusions These data provide novel evidence that strength, and possibly CRF, moderate the association between physical activity and mortality. The association between physical activity and mortality is strongest in those with the lowest strength (which is easily measured), and the lowest CRF, suggesting that these sub-groups could benefit most from interventions to increase physical activity.

Cognitive Test Scores in UK Biobank: Data Reduction in 480,416 Participants and Longitudinal Stability in 20,346 Participants

UK Biobank includes 502,649 middle- and older-aged adults from the general population who have undergone detailed phenotypic assessment. The majority of participants completed tests of cognitive functioning, and on average four years later a sub-group of N = 20,346 participants repeated most of the assessment. These measures will be used in a range of future studies of health outcomes in this cohort. The format and content of the cognitive tasks were partly novel. The aim of the present study was to validate and characterize the cognitive data: to describe the inter-correlational structure of the cognitive variables at baseline assessment, and the degree of stability in scores across longitudinal assessment. Baseline cognitive data were used to examine the inter-correlational/factor-structure, using principal components analysis (PCA). We also assessed the degree of stability in cognitive scores in the subsample of participants with repeat data. The different tests of cognitive ability showed significant raw inter-correlations in the expected directions. PCA suggested a one-factor solution (eigenvalue = 1.60), which accounted for around 40% of the variance. Scores showed varying levels of stability across time-points (intraclass correlation range = 0.16 to 0.65). UK Biobank cognitive data has the potential to be a significant resource for researchers looking to investigate predictors and modifiers of cognitive abilities and associated health outcomes in the general population.

Association of Body Mass Index With Cardiometabolic Disease in the UK Biobank: A Mendelian Randomization Study

Importance Higher body mass index (BMI) is a risk factor for cardiometabolic disease; however, the underlying causal associations remain unclear. Objectives To use UK Biobank data to report causal estimates of the association between BMI and cardiometabolic disease outcomes and traits, such as pulse rate, using mendelian randomization. Design, Setting, and Participants Cross-sectional baseline data from a population-based cohort study including 119 859 UK Biobank participants with complete phenotypic (medical and sociodemographic) and genetic data. Participants attended 1 of 22 assessment centers across the United Kingdom between 2006 and 2010. The present study was conducted from May 1 to July 11, 2016. Main Outcomes and Measures Prevalence of hypertension, coronary heart disease, and type 2 diabetes were determined at assessment, based on self-report. Blood pressure was measured clinically. Participants self-reported sociodemographic information pertaining to relevant confounders. A polygenic risk score comprising 93 single-nucleotide polymorphisms associated with BMI from previous genome-wide association studies was constructed, and the genetic risk score was applied to derive causal estimates using a mendelian randomization approach. Results Of the 119 859 individuals included in the study, 56 816 (47.4%) were men; mean (SD) age was 56.87 (7.93) years. Mendelian randomization analysis showed significant positive associations between genetically instrumented higher BMI and risk of hypertension (odds ratio [OR] per 1-SD higher BMI, 1.64; 95% CI, 1.48-1.83; P = 1.1 × 10−19), coronary heart disease (OR, 1.35; 95% CI, 1.09-1.69; P = .007) and type 2 diabetes (OR, 2.53; 95% CI, 2.04-3.13; P = 1.5 × 10−17), as well as systolic blood pressure (&bgr; = 1.65 mm Hg; 95% CI, 0.78-2.52 mm Hg; P = 2.0 × 10−04) and diastolic blood pressure (&bgr;  = 1.37 mm Hg; 95% CI, 0.88-1.85 mm Hg; P = 3.6 × 10−08). These associations were independent of age, sex, Townsend deprivation scores, alcohol intake, and smoking history. Conclusions and Relevance The results of this study add to the burgeoning evidence of an association between higher BMI and increased risk of cardiometabolic diseases. This finding has relevance for public health policies in many countries with increasing obesity levels.

The impact of confounding on the associations of different adiposity measures with the incidence of cardiovascular disease: a cohort study of 296 535 adults of white European descent

Abstract Aims The data regarding the associations of body mass index (BMI) with cardiovascular (CVD) risk, especially for those at the low categories of BMI, are conflicting. The aim of our study was to examine the associations of body composition (assessed by five different measures) with incident CVD outcomes in healthy individuals. Methods and results A total of 296 535 participants (57.8% women) of white European descent without CVD at baseline from the UK biobank were included. Exposures were five different measures of adiposity. Fatal and non-fatal CVD events were the primary outcome. Low BMI (≤18.5 kg m−2) was associated with higher incidence of CVD and the lowest CVD risk was exhibited at BMI of 22–23 kg m−2 beyond, which the risk of CVD increased. This J-shaped association attenuated substantially in subgroup analyses, when we excluded participants with comorbidities. In contrast, the associations for the remaining adiposity measures were more linear; 1 SD increase in waist circumference was associated with a hazard ratio of 1.16 [95% confidence interval (CI) 1.13–1.19] for women and 1.10 (95% CI 1.08–1.13) for men with similar magnitude of associations for 1 SD increase in waist-to-hip ratio, waist-to-height ratio, and percentage body fat mass. Conclusion Increasing adiposity has a detrimental association with CVD health in middle-aged men and women. The association of BMI with CVD appears more susceptible to confounding due to pre-existing comorbidities when compared with other adiposity measures. Any public misconception of a potential ‘protective’ effect of fat on CVD risk should be challenged. Take home figure The obesity paradox is mainly due to the effect of confounding on BMI and disappears on other adiposity measures.

Childhood IQ and risk of bipolar disorder in adulthood: prospective birth cohort study

Background Intellectual ability may be an endophenotypic marker for bipolar disorder. Aims Within a large birth cohort, we aimed to assess whether childhood IQ (including both verbal IQ (VIQ) and performance IQ (PIQ) subscales) was predictive of lifetime features of bipolar disorder assessed in young adulthood. Method We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a large UK birth cohort, to test for an association between measures of childhood IQ at age 8 years and lifetime manic features assessed at age 22–23 years using the Hypomania Checklist-32 (HCL-32; n=1881 individuals). An ordinary least squares linear regression model was used, with normal childhood IQ (range 90–109) as the referent group. We adjusted analyses for confounding factors, including gender, ethnicity, handedness, maternal social class at recruitment, maternal age, maternal history of depression and maternal education. Results There was a positive association between IQ at age 8 years and lifetime manic features at age 22–23 years (Pearson’s correlation coefficient 0.159 (95% CI 0.120–0.198), P>0.001). Individuals in the lowest decile of manic features had a mean full-scale IQ (FSIQ) which was almost 10 points lower than those in the highest decile of manic features: mean FSIQ 100.71 (95% CI 98.74–102.6) v. 110.14 (95% CI 107.79–112.50), P>0.001. The association between IQ and manic features was present for FSIQ, VIQ and for PIQ but was strongest for VIQ. Conclusions A higher childhood IQ score, and high VIQ in particular, may represent a marker of risk for the later development of bipolar disorder. This finding has implications for understanding of how liability to bipolar disorder may have been selected through generations. It will also inform future genetic studies at the interface of intelligence, creativity and bipolar disorder and is relevant to the developmental trajectory of bipolar disorder. It may also improve approaches to earlier detection and treatment of bipolar disorder in adolescents and young adults. Declaration of interest None. Copyright and usage

Childhood interleukin-6, C-reactive protein and atopic disorders as risk factors for hypomanic symptoms in young adulthood: a longitudinal birth cohort study

Background There are no existing longitudinal studies of inflammatory markers and atopic disorders in childhood and risk of hypomanic symptoms in adulthood. This study examined if childhood: (1) serum interleukin-6 (IL-6) and C-reactive protein (CRP); and (2) asthma and/or eczema are associated with features of hypomania in young adulthood. Method Participants in the Avon Longitudinal Study of Parents and Children, a prospective general population UK birth cohort, had non-fasting blood samples for IL-6 and CRP measurement at the age of 9 years (n = 4645), and parents answered a question about doctor-diagnosed atopic illness before the age of 10 years (n = 7809). These participants completed the Hypomania Checklist at age 22 years (n = 3361). Results After adjusting for age, sex, ethnicity, socio-economic status, past psychological and behavioural problems, body mass index and maternal postnatal depression, participants in the top third of IL-6 values at 9 years, compared with the bottom third, had an increased risk of hypomanic symptoms by age 22 years [adjusted odds ratio 1.77, 95% confidence interval (CI) 1.10–2.85, p < 0.001]. Higher IL-6 levels in childhood were associated with adult hypomania features in a dose–response fashion. After further adjustment for depression at the age of 18 years this association remained (adjusted odds ratio 1.70, 95% CI 1.03–2.81, p = 0.038). There was no evidence of an association of hypomanic symptoms with CRP levels, asthma or eczema in childhood. Conclusions Higher levels of systemic inflammatory marker IL-6 in childhood were associated with hypomanic symptoms in young adulthood, suggesting that inflammation may play a role in the pathophysiology of mania. Inflammatory pathways may be suitable targets for the prevention and intervention for bipolar disorder.

Adiposity among 132 479 UK Biobank participants; contribution of sugar intake vs other macronutrients

Background Policy makers are being encouraged to specifically target sugar intake in order to combat obesity. We examined the extent to which sugar, relative to other macronutrients, was associated with adiposity. Methods We used baseline data from UK Biobank to examine the associations between energy intake (total and individual macronutrients) and adiposity [body mass index (BMI), percentage body fat and waist circumference]. Linear regression models were conducted univariately and adjusted for age, sex, ethnicity and physical activity. Results Among 132 479 participants, 66.3% of men and 51.8% of women were overweight/obese. There was a weak correlation (r = 0.24) between energy from sugar and fat; 13% of those in the highest quintile for sugar were in the lowest for fat, and vice versa. Compared with normal BMI, obese participants had 11.5% higher total energy intake and 14.6%, 13.8%, 9.5% and 4.7% higher intake from fat, protein, starch and sugar, respectively. Hence, the proportion of energy derived from fat was higher (34.3% vs 33.4%, P < 0.001) but from sugar was lower (22.0% vs 23.4%, P < 0.001). BMI was more strongly associated with total energy [coefficient 2.47, 95% confidence interval (CI) 2.36-2.55] and energy from fat (coefficient 1.96, 95% CI 1.91-2.06) than sugar (coefficient 0.48, 95% CI 0.41-0.55). The latter became negative after adjustment for total energy. Conclusions Fat is the largest contributor to overall energy. The proportion of energy from fat in the diet, but not sugar, is higher among overweight/obese individuals. Focusing public health messages on sugar may mislead on the need to reduce fat and overall energy consumption.