Publications by authors named "Alexandra I Blakemore"

70 Publications

Secondary analyses of global datasets: do obesity and physical activity explain variation in diabetes risk across populations?

Int J Obes (Lond) 2021 05 11;45(5):944-956. Epub 2021 Feb 11.

Imperial College London Diabetes Centre, Abu Dhabi, United Arab Emirates.

Type 2 diabetes rates vary significantly across geographic regions. These differences are sometimes assumed to be entirely driven by differential distribution of environmental triggers, including obesity and insufficient physical activity (IPA). In this review, we discuss data which conflicts with this supposition. We carried out a secondary analysis of publicly available data to unravel the relative contribution of obesity and IPA towards diabetes risk across different populations. We used sex-specific, age-standardized estimates from Non-Communicable Disease Risk Factor Collaboration (NCD-RisC) on diabetes (1980-2014) and obesity (1975-2016) rates, in 200 countries, and from WHO on IPA rates in 168 countries in the year 2016. NCD-RisC and WHO organized countries into nine super-regions. All analyses were region- and sex-specific. Although obesity has been increasing since 1975 in every part of the world, this was not reflected in a proportional increase in diabetes rates in several regions, including Central and Eastern Europe, and High-income western countries region. Similarly, the association of physical inactivity with diabetes is not homogeneous across regions. Countries from different regions across the world could have very similar rates of diabetes, despite falling on opposite ends of IPA rate spectrum. The combined effect of obesity and IPA on diabetes risk was analyzed at the worldwide and country level. The overall findings highlighted the larger impact of obesity on disease risk; low IPA rates do not seem to be protective of diabetes, when obesity rates are high. Despite that, some countries deviate from this overall observation. Sex differences were observed across all our analyses. Overall, data presented in this review indicate that different populations, while experiencing similar environmental shifts, are apparently differentially subject to diabetes risk. Sex-related differences observed suggest that males and females are either subject to different risk factor exposures or have different responses to them.
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http://dx.doi.org/10.1038/s41366-021-00764-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081659PMC
May 2021

Who will benefit from bariatric surgery for diabetes? A protocol for an observational cohort study.

BMJ Open 2021 02 10;11(2):e042355. Epub 2021 Feb 10.

Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

Introduction: Type 2 diabetes mellitus (T2DM) and obesity are pandemic diseases that lead to a great deal of morbidity and mortality. The most effective treatment for obesity and T2DM is bariatric or metabolic surgery; it can lead to long-term diabetes remission with 4 in 10 of those undergoing surgery having normal blood glucose on no medication 1 year postoperatively. However, surgery carries risks and, additionally, due to resource limitations, there is a restricted number of patients who can access this treatment. Moreover, not all those who undertake surgery respond equally well metabolically. The objective of the current research is to prospectively investigate predictors of T2DM response following metabolic surgery, including those directly involved in its aetiopathogenesis such as fat distribution and genetic variants. This will inform development of a clinically applicable model to help prioritise this therapy to those predicted to have remission.

Methods And Analysis: A prospective multicentre observational cohort study of adult patients with T2DM and obesity undergoing Roux-en-Y gastric bypass surgery. Patients will be comprehensively assessed before surgery to determine their clinical, metabolic, psychological, genetic and fat distribution profiles. A multivariate logistic regression model will be used to assess the value of the factors derived from the preoperative assessment in terms of prediction of diabetes remission.

Ethics And Dissemination: Formal ethics review was undertaken with a favourable opinion (UK HRA RES reference number 18/LO/0931). The dissemination plan is to present the results at conferences, in peer-reviewed journals as well as to lay media and to patient organisations.

Trial Registration Details: ClinicalTrials.gov, Identifier: NCT03842475.
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http://dx.doi.org/10.1136/bmjopen-2020-042355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878155PMC
February 2021

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Hemizygous mutations in L1CAM in two unrelated male probands with childhood onset psychosis.

Psychiatr Genet 2020 06;30(3):73-82

Faculty of Medicine, Department of Brain Sciences, Imperial College London, Du Cane Road, London.

Objective: To identify genes underlying childhood onset psychosis.

Methods: Patients with onset of psychosis at age 13 or younger were identified from clinics across England, and they and their parents were exome sequenced and analysed for possible highly penetrant genetic contributors.

Results: We report two male childhood onset psychosis patients of different ancestries carrying hemizygous very rare possibly damaging missense variants (p.Arg846His and p.Pro145Ser) in the L1CAM gene. L1CAM is an X-linked Mendelian disease gene in which both missense and loss of function variants are associated with syndromic forms of intellectual disability and developmental disorder.

Conclusions: This is the first study reporting a possible extension of the phenotype of L1CAM variant carriers to childhood onset psychosis. The family history and presence of other significant rare genetic variants in the patients suggest that there may be genetic interactions modulating the presentation.
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http://dx.doi.org/10.1097/YPG.0000000000000253DOI Listing
June 2020

Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.

Am J Hum Genet 2020 03 27;106(3):389-404. Epub 2020 Feb 27.

Department of Cardiovascular Sciences, University of Leicester, LE3 9QP, United Kingdom; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, United Kingdom.

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
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http://dx.doi.org/10.1016/j.ajhg.2020.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058826PMC
March 2020

GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.

Sci Adv 2019 09 4;5(9):eaaw3095. Epub 2019 Sep 4.

Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
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http://dx.doi.org/10.1126/sciadv.aaw3095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904961PMC
September 2019

New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders.

Nat Hum Behav 2019 09 29;3(9):950-961. Epub 2019 Jul 29.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.
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http://dx.doi.org/10.1038/s41562-019-0653-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711277PMC
September 2019

Genome-Wide and Abdominal MRI Data Provide Evidence That a Genetically Determined Favorable Adiposity Phenotype Is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease, and Hypertension.

Diabetes 2019 01 23;68(1):207-219. Epub 2018 Oct 23.

Section of Investigative Medicine, Imperial College London, London, U.K.

Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such favorable adiposity alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined MRI data with genome-wide association studies of body fat percentage (%) and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity but a favorable metabolic profile. Consistent with previous studies, individuals carrying more favorable adiposity alleles had higher body fat % and higher BMI but lower risk of type 2 diabetes, heart disease, and hypertension. These individuals also had higher subcutaneous fat but lower liver fat and a lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in , , and , whereas the allele in was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified favorable adiposity alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglycerides in metabolically low-risk depots.
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http://dx.doi.org/10.2337/db18-0708DOI Listing
January 2019

Relationship between BMI and emotion-handling capacity in an adult Finnish population: The Northern Finland Birth Cohort 1966.

PLoS One 2018 26;13(9):e0203660. Epub 2018 Sep 26.

Section of Investigative Medicine, Division of Diabetes, Endocrinology, and Metabolism, Faculty of Medicine, Imperial College London, London, United Kingdom.

Background: Alexithymia, a difficulty in identifying and expressing emotions, has been associated with obesity and eating disorders in small-scale cross-sectional studies. Here, we assess the relationship between body mass index (BMI) and alexithymia in a large cohort of free-living Finnish adults over a 15-year period.

Methods: Participants were drawn from the Northern Finnish Birth Cohort 1966 (NFBC1966). The 20-Item Toronto Alexithymia Scale (TAS-20) was used as a measure of alexithymia and was completed at the age of 31 years (31y: n = 4841), and 46 years (46y: n = 5404). BMI was recorded at both time points. Where data at both time points were available (n = 3274), the relationship between changes in BMI and TAS-20 over this time period was also investigated.

Results: BMI was significantly and positively associated with TAS-20 score (p<0.0001, both at 31 years and at 46 years of ages). The association remained statistically significant after adjustment for potential confounders (sex, marital status and several socio-economic indicators). In individuals who experienced the greatest change in BMI (in either direction) over the 15-year period, there was a modest mean increase in TAS-20 score.

Conclusions: Our data revealed that TAS-20 score was correlated with and co-varied with body mass status. We suggest that future clinical research should consider the role of alexithymia in obesity. Further investigation of this relationship is warranted to ensure that the needs of obese subjects with undiagnosed alexithymia are considered in the design of weight management programmes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203660PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157858PMC
March 2019

New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals.

Circ Cardiovasc Genet 2017 Oct;10(5)

Background: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.

Methods And Results: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (<5×10) for BP, of which 4 are new BP loci: rs9678851 (missense, ), rs7437940 (), rs13303 (missense, ), and rs1055144 (). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, ) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at ) was genome-wide significant.

Conclusions: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.
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http://dx.doi.org/10.1161/CIRCGENETICS.117.001778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776077PMC
October 2017

Determinants of postprandial plasma bile acid kinetics in human volunteers.

Am J Physiol Gastrointest Liver Physiol 2017 Oct 29;313(4):G300-G312. Epub 2017 Jun 29.

Nutrition and Food Sciences, Technische Universität München, Freising-Weihenstephan, Germany.

Bile acids (BA) are signaling molecules with a wide range of biological effects, also identified among the most responsive plasma metabolites in the postprandial state. We here describe this response to different dietary challenges and report on key determinants linked to its interindividual variability. Healthy men and women ( = 72, 62 ± 8 yr, mean ± SE) were enrolled into a 12-wk weight loss intervention. All subjects underwent an oral glucose tolerance test and a mixed-meal tolerance test before and after the intervention. BA were quantified in plasma by liquid chromatography-tandem mass spectrometry combined with whole genome exome sequencing and fecal microbiota profiling. Considering the average response of all 72 subjects, no effect of the successful weight loss intervention was found on plasma BA profiles. Fasting and postprandial BA profiles revealed high interindividual variability, and three main patterns in postprandial BA response were identified using multivariate analysis. Although the women enrolled were postmenopausal, effects of sex difference in BA response were evident. Exome data revealed the contribution of preselected genes to the observed interindividual variability. In particular, a variant in the gene, encoding the small intestinal BA transporter organic anion-transporting polypeptide-1A2 (OATP1A2), was associated with delayed postprandial BA increases. Fecal microbiota analysis did not reveal evidence for a significant influence of bacterial diversity and/or composition on plasma BA profiles. The analysis of plasma BA profiles in response to two different dietary challenges revealed a high interindividual variability, which was mainly determined by genetics and sex difference of host with minimal effects of the microbiota. Considering the average response of all 72 subjects, no effect of the successful weight loss intervention was found on plasma bile acid (BA) profiles. Despite high interindividual variability, three main patterns in postprandial BA response were identified using multivariate analysis. A variant in the gene, encoding the small intestinal BA transporter organic anion-transporting polypeptide-1A2 (OATP1A2), was associated with delayed postprandial BA increases in response to both the oral glucose tolerance test and the mixed-meal tolerance test.
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http://dx.doi.org/10.1152/ajpgi.00157.2017DOI Listing
October 2017

Associations of Leukocyte Telomere Length With Aerobic and Muscular Fitness in Young Adults.

Am J Epidemiol 2017 04;185(7):529-537

Decline in both telomere length and physical fitness over the life course may contribute to increased risk of several chronic diseases. The relationship between telomere length and aerobic and muscular fitness is not well characterized. We examined whether there are cross-sectional associations of mean relative leukocyte telomere length (LTL) with objective measures of aerobic fitness, muscle strength, and muscle endurance, using data on 31-year-old participants of the Northern Finland Birth Cohort 1966 (n = 4,952-5,205, varying by exposure-outcome analysis). Aerobic fitness was assessed by means of heart rate measurement following a standardized submaximal step test; muscular fitness was assessed by means of a maximal isometric handgrip strength test and a test of lower-back trunk muscle endurance. Longer LTL was associated with higher aerobic fitness and better trunk muscle endurance in models including adjustment for age, sex, body mass index, socioeconomic position, diet, smoking, alcohol consumption, physical activity level, and C-reactive protein. In a sex-stratified analysis, LTL was not associated with handgrip strength in either men or women. LTL may relate to aspects of physical fitness in young adulthood, but replication of these findings is required, along with further studies to help assess directions and causality in these associations.
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http://dx.doi.org/10.1093/aje/kww123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860435PMC
April 2017

Limitations of the DiaRem Score in Predicting Remission of Diabetes Following Roux-En-Y Gastric Bypass (RYGB) in an ethnically Diverse Population from a Single Institution in the UK.

Obes Surg 2017 03;27(3):782-786

Department of Medicine, Imperial College London, London, UK.

Purpose: This study aimed to determine the predictive power of the DiaRem score following Roux-en-Y gastric bypass to identify patients who would have diabetes remission at 1 year in an ethnically diverse population.

Methods: We performed a retrospective review of 262 patients with type 2 diabetes mellitus who underwent RYGB at the Imperial Weight Centre, UK, from 2007 to 2014. Data was collected on the parameters required to calculate the DiaRem score as well as pre- and post-surgical weight and the ethnicity of the subjects.

Results: The studied cohort was ethnically diverse (61.3 % Caucasian, 10.3 % Asian, 5.3 % black, 2.6 % mixed and 20.6 % other). At 1-year post-surgery, there were significant reductions in mean weight (133.4 to 94.3 kg) and BMI (46.7 to 33.3 kg/m). The mean HbA1c decreased from 8.2 to 6.1 %, and 32.5 % of the cohort underwent either partial or complete remission. 67.8 % of the patients that were classified in group 1 of the DiaRem score (most likely to have remission) had complete remission. However, 22.9 % of the patients predicted to have the least chance of remission had either partial or complete remission.

Conclusions: In this ethnically diverse cohort, the DiaRem score remains a useful tool to predict diabetes remission in those that have a low DiaRem score (high chance for remission) but was more limited in its predictive power in those with a high DiaRem score (least likely to have remission). Caution must be used in the application of this model in populations other than the US white Caucasian population used to derive the score.
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http://dx.doi.org/10.1007/s11695-016-2368-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306254PMC
March 2017

Analysis with the exome array identifies multiple new independent variants in lipid loci.

Hum Mol Genet 2016 09 27;25(18):4094-4106. Epub 2016 Jul 27.

Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.

It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.
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http://dx.doi.org/10.1093/hmg/ddw227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291227PMC
September 2016

Guidelines for the follow-up of patients undergoing bariatric surgery.

Clin Obes 2016 Jun;6(3):210-24

Obesity Clinic, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Bariatric surgery can facilitate weight loss and improvement in medical comorbidities. It has a profound impact on nutrition, and patients need access to follow-up and aftercare. NICE CG189 Obesity emphasized the importance of a minimum of 2 years follow-up in the bariatric surgical service and recommended that following discharge from the surgical service, there should be annual monitoring as part of a shared care model of chronic disease management. NHS England Obesity Clinical Reference Group commissioned a multi-professional subgroup, which included patient representatives, to develop bariatric surgery follow-up guidelines. Terms of reference and scope were agreed upon. The group members took responsibility for different sections of the guidelines depending on their areas of expertise and experience. The quality of the evidence was rated and strength graded. Four different shared care models were proposed, taking into account the variation in access to bariatric surgical services and specialist teams across the country. The common features include annual review, ability for a GP to refer back to specialist centre, submission of follow-up data to the national data base to NBSR. Clinical commissioning groups need to ensure that a shared care model is implemented as patient safety and long-term follow-up are important.
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http://dx.doi.org/10.1111/cob.12145DOI Listing
June 2016

Quantified-Self for Obesity: Physical Activity Behaviour Sensing to Improve Health Outcomes.

Stud Health Technol Inform 2016 ;220:414-6

Department of Investigative Medicine, Imperial College London.

Physical activity levels in bariatric patients have not been well documented, despite their importance in maintaining weight loss following surgery. This study investigated the feasibility of tracking physical activity using a smartphone app with minimal user interaction. Thus far, we have obtained good quality data from 255 patients at various points in their weight loss journey. Preliminary analyses indicate little change in physical activity levels following surgery with pre-surgery patients reaching an average of 16 minutes per day and post-surgery patients achieving a daily average of 21 minutes. Further analyses using machine-learning techniques will be conducted to determine whether physical activity is a critical factor in distinguishing between successful and unsuccessful weight loss outcomes and in the resolution of comorbid conditions in patients with similar clinical profiles.
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January 2017

Body composition of the host influences dendritic cell phenotype in patients treated for colorectal cancer.

Tumour Biol 2016 Aug 10;37(8):11359-64. Epub 2016 Mar 10.

Antigen Presentation Research Group, Imperial College London, North West London Hospitals Campus, Watford Road, Harrow, HA1 3UJ, UK.

Dendritic cells (DCs) are antigen-presenting cells that can acquire tumour antigens and initiate cytotoxic T cell reactions. Obesity has been proposed as a cause for tumours escaping immune surveillance, but few studies investigate the impact of other body composition parameters. We examined the relationship of DC phenotype with computer tomography (CT)-defined parameters in patients with colorectal cancer (CRC). DCs were identified within peripheral blood mononuclear cells by flow cytometry as HLA-DR positive and negative for markers of other cell lineages in 21 patients. Analysis of CT scans was used to calculate lumbar skeletal muscle index (LSMI) and mean muscle attenuation (MA). Positive correlation between the LSMI and expression of CD40 in all DCs (r = 0.45; p = 0.04) was demonstrated. The MA was positively correlated with scavenger receptor CD36 [all DCs (r = 0.60; p = 0.01) and myeloid DCs (r = 0.63; p < 0.01)]. However, the MA was negatively correlated with CCR7 expression in all DCs (r = -0.46, p = 0.03.) and with CD83 [all DCs (r = -0.63; p = 0.01) and myeloid DCs (r = -0.75; p < 0.01)]. There were no relationships between the fat indexes and the DC phenotype. These results highlight a direct relationship between muscle depletion and changes in stimulatory, migratory and fatty acid-processing potential of DC in patients with CRC.
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http://dx.doi.org/10.1007/s13277-016-5009-yDOI Listing
August 2016

25-Hydroxyvitamin D Concentration and Leukocyte Telomere Length in Young Adults: Findings From the Northern Finland Birth Cohort 1966.

Am J Epidemiol 2016 Feb 20;183(3):191-8. Epub 2016 Jan 20.

Higher vitamin D status, lower adiposity, and longer telomere length are each reportedly associated with lower risk of several chronic diseases and all-cause mortality. However, direct relationships between vitamin D status (measured by circulating 25-hydroxyvitamin D (25(OH)D) concentration), adiposity, and telomere length are not well established. We conducted a cross-sectional analysis of associations of 25(OH)D and body mass index (BMI; weight (kg)/height (m)(2)) with mean relative leukocyte telomere length (LTL) using data gathered on 5,096 participants from Northern Finland Birth Cohort 1966 at age 31 years (1997). 25(OH)D was not associated with LTL in either basic or confounder/mediator-adjusted models. BMI was inversely associated with LTL after adjustment for potential confounding by age, sex, socioeconomic position, physical activity, diet, smoking, alcohol intake, and use of oral contraceptives (per 1-unit increase in BMI, mean difference in LTL = -0.4%, 95% confidence interval: -0.6, -0.2). The BMI-LTL association was also independent of 25(OH)D and was attenuated slightly, but remained, after adjustment for C-reactive protein, a marker of low-grade inflammation (mean difference in LTL = -0.3%, 95% confidence interval -0.6, -0.1). These findings suggest that vitamin D status is unlikely to be an important determinant of LTL, at least by young adulthood. Inflammation may partly mediate associations of adiposity with LTL.
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http://dx.doi.org/10.1093/aje/kwv203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724094PMC
February 2016

Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.

Hum Mol Genet 2016 Jan 24;25(2):389-403. Epub 2015 Nov 24.

School of Women's and Infants' Health, The University of Western Australia, Perth, Australia.

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.
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http://dx.doi.org/10.1093/hmg/ddv472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854022PMC
January 2016

The prognostic significance and relationship with body composition of CCR7-positive cells in colorectal cancer.

J Surg Oncol 2015 Jul 14;112(1):86-92. Epub 2015 Jul 14.

Department of Surgery St. Marks Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ, UK.

Background And Objectives: The host local immune response (LIR) to cancer is a determinant of cancer outcome. Regulation of this local response is largely achieved through chemokine synthesis from the tumor microenvironment such as C-Chemokine-Receptor-7 (CCR7). We examined the LIR measured as CCR7 expression, in colorectal cancers (CRC) and explored relationships with body composition (BC) and survival.

Methods: A study of paraffin-embedded tissue specimens was carried out in 116 patients with non-metastatic CRC. CCR7 expression was determined by immunohistochemistry. Analysis of computer tomography scans was used to calculate BC parameters. Survival analyses and multivariate regression models were used.

Results: High CCR7(+) cell density within the tumor stroma and at the margin was significantly associated with increased age, the presence of lymphovascular invasion, higher tumor stage, lymph node metastasis, high Klintrup-Makinen immune score, and myosteatosis. High CCR7(+) cell density in the tumor margin was significantly associated with shorter disease-free (DFS) and overall survival (OS) (P < 0.001). This was also significantly associated with shorter survival in multivariate analysis (HR = 8.87; 95%CI [2.51-31.3]; P < 0.01 for OS and HR = 4.72; 95%CI (1.24-12.9); P = 0.02 for DFS).

Conclusions: Our results suggest that a specific immune microenvironment may be associated with altered host's BC and tumor behavior, and that CCR7 may serve as a novel prognostic biomarker.
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http://dx.doi.org/10.1002/jso.23959DOI Listing
July 2015

Truncating Homozygous Mutation of Carboxypeptidase E (CPE) in a Morbidly Obese Female with Type 2 Diabetes Mellitus, Intellectual Disability and Hypogonadotrophic Hypogonadism.

PLoS One 2015 29;10(6):e0131417. Epub 2015 Jun 29.

Section of Investigative Medicine, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom.

Carboxypeptidase E is a peptide processing enzyme, involved in cleaving numerous peptide precursors, including neuropeptides and hormones involved in appetite control and glucose metabolism. Exome sequencing of a morbidly obese female from a consanguineous family revealed homozygosity for a truncating mutation of the CPE gene (c.76_98del; p.E26RfsX68). Analysis detected no CPE expression in whole blood-derived RNA from the proband, consistent with nonsense-mediated decay. The morbid obesity, intellectual disability, abnormal glucose homeostasis and hypogonadotrophic hypogonadism seen in this individual recapitulates phenotypes in the previously described fat/fat and Cpe knockout mouse models, evidencing the importance of this peptide/hormone-processing enzyme in regulating body weight, metabolism, and brain and reproductive function in humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0131417PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485893PMC
March 2016

PDGFRα demarcates the cardiogenic clonogenic Sca1+ stem/progenitor cell in adult murine myocardium.

Nat Commun 2015 May 18;6:6930. Epub 2015 May 18.

1] British Heart Foundation Centre of Research Excellence, Imperial College London, London SW7 2AZ, UK [2] National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.

Cardiac progenitor/stem cells in adult hearts represent an attractive therapeutic target for heart regeneration, though (inter)-relationships among reported cells remain obscure. Using single-cell qRT-PCR and clonal analyses, here we define four subpopulations of cardiac progenitor/stem cells in adult mouse myocardium all sharing stem cell antigen-1 (Sca1), based on side population (SP) phenotype, PECAM-1 (CD31) and platelet-derived growth factor receptor-α (PDGFRα) expression. SP status predicts clonogenicity and cardiogenic gene expression (Gata4/6, Hand2 and Tbx5/20), properties segregating more specifically to PDGFRα(+) cells. Clonal progeny of single Sca1(+) SP cells show cardiomyocyte, endothelial and smooth muscle lineage potential after cardiac grafting, augmenting cardiac function although durable engraftment is rare. PDGFRα(-) cells are characterized by Kdr/Flk1, Cdh5, CD31 and lack of clonogenicity. PDGFRα(+)/CD31(-) cells derive from cells formerly expressing Mesp1, Nkx2-5, Isl1, Gata5 and Wt1, distinct from PDGFRα(-)/CD31(+) cells (Gata5 low; Flk1 and Tie2 high). Thus, PDGFRα demarcates the clonogenic cardiogenic Sca1(+) stem/progenitor cell.
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http://dx.doi.org/10.1038/ncomms7930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479024PMC
May 2015

Genetic determinants of leucocyte telomere length in children: a neglected and challenging field.

Paediatr Perinat Epidemiol 2015 Mar 1;29(2):146-50. Epub 2015 Feb 1.

UMR INSERM U1122, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Université de Lorraine, Nancy, France.

Background: Telomere length is associated with a large range of human diseases. Genome-wide association studies (GWAS) have identified genetic variants that are associated with leucocyte telomere length (LTL). However, these studies are limited to adult populations. Nevertheless, childhood is a crucial period for the determination of LTL, and the assessment of age-specific genetic determinants, although neglected, could be of great importance. Our aim was to provide insights and preliminary results on genetic determinants of LTL in children.

Methods: Healthy children (n = 322, age range = 6.75-17 years) with available GWAS data (Illumina Human CNV370-Duo array) were included. The LTL was measured using multiplex quantitative real-time polymerase chain reaction. Linear regression models adjusted for age, gender, parental age at child's birth, and body mass index were used to test the associations of LTL with polymorphisms identified in adult GWAS and to perform a discovery-only GWAS.

Results: The previously GWAS-identified variants in adults were not associated with LTL in our paediatric sample. This lack of association was not due to possible interactions with age or gene × gene interactions. Furthermore, a discovery-only GWAS approach demonstrated six novel variants that reached the level of suggestive association (P ≤ 5 × 10(-5)) and explain a high percentage of children's LTL.

Conclusions: The study of genetic determinants of LTL in children may identify novel variants not previously identified in adults. Studies in large-scale children populations are needed for the confirmation of these results, possibly through a childhood consortium that could better handle the methodological challenges of LTL genetic epidemiology field.
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http://dx.doi.org/10.1111/ppe.12173DOI Listing
March 2015

A novel common variant in DCST2 is associated with length in early life and height in adulthood.

Hum Mol Genet 2015 Feb 3;24(4):1155-68. Epub 2014 Oct 3.

MRC Integrative Epidemiology Unit .

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
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http://dx.doi.org/10.1093/hmg/ddu510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447786PMC
February 2015

Multiple measures of adiposity are associated with mean leukocyte telomere length in the northern Finland birth cohort 1966.

PLoS One 2014 11;9(6):e99133. Epub 2014 Jun 11.

Section of Investigative Medicine, Department of Medicine, Imperial College London, London, United Kingdom.

Studies of leukocyte telomere length (LTL) and adiposity have produced conflicting results, and the relationship between body mass index (BMI) and telomere length throughout life remains unclear. We therefore tested association of adult LTL measured in 5,598 participants with: i) childhood growth measures (BMI and age at adiposity rebound (AR)); ii) change in BMI from childhood to adulthood and iii) adult BMI, waist-to-hip ratio (WHR), body adiposity index (BAI). Childhood BMI at AR was positively associated with LTL at 31 years in women (P = 0.041). Adult BMI and WHR in both men (P = 0.025 and P = 0.049, respectively) and women (P = 0.029 and P = 0.008, respectively), and BAI in women (P = 0.021) were inversely associated with LTL at 31 years. An increase in standardised BMI between early childhood and adulthood was associated with shorter adult LTL in women (P = 0.008). We show that LTL is inversely associated with multiple measures of adiposity in both men and women. Additionally, BMI increase in women from childhood to adulthood is associated with shorter telomeres at age 31, potentially indicating accelerated biological ageing.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0099133PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053385PMC
February 2015

Human leukocyte telomere length is associated with DNA methylation levels in multiple subtelomeric and imprinted loci.

Sci Rep 2014 May 14;4:4954. Epub 2014 May 14.

UCL Institute of Child Health, London, UK.

In humans, leukocyte telomere length (LTL) is positively correlated with lifespan, and shorter LTL is associated with increased risk of age-related disease. In this study we tested for association between telomere length and methylated cytosine levels. Measurements of mean telomere length and DNA methylation at >450,000 CpG sites were obtained for both blood (N = 24) and EBV-transformed cell-line (N = 36) DNA samples from men aged 44-45 years. We identified 65 gene promoters enriched for CpG sites at which methylation levels are associated with leukocyte telomere length, and 36 gene promoters enriched for CpG sites at which methylation levels are associated with telomere length in DNA from EBV-transformed cell-lines. We observed significant enrichment of positively associated methylated CpG sites in subtelomeric loci (within 4 Mb of the telomere) (P < 0.01), and also at loci in imprinted regions (P < 0.001). Our results pave the way for further investigations to help elucidate the relationships between telomere length, DNA methylation and gene expression in health and disease.
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http://dx.doi.org/10.1038/srep04954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4344300PMC
May 2014

Obesity, genetic risk, and environment.

BMJ 2014 Mar 19;348:g1900. Epub 2014 Mar 19.

Section of Investigative Medicine, Division of Diabetes, Endocrinology, and Metabolism, Faculty of Medicine, Imperial College, London W12 0NN, UK.

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http://dx.doi.org/10.1136/bmj.g1900DOI Listing
March 2014

Imprinted expression of UBE3A in non-neuronal cells from a Prader-Willi syndrome patient with an atypical deletion.

Hum Mol Genet 2014 May 20;23(9):2364-73. Epub 2013 Dec 20.

Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT, USA.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two neurodevelopmental disorders most often caused by deletions of the same region of paternally inherited and maternally inherited human chromosome 15q, respectively. AS is a single gene disorder, caused by the loss of function of the ubiquitin ligase E3A (UBE3A) gene, while PWS is still considered a contiguous gene disorder. Rare individuals with PWS who carry atypical microdeletions on chromosome 15q have narrowed the critical region for this disorder to a 108 kb region that includes the SNORD116 snoRNA cluster and the Imprinted in Prader-Willi (IPW) non-coding RNA. Here we report the derivation of induced pluripotent stem cells (iPSCs) from a PWS patient with an atypical microdeletion that spans the PWS critical region. We show that these iPSCs express brain-specific portions of the transcripts driven by the PWS imprinting center, including the UBE3A antisense transcript (UBE3A-ATS). Furthermore, UBE3A expression is imprinted in most of these iPSCs. These data suggest that UBE3A imprinting in neurons only requires UBE3A-ATS expression, and no other neuron-specific factors. These data also suggest that a boundary element lying within the PWS critical region prevents UBE3A-ATS expression in non-neural tissues.
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http://dx.doi.org/10.1093/hmg/ddt628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976333PMC
May 2014
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