Variation at the Klotho gene locus does not affect cognitive function in up to 335,074 British Caucasians in the UK Biobank

Version 2 issued 19 November 2019.Copyright © The Author(s)/Funder. The proportion of older adults in Western populations is increasing and there is, therefore, a need to define factors affecting maintenance of physical and cognitive health in old age. Variations in the Klotho (KL) gene, and specifically the KL-VS haplotype, have been identified by several authors as potentially influencing cognitive function and decline. We have attempted to verify the reported associations between KL variants, including the KL-VS haplotype, and cognitive function in up to 335,074 British Caucasian participants aged 40-79 years from the UK Biobank. We do not find evidence that KL-VS affects cognitive function or its decline with increasing age. We examined a further 244 KL variants and found that rs117650866 was associated with Prospective Memory, but could not replicate this in follow-up samples. In conclusion, there is insufficient evidence in the UK Biobank to support the concept that KL variants affect cognitive function or its rate of decline.Calico LLC (South San Francisco, California, United States)

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

Copyright © 2021 The Author(s). 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.The work presented in this paper is part of a PhD project by the first author (Budour Alkaf); internal funding by Imperial College London Diabetes Centre is gratefully acknowledged. The authors are also grateful for The Medical Research Council, UK (grant numbers: MR/M013138/1, MRC/BBSRC MR/S03658X/1 (JPI HDHL H2020)) for their financial support during the authors time when conducting this piece of work and writing this paper

Mendelian randomisation analyses of UK Biobank and published data suggest that increased adiposity lowers risk of breast and prostate cancer

Copyright © The Authors 2022. Breast (BCa) and prostate (PrCa) cancer are the first and second most common types of cancer in women and men, respectively. We aimed to explore the causal effect of adiposity on BCa and PrCa risk in the UK Biobank and published data. We used Mendelian randomisation (MR) to assess the causal effect of body mass index (BMI), body fat percentage (BFP), waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR) on BCa and PrCa risk. We found that increased BMI, WC and HC decreased the risk of breast cancer (OR 0.70 per 5.14 kg/m2 [0.59–0.85, p = 2.1 × 10–4], 0.76 per 12.49 cm [60–0.97, p = 0.028] and 0.73 per 10.31 cm [0.59–0.90, p = 3.7 × 10–3], respectively) and increased WC and BMI decreased the risk of prostate cancer (0.68 per 11.32 cm [0.50–0.91, p = 0.01] and 0.76 per 10.23 kg/m2 [0.61–0.95, p = 0.015], respectively) in UK Biobank participants. We confirmed our results with a two-sample-MR of published data. In conclusion, our results suggest a protective effect of adiposity on the risk of BCa and PrCa highlighting the need to re-evaluate the role of adiposity as cancer risk factor.Brunel Research Initiative and Enterprise Fund; HAA is the recipient of a PhD studentship from the College of Health and Life Sciences, Brunel University London

Associations of adolescents’ diet and meal patterns with school performance in the Northern Finland Birth Cohort 1986: A Mendelian randomisation study

Data availability: Data will be made available on request.Supplementary data are available online at https://www.sciencedirect.com/science/article/pii/S0195666323024984?via%3Dihub#appsec1 .Copyright © 2023 The Authors. Background: Several observational studies indicate that dietary habits in children and adolescents are associated with school performance. These associations are heavily confounded by socio-economic characteristics, such as household income and parents’ educational attainment, amongst other factors. The objective of this study was to explore the association between diet and school performance in adolescents from the Northern Finland Birth Cohort 1986 (NFBC1986). Methods: Dietary and school performance data were collected using self-reported questionnaires from adolescents in the NFBC1986 cross-sectional, 16-year follow-up study. In this work we derived exploratory factors for the dietary variables, frequency of skipping main meals and school performance variables, performed genome-wide association studies (GWAS) against these factors to obtain genetic association data and conducted one-sample and two-sample Mendelian randomisation (MR) analyses using individual level data for up to 9220 adolescents in NFBC1986 and GWAS results from external cohorts. We report observational and MR effects of diet on school performance and cognition-related phenotypes. Results: The observational study and the one-sample Mendelian randomisation analysis showed that high fat, salt and sugar (HFSS) consumption was associated with poor school performance in general/science subjects (−0.080, −0.128 to −0.033) and staple food consumption with better school performance in general/science subjects (0.071, 0.024 to 0.119) and physical education (0.065, 0.021 to 0.110). Findings from our two-sample MR analysis identified dietary principal components described best as whole brain bread, wheat, cheese, oat cereal and red wine to be associated with higher educational attainment and other cognition-related phenotypes. Conclusion: Using genetics, we highlighted the potential role of HFSS food consumption and consumption of the components of a staple food diet for school performance. However, further research is required to find conclusive evidence that could support a causal role of diet on school performance.This work was supported by the Waterloo foundation [to L.Z., F.D., T.D.]. The funders were not involved in the analysis and interpretation of the data; in the writing of the report; or in the decision to submit the paper for publication. The NFBC1986 genetic data generation and dietary data collection was supported by NIMH (MH063706, Smalley and Järvelin), the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643, coordinator: Järvelin) and Academy of Finland (EGEA-project nro 285 547), and is currently funded by the Joint Programming Initiative a Healthy Diet for a Healthy Life (EU JPI HDHL) (proposal number 655), with joint funding by the Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC) [MR/S03658X/1]

No Evidence That Genetic Variation at the Klotho Locus Is Associated With Longevity in Caucasians from the Newcastle 85+ Study and the UK Biobank

Copyright © The Author(s) 2021. The demographics of Western populations are changing, with an increase in the proportion of older adults. There is evidence to suggest that genetic factors may influence the aging process: studying these may lead to interventions to help individuals live a longer and healthier life. Evidence from several groups indicates that Klotho (KL), a gene encoding a single-pass transmembrane protein that acts as an FGF23 co-receptor, may be associated with longevity and healthy aging. We aimed to explore this area further by comparing the genotype counts in 642 long-lived individuals from the Newcastle 85+ Study with 18 295 middle-aged Newcastle-based controls from the UK Biobank to test whether variants at the KL gene locus are over- or under-represented in older individuals. If KL is associated with longevity, then we would expect the genotype counts to differ between the 2 cohorts. We found that the rs2283368 CC genotype and the rs9536338 C allele, but not the KL-VS haplotype, were associated with reaching very old age. However, these associations did not replicate in the remainder of the UK Biobank cohort. Thus, our results do not reliably support the role of KL as a longevity factor.Calico LLC (South San Francisco, California, United States); HAA is the recipient of a PhD studentship from the College of Health, Medical and Life Sciences, Brunel University London

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

Copyright © Author(s) (or their employer(s)) 2021. 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.NIHR grant number (DRF-2017-10-042); National Institute for Health Research (NIHR) Doctoral Research Fellowship

Sulfatase‐mediated manipulation of the astrocyte‐Schwann cell interface

Schwann cell (SC) transplantation following spinal cord injury (SCI) may have therapeutic potential. Functional recovery is limited however, due to poor SC interactions with host astrocytes and the induction of astrogliosis. Olfactory ensheathing cells (OECs) are closely related to SCs, but intermix more readily with astrocytes in culture and induce less astrogliosis. We previously demonstrated that OECs express higher levels of sulfatases, enzymes that remove 6‐O‐sulfate groups from heparan sulphate proteoglycans, than SCs and that RNAi knockdown of sulfatase prevented OEC‐astrocyte mixing in vitro. As human OECs are difficult to culture in large numbers we have genetically engineered SCs using lentiviral vectors to express sulfatase 1 and 2 (SC‐S1S2) and assessed their ability to interact with astrocytes. We demonstrate that SC‐S1S2s have increased integrin‐dependent motility in the presence of astrocytes via modulation of NRG and FGF receptor‐linked PI3K/AKT intracellular signaling and do not form boundaries with astrocytes in culture. SC‐astrocyte mixing is dependent on local NRG concentration and we propose that sulfatase enzymes influence the bioavailability of NRG ligand and thus influence SC behavior. We further demonstrate that injection of sulfatase expressing SCs into spinal cord white matter results in less glial reactivity than control SC injections comparable to that of OEC injections. Our data indicate that sulfatase‐mediated modification of the extracellular matrix can influence glial interactions with astrocytes, and that SCs engineered to express sulfatase may be more OEC‐like in character. This approach may be beneficial for cell transplant‐mediated spinal cord repair. GLIA 2016 GLIA 2017;65:19–3

A modified AUGIS/BOMSS Delphi process to establish research priorities in bariatric and metabolic surgery

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordBackground: Delphi methodology may be utilised to develop consensus opinion amongst a group of experts. The aim of our study was to use a modified Delphi process to determine the future research priorities amongbariatric and metabolic healthcare professionalsin the United Kingdom. Methods: Members of the Association of Upper Gastrointestinal Surgeons and the British Obesity and Metabolic Surgery Society (BOMSS) were invited to submit individual research questions viaan online survey (phase I). Two rounds of prioritisation by multidisciplinary expert healthcare professionals (phase II and III) were completed to determine a final list of high priority research questions. Results: Fifty-one bariatric and metabolic surgery-focused questions were identified in phase I. 35questions were taken forward for prioritisation in phase II. Eleven high priority questions were identified in phase III. The final list of high priority questions had an emphasis on the pathophysiology and long-term sequelae of bariatric and metabolic surgery.ConclusionA modified Delphi process has produced a list of 11 high priority research questions in bariatric and metabolic surgery. Future studies and awards from funding bodies should reflect this consensus list of prioritised questions in the interest of improving patient care and encouraging collaborative research across multiple centres

First report of generalized face processing difficulties in möbius sequence.

Reverse simulation models of facial expression recognition suggest that we recognize the emotions of others by running implicit motor programmes responsible for the production of that expression. Previous work has tested this theory by examining facial expression recognition in participants with Möbius sequence, a condition characterized by congenital bilateral facial paralysis. However, a mixed pattern of findings has emerged, and it has not yet been tested whether these individuals can imagine facial expressions, a process also hypothesized to be underpinned by proprioceptive feedback from the face. We investigated this issue by examining expression recognition and imagery in six participants with Möbius sequence, and also carried out tests assessing facial identity and object recognition, as well as basic visual processing. While five of the six participants presented with expression recognition impairments, only one was impaired at the imagery of facial expressions. Further, five participants presented with other difficulties in the recognition of facial identity or objects, or in lower-level visual processing. We discuss the implications of our findings for the reverse simulation model, and suggest that facial identity recognition impairments may be more severe in the condition than has previously been noted

Determinants of post-prandial plasma bile acid kinetics in human volunteers

The authors are thankful for the funding received through the EU 7th Framework, to all study participants and all members of the NutriTech consortium. The microbiota analysis was funded by the TNO Systems Biology program