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Article ; Online: Causal associations between cardiorespiratory fitness and type 2 diabetes

Lina Cai / Tomas Gonzales / Eleanor Wheeler / Nicola D. Kerrison / Felix R. Day / Claudia Langenberg / John R. B. Perry / Soren Brage / Nicholas J. Wareham

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 13

Abstract: Abstract Higher cardiorespiratory fitness is associated with lower risk of type 2 diabetes. However, the causality of this relationship and the biological mechanisms that underlie it are unclear. Here, we examine genetic determinants of cardiorespiratory ...

Abstract	Abstract Higher cardiorespiratory fitness is associated with lower risk of type 2 diabetes. However, the causality of this relationship and the biological mechanisms that underlie it are unclear. Here, we examine genetic determinants of cardiorespiratory fitness in 450k European-ancestry individuals in UK Biobank, by leveraging the genetic overlap between fitness measured by an exercise test and resting heart rate. We identified 160 fitness-associated loci which we validated in an independent cohort, the Fenland study. Gene-based analyses prioritised candidate genes, such as CACNA1C, SCN10A, MYH11 and MYH6, that are enriched in biological processes related to cardiac muscle development and muscle contractility. In a Mendelian Randomisation framework, we demonstrate that higher genetically predicted fitness is causally associated with lower risk of type 2 diabetes independent of adiposity. Integration with proteomic data identified N-terminal pro B-type natriuretic peptide, hepatocyte growth factor-like protein and sex hormone-binding globulin as potential mediators of this relationship. Collectively, our findings provide insights into the biological mechanisms underpinning cardiorespiratory fitness and highlight the importance of improving fitness for diabetes prevention.
Keywords	Science ; Q
Subject code	612
Language	English
Publishing date	2023-07-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Causal effects of maternal circulating amino acids on offspring birthweight

Jian Zhao / Isobel D. Stewart / Denis Baird / Dan Mason / John Wright / Jie Zheng / Tom R. Gaunt / David M. Evans / Rachel M. Freathy / Claudia Langenberg / Nicole M. Warrington / Deborah A. Lawlor / Maria Carolina Borges

EBioMedicine, Vol 88, Iss , Pp 104441- (2023)

a Mendelian randomisation studyResearch in context

2023

Abstract: Summary: Background: Amino acids are key to protein synthesis, energy metabolism, cell signaling and gene expression; however, the contribution of specific maternal amino acids to fetal growth is unclear. Methods: We explored the effect of maternal ... ...

Abstract	Summary: Background: Amino acids are key to protein synthesis, energy metabolism, cell signaling and gene expression; however, the contribution of specific maternal amino acids to fetal growth is unclear. Methods: We explored the effect of maternal circulating amino acids on fetal growth, proxied by birthweight, using two-sample Mendelian randomisation (MR) and summary data from a genome-wide association study (GWAS) of serum amino acids levels (sample 1, n = 86,507) and a maternal GWAS of offspring birthweight in UK Biobank and Early Growth Genetics Consortium, adjusting for fetal genotype effects (sample 2, n = 406,063 with maternal and/or fetal genotype effect estimates). A total of 106 independent single nucleotide polymorphisms robustly associated with 19 amino acids (p < 4.9 × 10−10) were used as genetic instrumental variables (IV). Wald ratio and inverse variance weighted methods were used in MR main analysis. A series of sensitivity analyses were performed to explore IV assumption violations. Findings: Our results provide evidence that maternal circulating glutamine (59 g offspring birthweight increase per standard deviation increase in maternal amino acid level, 95% CI: 7, 110) and serine (27 g, 95% CI: 9, 46) raise, while leucine (−59 g, 95% CI: −106, −11) and phenylalanine (−25 g, 95% CI: −47, −4) lower offspring birthweight. These findings are supported by sensitivity analyses. Interpretation: Our findings strengthen evidence for key roles of maternal circulating amino acids during pregnancy in healthy fetal growth. Funding: A full list of funding bodies that contributed to this study can be found under Acknowledgments.
Keywords	Amino acids ; Birthweight ; GWAS ; Mendelian randomisation ; Causal effect ; Medicine ; R ; Medicine (General) ; R5-920
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The potential shared role of inflammation in insulin resistance and schizophrenia

Benjamin I Perry / Stephen Burgess / Hannah J Jones / Stan Zammit / Rachel Upthegrove / Amy M Mason / Felix R Day / Claudia Langenberg / Nicholas J Wareham / Peter B Jones / Golam M Khandaker

PLoS Medicine, Vol 18, Iss 3, p e

A bidirectional two-sample mendelian randomization study.

2021 Volume 1003455

Abstract: Background Insulin resistance predisposes to cardiometabolic disorders, which are commonly comorbid with schizophrenia and are key contributors to the significant excess mortality in schizophrenia. Mechanisms for the comorbidity remain unclear, but ... ...

Abstract	Background Insulin resistance predisposes to cardiometabolic disorders, which are commonly comorbid with schizophrenia and are key contributors to the significant excess mortality in schizophrenia. Mechanisms for the comorbidity remain unclear, but observational studies have implicated inflammation in both schizophrenia and cardiometabolic disorders separately. We aimed to examine whether there is genetic evidence that insulin resistance and 7 related cardiometabolic traits may be causally associated with schizophrenia, and whether evidence supports inflammation as a common mechanism for cardiometabolic disorders and schizophrenia. Methods and findings We used summary data from genome-wide association studies of mostly European adults from large consortia (Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) featuring up to 108,557 participants; Diabetes Genetics Replication And Meta-analysis (DIAGRAM) featuring up to 435,387 participants; Global Lipids Genetics Consortium (GLGC) featuring up to 173,082 participants; Genetic Investigation of Anthropometric Traits (GIANT) featuring up to 339,224 participants; Psychiatric Genomics Consortium (PGC) featuring up to 105,318 participants; and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium featuring up to 204,402 participants). We conducted two-sample uni- and multivariable mendelian randomization (MR) analysis to test whether (i) 10 cardiometabolic traits (fasting insulin, high-density lipoprotein and triglycerides representing an insulin resistance phenotype, and 7 related cardiometabolic traits: low-density lipoprotein, fasting plasma glucose, glycated haemoglobin, leptin, body mass index, glucose tolerance, and type 2 diabetes) could be causally associated with schizophrenia; and (ii) inflammation could be a shared mechanism for these phenotypes. We conducted a detailed set of sensitivity analyses to test the assumptions for a valid MR analysis. We did not find statistically significant evidence in support of a ...
Keywords	Medicine ; R
Subject code	150
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Synergistic insights into human health from aptamer- and antibody-based proteomic profiling

Maik Pietzner / Eleanor Wheeler / Julia Carrasco-Zanini / Nicola D. Kerrison / Erin Oerton / Mine Koprulu / Jian’an Luan / Aroon D. Hingorani / Steve A. Williams / Nicholas J. Wareham / Claudia Langenberg

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 13

Abstract: Broad-capture affinity-based proteomic technologies inform how the readout of our genes affects human health. Here, the authors integrate aptamer- and antibody-based profiling to understand the mechanisms underlying gene-protein-disease associations. ...

Abstract	Broad-capture affinity-based proteomic technologies inform how the readout of our genes affects human health. Here, the authors integrate aptamer- and antibody-based profiling to understand the mechanisms underlying gene-protein-disease associations.
Keywords	Science ; Q
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression

Roberto Bonelli / Brendan R. E. Ansell / Luca Lotta / Thomas Scerri / Traci E. Clemons / Irene Leung / The MacTel Consortium / Tunde Peto / Alan C. Bird / Ferenc B. Sallo / Claudia Langenberg / Melanie Bahlo

Genome Medicine, Vol 13, Iss 1, Pp 1-

2021 Volume 11

Abstract: Abstract Background Macular telangiectasia type 2 (MacTel) is a rare, heritable and largely untreatable retinal disorder, often comorbid with diabetes. Genetic risk loci subtend retinal vascular calibre and glycine/serine/threonine metabolism genes. ... ...

Abstract	Abstract Background Macular telangiectasia type 2 (MacTel) is a rare, heritable and largely untreatable retinal disorder, often comorbid with diabetes. Genetic risk loci subtend retinal vascular calibre and glycine/serine/threonine metabolism genes. Serine deficiency may contribute to MacTel via neurotoxic deoxysphingolipid production; however, an independent vascular contribution is also suspected. Here, we use statistical genetics to dissect the causal mechanisms underpinning this complex disease. Methods We integrated genetic markers for MacTel, vascular and metabolic traits, and applied Mendelian randomisation and conditional and interaction genome-wide association analyses to discover the causal contributors to both disease and spatial retinal imaging sub-phenotypes. Results Genetically induced serine deficiency is the primary causal metabolic driver of disease occurrence and progression, with a lesser, but significant, causal contribution of type 2 diabetes genetic risk. Conversely, glycine, threonine and retinal vascular traits are unlikely to be causal for MacTel. Conditional regression analysis identified three novel disease loci independent of endogenous serine biosynthetic capacity. By aggregating spatial retinal phenotypes into endophenotypes, we demonstrate that SNPs constituting independent risk loci act via related endophenotypes. Conclusions Follow-up studies after GWAS integrating publicly available data with deep phenotyping are still rare. Here, we describe such analysis, where we integrated retinal imaging data with MacTel and other traits genomics data to identify biochemical mechanisms likely causing this disorder. Our findings will aid in early diagnosis and accurate prognosis of MacTel and improve prospects for effective therapeutic intervention. Our integrative genetics approach also serves as a useful template for post-GWAS analyses in other disorders.
Keywords	Retinal disease ; Mendelian randomisation ; Metabolomics ; GWAS ; Serine ; Medicine ; R ; Genetics ; QH426-470
Subject code	610
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The current and potential health benefits of the National Health Service Health Check cardiovascular disease prevention programme in England

Oliver T Mytton / Christopher Jackson / Arno Steinacher / Anna Goodman / Claudia Langenberg / Simon Griffin / Nick Wareham / James Woodcock

PLoS Medicine, Vol 15, Iss 3, p e

A microsimulation study.

2018 Volume 1002517

Abstract: Background The National Health Service (NHS) Health Check programme was introduced in 2009 in England to systematically assess all adults in midlife for cardiovascular disease risk factors. However, its current benefit and impact on health inequalities ... ...

Abstract	Background The National Health Service (NHS) Health Check programme was introduced in 2009 in England to systematically assess all adults in midlife for cardiovascular disease risk factors. However, its current benefit and impact on health inequalities are unknown. It is also unclear whether feasible changes in how it is delivered could result in increased benefits. It is one of the first such programmes in the world. We sought to estimate the health benefits and effect on inequalities of the current NHS Health Check programme and the impact of making feasible changes to its implementation. Methods and findings We developed a microsimulation model to estimate the health benefits (incident ischaemic heart disease, stroke, dementia, and lung cancer) of the NHS Health Check programme in England. We simulated a population of adults in England aged 40-45 years and followed until age 100 years, using data from the Health Survey of England (2009-2012) and the English Longitudinal Study of Aging (1998-2012), to simulate changes in risk factors for simulated individuals over time. We used recent programme data to describe uptake of NHS Health Checks and of 4 associated interventions (statin medication, antihypertensive medication, smoking cessation, and weight management). Estimates of treatment efficacy and adherence were based on trial data. We estimated the benefits of the current NHS Health Check programme compared to a healthcare system without systematic health checks. This counterfactual scenario models the detection and treatment of risk factors that occur within 'routine' primary care. We also explored the impact of making feasible changes to implementation of the programme concerning eligibility, uptake of NHS Health Checks, and uptake of treatments offered through the programme. We estimate that the NHS Health Check programme prevents 390 (95% credible interval 290 to 500) premature deaths before 80 years of age and results in an additional 1,370 (95% credible interval 1,100 to 1,690) people being free of ...
Keywords	Medicine ; R
Subject code	360
Language	English
Publishing date	2018-03-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Meta-analysis investigating the role of interleukin-6 mediated inflammation in type 2 diabetes

Nicholas Bowker / Rupal L. Shah / Stephen J. Sharp / Jian'an Luan / Isobel D. Stewart / Eleanor Wheeler / Manuel A.R. Ferreira / Aris Baras / Nicholas J. Wareham / Claudia Langenberg / Luca A. Lotta

EBioMedicine, Vol 61, Iss , Pp 103062- (2020)

2020

Abstract: Background: Evidence from animal models and observational epidemiology points to a role for chronic inflammation, in which interleukin 6 (IL-6) is a key player, in the pathophysiology of type 2 diabetes (T2D). However, it is unknown whether IL-6 mediated ...

Abstract	Background: Evidence from animal models and observational epidemiology points to a role for chronic inflammation, in which interleukin 6 (IL-6) is a key player, in the pathophysiology of type 2 diabetes (T2D). However, it is unknown whether IL-6 mediated inflammation is implicated in the pathophysiology of T2D. Methods: We performed a meta-analysis of 15 prospective studies to investigate associations between IL-6 levels and incident T2D including 5,421 cases and 31,562 non-cases. We also estimated the association of a loss-of-function missense variant (Asp358Ala) in the IL-6 receptor gene (IL6R), previously shown to mimic the effects of IL-6R inhibition, in a large trans-ethnic meta-analysis of six T2D case-control studies including 260,614 cases and 1,350,640 controls. Findings: In a meta-analysis of 15 prospective studies, higher levels of IL-6 (per log pg/mL) were significantly associated with a higher risk of incident T2D (1·24 95% CI, 1·17, 1·32; P = 1 × 10−12). In a trans-ethnic meta-analysis of 260,614 cases and 1,350,640 controls, the IL6R Asp358Ala missense variant was associated with lower odds of T2D (OR, 0·98; 95% CI, 0·97, 0·99; P = 2 × 10−7). This association was not due to diagnostic misclassification and was consistent across ethnic groups. IL-6 levels mediated up to 5% of the association between higher body mass index and T2D. Interpretation: Large-scale human prospective and genetic data provide evidence that IL-6 mediated inflammation is implicated in the etiology of T2D but suggest that the impact of this pathway on disease risk in the general population is likely to be small. Funding: The EPICNorfolk study has received funding from the Medical Research Council (MRC) (MR/N003284/1, MC-UU_12015/1 and MC_PC_13048) and Cancer Research UK (C864/A14136). The Fenland Study is funded by the MRC (MC_UU_12015/1 and MC_PC_13046).
Keywords	Interleukin-6 ; Type 2 diabetes ; Genetic ; Trans-ethnic ; Medicine ; R ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Corrigendum to “Genome-wide association study of adipocyte lipolysis in the GENetics of adipocyte lipolysis (GENiAL) cohort” [Molecular Metabolism 34 (2020) 85–96]

Agné Kulyté / Veroniqa Lundbäck / Cecilia M. Lindgren / Jian'an Luan / Luca A. Lotta / Claudia Langenberg / Peter Arner / Rona J. Strawbridge / Ingrid Dahlman

Molecular Metabolism, Vol 41, Iss , Pp 101072- (2020)

2020

Keywords	Internal medicine ; RC31-1245
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genome-wide association study of adipocyte lipolysis in the GENetics of adipocyte lipolysis (GENiAL) cohort

Agné Kulyté / Veroniqa Lundbäck / Cecilia M. Lindgren / Jian'an Luan / Luca A. Lotta / Claudia Langenberg / Peter Arner / Rona J. Strawbridge / Ingrid Dahlman

Molecular Metabolism, Vol 34, Iss , Pp 85-

2020 Volume 96

Abstract: Objectives: Lipolysis, hydrolysis of triglycerides to fatty acids in adipocytes, is tightly regulated, poorly understood, and, if perturbed, can lead to metabolic diseases including obesity and type 2 diabetes. The goal of this study was to identify the ... ...

Abstract	Objectives: Lipolysis, hydrolysis of triglycerides to fatty acids in adipocytes, is tightly regulated, poorly understood, and, if perturbed, can lead to metabolic diseases including obesity and type 2 diabetes. The goal of this study was to identify the genetic regulators of lipolysis and elucidate their molecular mechanisms. Methods: Adipocytes from abdominal subcutaneous adipose tissue biopsies were isolated and were incubated without (spontaneous lipolysis) or with a catecholamine (stimulated lipolysis) to analyze lipolysis. DNA was extracted and genome-wide genotyping and imputation conducted. After quality control, 939 samples with genetic and lipolysis data were available. Genome-wide association studies of spontaneous and stimulated lipolysis were conducted. Subsequent in vitro gene expression analyses were used to identify candidate genes and explore their regulation of adipose tissue biology. Results: One locus on chromosome 19 demonstrated genome-wide significance with spontaneous lipolysis. 60 loci showed suggestive associations with spontaneous or stimulated lipolysis, of which many influenced both traits. In the chromosome 19 locus, only HIF3A was expressed in the adipocytes and displayed genotype-dependent gene expression. HIF3A knockdown in vitro increased lipolysis and the expression of key lipolysis-regulating genes. Conclusions: In conclusion, we identified a genetic regulator of spontaneous lipolysis and provided evidence of HIF3A as a novel key regulator of lipolysis in subcutaneous adipocytes as the mechanism through which the locus influences adipose tissue biology. Keywords: Genetic variants, Lipolysis, Subcutaneous, Adipocytes, Gene expression
Keywords	Internal medicine ; RC31-1245
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mapping the serum proteome to neurological diseases using whole genome sequencing

Grace Png / Andrei Barysenka / Linda Repetto / Pau Navarro / Xia Shen / Maik Pietzner / Eleanor Wheeler / Nicholas J. Wareham / Claudia Langenberg / Emmanouil Tsafantakis / Maria Karaleftheri / George Dedoussis / Anders Mälarstig / James F. Wilson / Arthur Gilly / Eleftheria Zeggini

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 12

Abstract: Serum proteins are easily accessible biomarkers and drug targets. Here, the authors use whole genome sequencing data to describe the genetic architecture of neurologically-relevant serum proteins and establish causal protein-neurological disease ... ...

Abstract	Serum proteins are easily accessible biomarkers and drug targets. Here, the authors use whole genome sequencing data to describe the genetic architecture of neurologically-relevant serum proteins and establish causal protein-neurological disease relationships.
Keywords	Science ; Q
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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