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Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
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Diabetes Mellitus Tipo 2 , Proinsulina , Humanos , Proinsulina/genética , Proinsulina/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Estudio de Asociación del Genoma Completo/métodos , Insulina/genética , Insulina/metabolismo , Glucosa , Factores de Transcripción/genética , Proteínas de Homeodominio/genéticaRESUMEN
AIMS/HYPOTHESIS: High-throughput metabolomics technologies in a variety of study designs have demonstrated a consistent metabolomic signature of overweight and type 2 diabetes. However, the extent to which these metabolomic patterns can be reversed with weight loss and diabetes remission has been weakly investigated. We aimed to characterise the metabolomic consequences of a weight-loss intervention in individuals with type 2 diabetes. METHODS: We analysed 574 fasted serum samples collected within an existing RCT (the Diabetes Remission Clinical Trial [DiRECT]) (N=298). In the trial, participating primary care practices were randomly assigned (1:1) to provide either a weight management programme (intervention) or best-practice care by guidelines (control) treatment to individuals with type 2 diabetes. Here, metabolomics analysis was performed on samples collected at baseline and 12 months using both untargeted MS and targeted 1H-NMR spectroscopy. Multivariable regression models were fitted to evaluate the effect of the intervention on metabolite levels. RESULTS: Decreases in branched-chain amino acids, sugars and LDL triglycerides, and increases in sphingolipids, plasmalogens and metabolites related to fatty acid metabolism were associated with the intervention (Holm-corrected p<0.05). In individuals who lost more than 9 kg between baseline and 12 months, those who achieved diabetes remission saw greater reductions in glucose, fructose and mannose, compared with those who did not achieve remission. CONCLUSIONS/INTERPRETATION: We have characterised the metabolomic effects of an integrated weight management programme previously shown to deliver weight loss and diabetes remission. A large proportion of the metabolome appears to be modifiable. Patterns of change were largely and strikingly opposite to perturbances previously documented with the development of type 2 diabetes. DATA AVAILABILITY: The data used for analysis are available on a research data repository ( https://researchdata.gla.ac.uk/ ) with access given to researchers subject to appropriate data sharing agreements. Metabolite data preparation, data pre-processing, statistical analyses and figure generation were performed in R Studio v.1.0.143 using R v.4.0.2. The R code for this study has been made publicly available on GitHub at: https://github.com/lauracorbin/metabolomics_of_direct .
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Diabetes Mellitus Tipo 2 , Humanos , Glucosa , Metaboloma , Metabolómica , Pérdida de Peso , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: DNA hypomethylation at the F2RL3 (F2R like thrombin or trypsin receptor 3) locus has been associated with both smoking and atherosclerotic cardiovascular disease; whether these smoking-related associations form a pathway to disease is unknown. F2RL3 encodes protease-activated receptor 4, a potent thrombin receptor expressed on platelets. Given the role of thrombin in platelet activation and the role of thrombus formation in myocardial infarction, alterations to this biological pathway could be important for ischemic cardiovascular disease. METHODS: We conducted multiple independent experiments to assess whether DNA hypomethylation at F2RL3 in response to smoking is associated with risk of myocardial infarction via changes to platelet reactivity. Using cohort data (N=3205), we explored the relationship between smoking, DNA hypomethylation at F2RL3, and myocardial infarction. We compared platelet reactivity in individuals with low versus high DNA methylation at F2RL3 (N=41). We used an in vitro model to explore the biological response of F2RL3 to cigarette smoke extract. Finally, a series of reporter constructs were used to investigate how differential methylation could impact F2RL3 gene expression. RESULTS: Observationally, DNA methylation at F2RL3 mediated an estimated 34% of the smoking effect on increased risk of myocardial infarction. An association between methylation group (low/high) and platelet reactivity was observed in response to PAR4 (protease-activated receptor 4) stimulation. In cells, cigarette smoke extract exposure was associated with a 4.9% to 9.3% reduction in DNA methylation at F2RL3 and a corresponding 1.7-(95% CI, 1.2-2.4, P=0.04) fold increase in F2RL3 mRNA. Results from reporter assays suggest the exon 2 region of F2RL3 may help control gene expression. CONCLUSIONS: Smoking-induced epigenetic DNA hypomethylation at F2RL3 appears to increase PAR4 expression with potential downstream consequences for platelet reactivity. Combined evidence here not only identifies F2RL3 DNA methylation as a possible contributory pathway from smoking to cardiovascular disease risk but from any feature potentially influencing F2RL3 regulation in a similar manner.
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Plaquetas/metabolismo , Epigénesis Genética , Infarto del Miocardio/genética , Receptores de Trombina/genética , Anciano , Metilación de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/sangre , Infarto del Miocardio/epidemiología , Receptores de Trombina/metabolismo , Fumar/epidemiologíaRESUMEN
MOTIVATION: Metabolomics is an increasingly common part of health research and there is need for preanalytical data processing. Researchers typically need to characterize the data and to exclude errors within the context of the intended analysis. Whilst some preprocessing steps are common, there is currently a lack of standardization and reporting transparency for these procedures. RESULTS: Here, we introduce metaboprep, a standardized data processing workflow to extract and characterize high quality metabolomics datasets. The package extracts data from preformed worksheets, provides summary statistics and enables the user to select samples and metabolites for their analysis based on a set of quality metrics. A report summarizing quality metrics and the influence of available batch variables on the data are generated for the purpose of open disclosure. Where possible, we provide users flexibility in defining their own selection thresholds. AVAILABILITY AND IMPLEMENTATION: metaboprep is an open-source R package available at https://github.com/MRCIEU/metaboprep. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Metabolómica , Programas Informáticos , Humanos , Flujo de Trabajo , InvestigadoresRESUMEN
Glycosuria is a condition where glucose is detected in urine at higher concentrations than normal (i.e. not detectable). Glycosuria at some point during pregnancy has an estimated prevalence of 50% and is associated with adverse outcomes in both mothers and offspring. Little is currently known about the genetic contribution to this trait or the extent to which it overlaps with other seemingly related traits, e.g. diabetes. We performed a genome-wide association study (GWAS) for self-reported glycosuria in pregnant mothers from the Avon Longitudinal Study of Parents and Children (cases/controls = 1249/5140). We identified two loci, one of which (lead SNP = rs13337037; chromosome 16; odds ratio of glycosuria per effect allele: 1.42; 95% CI: 1.30, 1.56; P = 1.97 × 10-13) was then validated using an obstetric measure of glycosuria measured in the same cohort (227/6639). We performed a secondary GWAS in the 1986 Northern Finland Birth Cohort (NFBC1986; 747/2991) using midwife-reported glycosuria and offspring genotype as a proxy for maternal genotype. The combined results revealed evidence for a consistent effect on glycosuria at the chromosome 16 locus. In follow-up analyses, we saw little evidence of shared genetic underpinnings with the exception of urinary albumin-to-creatinine ratio (Rg = 0.64; SE = 0.22; P = 0.0042), a biomarker of kidney disease. In conclusion, we identified a genetic association with self-reported glycosuria during pregnancy, with the lead SNP located 15kB upstream of SLC5A2, a target of antidiabetic drugs. The lack of strong genetic correlation with seemingly related traits such as type 2 diabetes suggests different genetic risk factors exist for glycosuria during pregnancy.
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Diabetes Mellitus Tipo 2/genética , Glucosuria/genética , Complicaciones del Embarazo/genética , Transportador 2 de Sodio-Glucosa/genética , Adolescente , Adulto , Índice de Masa Corporal , Cromosomas Humanos Par 16/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/patología , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Glucosuria/epidemiología , Glucosuria/patología , Humanos , Polimorfismo de Nucleótido Simple/genética , Embarazo , Complicaciones del Embarazo/patología , Adulto JovenRESUMEN
Higher body mass index (BMI) is a risk factor for thrombosis. Platelets are essential for hemostasis but contribute to thrombosis when activated pathologically. We hypothesized that higher BMI leads to changes in platelet characteristics, thereby increasing thrombotic risk. The effect of BMI on platelet traits (measured by Sysmex) was explored in 33 388 UK blood donors (INTERVAL study). Linear regression showed that higher BMI was positively associated with greater plateletcrit (PCT), platelet count (PLT), immature platelet count (IPC), and side fluorescence (SFL, a measure of mRNA content used to derive IPC). Mendelian randomization (MR), applied to estimate a causal effect with BMI proxied by a genetic risk score, provided causal estimates for a positive effect of BMI on both SFL and IPC, but there was little evidence for a causal effect of BMI on PCT or PLT. Follow-up analyses explored the functional relevance of platelet characteristics in a pre-operative cardiac cohort (COPTIC). Linear regression provided observational evidence for a positive association between IPC and agonist-induced whole blood platelet aggregation. Results indicate that higher BMI raises the number of immature platelets, which is associated with greater whole blood platelet aggregation in a cardiac cohort. Higher IPC could therefore contribute to obesity-related thrombosis.
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Plaquetas , Trombosis , Índice de Masa Corporal , Humanos , Obesidad/complicaciones , Recuento de Plaquetas , Trombosis/etiologíaRESUMEN
The variation in weight within a shared environment is largely attributable to genetic factors. Whilst many genes/loci confer susceptibility to obesity, little is known about the genetic architecture of healthy thinness. Here, we characterise the heritability of thinness which we found was comparable to that of severe obesity (h2 = 28.07 vs 32.33% respectively), although with incomplete genetic overlap (r = -0.49, 95% CI [-0.17, -0.82], p = 0.003). In a genome-wide association analysis of thinness (n = 1,471) vs severe obesity (n = 1,456), we identified 10 loci previously associated with obesity, and demonstrate enrichment for established BMI-associated loci (pbinomial = 3.05x10-5). Simulation analyses showed that different association results between the extremes were likely in agreement with additive effects across the BMI distribution, suggesting different effects on thinness and obesity could be due to their different degrees of extremeness. In further analyses, we detected a novel obesity and BMI-associated locus at PKHD1 (rs2784243, obese vs. thin p = 5.99x10-6, obese vs. controls p = 2.13x10-6 pBMI = 2.3x10-13), associations at loci recently discovered with much larger sample sizes (e.g. FAM150B and PRDM6-CEP120), and novel variants driving associations at previously established signals (e.g. rs205262 at the SNRPC/C6orf106 locus and rs112446794 at the PRDM6-CEP120 locus). Our ability to replicate loci found with much larger sample sizes demonstrates the value of clinical extremes and suggest that characterisation of the genetics of thinness may provide a more nuanced understanding of the genetic architecture of body weight regulation and may inform the identification of potential anti-obesity targets.
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Proteínas Musculares/genética , Proteínas de Neoplasias/genética , Obesidad Mórbida/genética , Receptores de Superficie Celular/genética , Delgadez/genética , Factores de Transcripción/genética , Adulto , Alelos , Índice de Masa Corporal , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Obesidad Mórbida/fisiopatología , Polimorfismo de Nucleótido Simple , Delgadez/fisiopatologíaRESUMEN
BACKGROUND: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI). METHODS AND FINDINGS: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds. CONCLUSIONS: This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer.
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Índice de Masa Corporal , Neoplasias Renales/sangre , Metaboloma , Obesidad/sangre , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Europa (Continente)/epidemiología , Femenino , Humanos , Incidencia , Neoplasias Renales/diagnóstico , Neoplasias Renales/epidemiología , Neoplasias Renales/genética , Masculino , Análisis de la Aleatorización Mendeliana , Metabolómica , Persona de Mediana Edad , Obesidad/diagnóstico , Obesidad/epidemiología , Obesidad/genética , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Victoria/epidemiologíaRESUMEN
BACKGROUND: Variation in adiposity is associated with cardiometabolic disease outcomes, but mechanisms leading from this exposure to disease are unclear. This study aimed to estimate effects of body mass index (BMI) on an extensive set of circulating proteins. METHODS: We used SomaLogic proteomic data from up to 2737 healthy participants from the INTERVAL study. Associations between self-reported BMI and 3622 unique plasma proteins were explored using linear regression. These were complemented by Mendelian randomisation (MR) analyses using a genetic risk score (GRS) comprised of 654 BMI-associated polymorphisms from a recent genome-wide association study (GWAS) of adult BMI. A disease enrichment analysis was performed using DAVID Bioinformatics 6.8 for proteins which were altered by BMI. RESULTS: Observationally, BMI was associated with 1576 proteins (P < 1.4 × 10-5), with particularly strong evidence for a positive association with leptin and fatty acid-binding protein-4 (FABP4), and a negative association with sex hormone-binding globulin (SHBG). Observational estimates were likely confounded, but the GRS for BMI did not associate with measured confounders. MR analyses provided evidence for a causal relationship between BMI and eight proteins including leptin (0.63 standard deviation (SD) per SD BMI, 95% CI 0.48-0.79, P = 1.6 × 10-15), FABP4 (0.64 SD per SD BMI, 95% CI 0.46-0.83, P = 6.7 × 10-12) and SHBG (-0.45 SD per SD BMI, 95% CI -0.65 to -0.25, P = 1.4 × 10-5). There was agreement in the magnitude of observational and MR estimates (R2 = 0.33) and evidence that proteins most strongly altered by BMI were enriched for genes involved in cardiovascular disease. CONCLUSIONS: This study provides evidence for a broad impact of adiposity on the human proteome. Proteins strongly altered by BMI include those involved in regulating appetite, sex hormones and inflammation; such proteins are also enriched for cardiovascular disease-related genes. Altogether, results help focus attention onto new proteomic signatures of obesity-related disease.
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Adiposidad/fisiología , Proteoma/análisis , Adulto , Índice de Masa Corporal , Estudios de Cohortes , Femenino , Humanos , Masculino , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Estudios Prospectivos , Proteoma/metabolismo , Encuestas y CuestionariosRESUMEN
INTRODUCTION: High plasma triacylglyceride levels are known to be associated with increased risk of atherosclerotic cardiovascular disease. Apolipoprotein C-III (apoC-III) is a key regulator of plasma triacylglyceride levels and is associated with hypertriglyceridemia via a number of pathways. There is consistent evidence for an association of cardiovascular events with blood apoC-III level, with support from human genetic studies of APOC3 variants. As such, apoC-III has been recognised as a potential therapeutic target for patients with severe hypertriglyceridaemia with one of the most promising apoC-III-targeting drugs, volanesorsen, having recently progressed through Phase III trials. OBJECTIVES: To exploit a rare loss of function variant in APOC3 (rs138326449) to characterise the potential long-term treatment effects of apoC-III targeting interventions on the metabolome. METHODS: In a recall-by-genotype study, 115 plasma samples were analysed by UHPLC-MS to acquire non-targeted metabolomics data. The study included samples from 57 adolescents and 33 adults. Overall, 12 985 metabolic features were tested for an association with APOC3 genotype. RESULTS: 161 uniquely annotated metabolites were found to be associated with rs138326449(APOC3). The highest proportion of associated metabolites belonged to the acyl-acyl glycerophospholipid and triacylglyceride metabolite classes. In addition to the anticipated (on-target) reduction of metabolites in the triacylglyceride and related classes, carriers of the rare variant exhibited previously unreported increases in levels of a number of metabolites from the acyl-alkyl glycerophospholipid class. CONCLUSION: Overall, our results suggest that therapies targeting apoC-III may potentially achieve a broad shift in lipid profile that favours better metabolic health.
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Apolipoproteína C-III/genética , Apolipoproteína C-III/metabolismo , Adolescente , Adulto , Apolipoproteína C-III/sangre , Femenino , Genotipo , Humanos , Hipertrigliceridemia/metabolismo , Lípidos/fisiología , Lipoproteínas/metabolismo , Masculino , Metaboloma/fisiología , Metabolómica , Triglicéridos/sangre , Triglicéridos/metabolismo , Triglicéridos/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: Schizophrenia is a complex, polygenic disorder for which over 100 genetic variants have been identified that correlate with diagnosis. However, the biological mechanisms underpinning the different symptom clusters remain undefined. The rs1344706 single nucleotide polymorphism within ZNF804A was among the first genetic variants found to be associated with schizophrenia. Previously, neuroimaging and cognitive studies have revealed several associations between rs1344706 and brain structure and function. The aim of this study is to use a recall-by-genotype (RBG) design to investigate the biological basis for the association of ZNF804A variants with schizophrenia. A RBG study, implemented in a population cohort, will be used to evaluate the impact of genetic variation at rs1344706 on sleep neurophysiology and procedural memory consolidation in healthy participants. METHODS/DESIGN: Participants will be recruited from the Avon Longitudinal Study of Parents and Children (ALSPAC) on the basis of genotype at rs1344706 (n = 24). Each participant will be asked to take part in two nights of in-depth sleep monitoring (polysomnography) allowing collection of neurophysiological sleep data in a manner not amenable to large-scale study. Sleep questionnaires will be used to assess general sleep quality and subjective sleep experience after each in-house recording. A motor sequencing task (MST) will be performed before and after the second night of polysomnography. In order to gather additional data about habitual sleep behaviour participants will be asked to wear a wrist worn activity monitor (actiwatch) and complete a sleep diary for two weeks. DISCUSSION: This study will explore the biological function of ZNF804A genotype (rs1344706) in healthy volunteers by examining detailed features of sleep architecture and physiology in relation to motor learning. Using a RBG approach will enable us to collect precise and detailed phenotypic data whilst achieving an informative biological gradient. It would not be feasible to collect such data in the large sample sizes that would be required under a random sampling scheme. By dissecting the role of individual variants associated with schizophrenia in this way, we can begin to unravel the complex genetic mechanisms of psychiatric disorders and pave the way for future development of novel therapeutic approaches.
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Factores de Transcripción de Tipo Kruppel/genética , Consolidación de la Memoria/fisiología , Actividad Motora/fisiología , Polimorfismo de Nucleótido Simple , Sueño/fisiología , Adulto , Encéfalo/fisiología , Voluntarios Sanos/psicología , Humanos , Estudios Longitudinales , Masculino , Proyectos Piloto , Polisomnografía/métodos , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: Despite the dramatic reduction in the cost of high-density genotyping that has occurred over the last decade, it remains one of the limiting factors for obtaining the large datasets required for genomic studies of disease in the horse. In this study, we investigated the potential for low-density genotyping and subsequent imputation to address this problem. RESULTS: Using the haplotype phasing and imputation program, BEAGLE, it is possible to impute genotypes from low- to high-density (50K) in the Thoroughbred horse with reasonable to high accuracy. Analysis of the sources of variation in imputation accuracy revealed dependence both on the minor allele frequency of the single nucleotide polymorphisms (SNPs) being imputed and on the underlying linkage disequilibrium structure. Whereas equidistant spacing of the SNPs on the low-density panel worked well, optimising SNP selection to increase their minor allele frequency was advantageous, even when the panel was subsequently used in a population of different geographical origin. Replacing base pair position with linkage disequilibrium map distance reduced the variation in imputation accuracy across SNPs. Whereas a 1K SNP panel was generally sufficient to ensure that more than 80% of genotypes were correctly imputed, other studies suggest that a 2K to 3K panel is more efficient to minimize the subsequent loss of accuracy in genomic prediction analyses. The relationship between accuracy and genotyping costs for the different low-density panels, suggests that a 2K SNP panel would represent good value for money. CONCLUSIONS: Low-density genotyping with a 2K SNP panel followed by imputation provides a compromise between cost and accuracy that could promote more widespread genotyping, and hence the use of genomic information in horses. In addition to offering a low cost alternative to high-density genotyping, imputation provides a means to combine datasets from different genotyping platforms, which is becoming necessary since researchers are starting to use the recently developed equine 70K SNP chip. However, more work is needed to evaluate the impact of between-breed differences on imputation accuracy.
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Técnicas de Genotipaje/métodos , Caballos/genética , Animales , Femenino , Frecuencia de los Genes , Genoma , Genotipo , Técnicas de Genotipaje/economía , Desequilibrio de Ligamiento , Masculino , Polimorfismo de Nucleótido Simple , Carácter Cuantitativo HeredableRESUMEN
BACKGROUND: Type 2 diabetes is associated with higher risk of several cancer types. However, the biological intermediates driving this relationship are not fully understood. As novel interventions for treating and managing type 2 diabetes become increasingly available, whether they also disrupt the pathways leading to increased cancer risk is currently unknown. We investigated the effect of a type 2 diabetes intervention, in the form of intentional weight loss, on circulating proteins associated with cancer risk to gain insight into potential mechanisms linking type 2 diabetes and adiposity with cancer development. METHODS: Fasting serum samples from participants with diabetes enrolled in the Diabetes Remission Clinical Trial (DiRECT) receiving the Counterweight-Plus weight-loss programme (intervention, N = 117, mean weight-loss 10 kg, 46% diabetes remission) or best-practice care by guidelines (control, N = 143, mean weight-loss 1 kg, 4% diabetes remission) were subject to proteomic analysis using the Olink Oncology-II platform (48% of participants were female; 52% male). To identify proteins which may be altered by the weight-loss intervention, the difference in protein levels between groups at baseline and 1 year was examined using linear regression. Mendelian randomization (MR) was performed to extend these results to evaluate cancer risk and elucidate possible biological mechanisms linking type 2 diabetes and cancer development. MR analyses were conducted using independent datasets, including large cancer meta-analyses, UK Biobank, and FinnGen, to estimate potential causal relationships between proteins modified during intentional weight loss and the risk of colorectal, breast, endometrial, gallbladder, liver, and pancreatic cancers. FINDINGS: Nine proteins were modified by the intervention: glycoprotein Nmb; furin; Wnt inhibitory factor 1; toll-like receptor 3; pancreatic prohormone; erb-b2 receptor tyrosine kinase 2; hepatocyte growth factor; endothelial cell specific molecule 1 and Ret proto-oncogene (Holm corrected P-value <0.05). Mendelian randomization analyses indicated a causal relationship between predicted circulating furin and glycoprotein Nmb on breast cancer risk (odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.67-0.99, P-value = 0.03; and OR = 0.88, 95% CI = 0.78-0.99, P-value = 0.04 respectively), though these results were not supported in sensitivity analyses examining violations of MR assumptions. INTERPRETATION: Intentional weight loss among individuals with recently diagnosed diabetes may modify levels of cancer-related proteins in serum. Further evaluation of the proteins identified in this analysis could reveal molecular pathways that mediate the effect of adiposity and type 2 diabetes on cancer risk. FUNDING: The main sources of funding for this work were Diabetes UK, Cancer Research UK, World Cancer Research Fund, and Wellcome.
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Diabetes Mellitus Tipo 2 , Neoplasias , Humanos , Masculino , Femenino , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/terapia , Furina , Proteómica , Obesidad/complicaciones , Obesidad/terapia , Pérdida de Peso , Glicoproteínas , Análisis de la Aleatorización Mendeliana , Neoplasias/etiologíaRESUMEN
Thousands of proteins circulate in the bloodstream; identifying those which associate with weight and intervention-induced weight loss may help explain mechanisms of diseases associated with adiposity. We aimed to identify consistent protein signatures of weight loss across independent studies capturing changes in body mass index (BMI). We analysed proteomic data from studies implementing caloric restriction (Diabetes Remission Clinical trial) and bariatric surgery (By-Band-Sleeve), using SomaLogic and Olink Explore1536 technologies, respectively. Linear mixed models were used to estimate the effect of the interventions on circulating proteins. Twenty-three proteins were altered in a consistent direction after both bariatric surgery and caloric restriction, suggesting that these proteins are modulated by weight change, independent of intervention type. We also integrated Mendelian randomisation (MR) estimates of the effect of BMI on proteins measured by SomaLogic from a UK blood donor cohort as a third line of causal evidence. These MR estimates provided further corroborative evidence for a role of BMI in regulating the levels of six proteins including alcohol dehydrogenase-4, nogo receptor and interleukin-1 receptor antagonist protein. These results indicate the importance of triangulation in interrogating causal relationships; further study into the role of proteins modulated by weight in disease is now warranted.
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Cirugía Bariátrica , Proteoma , Humanos , Índice de Masa Corporal , Restricción Calórica , Proteómica , Pérdida de Peso/fisiologíaRESUMEN
CONTEXT: The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown. OBJECTIVE: This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH). METHODS: We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort. RESULTS: MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07). CONCLUSION: We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.
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Hipogonadismo , Pubertad Tardía , Adolescente , Humanos , Femenino , Animales , Ratones , Receptor de Melanocortina Tipo 3 , Prevalencia , Hipogonadismo/epidemiología , Hipogonadismo/genética , Hipogonadismo/complicaciones , Pubertad Tardía/epidemiología , Pubertad Tardía/genética , Pubertad Tardía/diagnóstico , Pubertad/genética , Trastornos del Crecimiento/genéticaRESUMEN
Osteochondrosis is a developmental orthopaedic disease that occurs in horses, other livestock species, companion animal species, and humans. The principal aim of this study was to identify quantitative trait loci (QTL) associated with osteochondritis dissecans (OCD) in the Thoroughbred using a genome-wide association study. A secondary objective was to test the effect of previously identified QTL in the current population. Over 300 horses, classified as cases or controls according to clinical findings, were genotyped for the Illumina Equine SNP50 BeadChip. An animal model was first implemented in order to adjust each horse's phenotypic status for average relatedness among horses and other potentially confounding factors which were present in the data. The genome-wide association test was then conducted on the residuals from the animal model. A single SNP on chromosome 3 was found to be associated with OCD at a genome-wide level of significance, as determined by permutation. According to the current sequence annotation, the SNP is located in an intergenic region of the genome. The effects of 24 SNPs, representing QTL previously identified in a sample of Hanoverian Warmblood horses, were tested directly in the animal model. When fitted alongside the significant SNP on ECA3, two of these SNPs were found to be associated with OCD. Confirmation of the putative QTL identified on ECA3 requires validation in an independent sample. The results of this study suggest that a significant challenge faced by equine researchers is the generation of sufficiently large data sets to effectively study complex diseases such as osteochondrosis.
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Estudio de Asociación del Genoma Completo/veterinaria , Enfermedades de los Caballos/genética , Osteocondritis Disecante/veterinaria , Animales , Femenino , Caballos , Masculino , Osteocondritis Disecante/genética , Polimorfismo de Nucleótido Simple , Sitios de Carácter CuantitativoRESUMEN
BACKGROUND: Pain is a complex polygenic trait whose common genetic underpinnings are relatively ill-defined due in part to challenges in measuring pain as a phenotype. Pain sensitivity can be quantified, but this is difficult to perform at the scale required for genome wide association studies (GWAS). Existing GWAS of pain have identified surprisingly few loci involved in nociceptor function which contrasts strongly with rare monogenic pain states. This suggests a lack of resolution with current techniques. We propose an adaptive methodology within a recall-by-genotype (RbG) framework using detailed phenotyping to screen minor alleles in a candidate 'nociceptor' gene in an attempt to estimate their genetic contribution to pain. METHODS/DESIGN: Participants of the Avon Longitudinal Study of Parents and Children will be recalled on the basis of genotype at five common non-synonomous SNPs in the 'nociceptor' gene transient receptor potential ankylin 1 (TRPA1). Those homozygous for the common alleles at each of the five SNPs will represent a control group. Individuals homozygous for the minor alleles will then be recruited in a series of three sequential test groups. The outcome of a pre-planned early assessment (interim) of the current test group will determine whether to continue recruitment or switch to the next test group. Pain sensitivity will be assessed using quantitative sensory testing (QST) before and after topical application of 10% cinnamaldehyde (a TRPA1 agonist). DISCUSSION: The design of this adaptive RbG study offers efficiency in the assessment of associations between genetic variation at TRPA1 and detailed pain phenotypes. The possibility to change the test group in response to preliminary data increases the likelihood to observe smaller effect sizes relative to a conventional multi-armed design, as well as reducing futile testing of participants where an effect is unlikely to be observed. This specific adaptive RbG design aims to uncover the influence of common TRPA1 variants on pain sensation but can be applied to any hypothesis-led genotype study where costly and time intensive investigation is required and / or where there is large uncertainty around the expected effect size. TRIAL REGISTRATION: ISRCTN, ISRCTN16294731. Retrospectively registered 25th November 2021.
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Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Genotipo , Humanos , Estudios Longitudinales , Dolor/genética , Fenotipo , Canal Catiónico TRPA1/genéticaRESUMEN
OBJECTIVE: This study estimated the effect of BMI on circulating metabolites in young adults using a recall-by-genotype study design. METHODS: A recall-by-genotype study was implemented in the Avon Longitudinal Study of Parents and Children. Samples from 756 participants were selected for untargeted metabolomics analysis based on low versus high genetic liability for higher BMI defined by a genetic risk score (GRS). Regression analyses were performed to investigate associations between BMI GRS group and relative abundance of 973 metabolites. RESULTS: After correction for multiple testing, 29 metabolites were associated with BMI GRS group. Bilirubin was among the most strongly associated metabolites, with reduced levels measured in individuals in the high-BMI GRS group (ß = -0.32, 95% CI: -0.46 to -0.18, Benjamini-Hochberg adjusted p = 0.005). This study observed associations between BMI GRS group and the levels of several potentially diet-related metabolites, including hippurate, which had lower mean abundance in individuals in the high-BMI GRS group (ß = -0.29, 95% CI: -0.44 to -0.15, Benjamini-Hochberg adjusted p = 0.008). CONCLUSIONS: Together with existing literature, these results suggest that a genetic predisposition to higher BMI captures differences in metabolism leading to adiposity gain. In the absence of prospective data, separating these effects from the downstream consequences of weight gain is challenging.
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Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Índice de Masa Corporal , Niño , Genotipo , Humanos , Estudios Longitudinales , Metabolómica , Estudios Prospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Mendelian randomization (MR) is increasingly used for generating estimates of the causal impact of exposures on outcomes. Evidence suggests a causal role of excess adipose tissue (adiposity) on many health outcomes. However, this body of work has not been systematically appraised. We systematically reviewed and meta-analysed results from MR studies investigating the association between adiposity and health outcomes prior to the SARS-CoV-2/COVID-19 pandemic (PROSPERO: CRD42018096684). We searched Medline, EMBASE, and bioRxiv up to February 2019 and obtained data on 2,214 MR analyses from 173 included articles. 29 meta-analyses were conducted using data from 34 articles (including 66 MR analyses) and results not able to be meta-analysed were narratively synthesised. Body mass index (BMI) was the predominant exposure used and was primarily associated with an increase in investigated outcomes; the largest effect in the meta-analyses was observed for the association between BMI and polycystic ovary syndrome (estimates reflect odds ratios (OR) per standard deviation change in each adiposity measure): OR = 2.55; 95% confidence interval (CI) = 1.22-5.33. Only colorectal cancer was investigated with two exposures in the meta-analysis: BMI (OR = 1.18; 95% CI = 1.01-1.37) and waist-hip ratio (WHR; OR = 1.48; 95% CI = 1.08-2.03). Broadly, results were consistent across the meta-analyses and narrative synthesis. Consistent with many observational studies, this work highlights the impact of adiposity across a broad spectrum of health outcomes, enabling targeted follow-up analyses. However, missing and incomplete data mean results should be interpreted with caution.