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2.
Artigo em Inglês | MEDLINE | ID: mdl-33798464

RESUMO

BACKGROUND: In patients with type 2 diabetes, hyperglycaemia is an independent risk factor for COVID-19-related mortality. Associations between pre-infection prescription for glucose-lowering drugs and COVID-19-related mortality in people with type 2 diabetes have been postulated but only investigated in small studies and limited to a few agents. We investigated whether there are associations between prescription of different classes of glucose-lowering drugs and risk of COVID-19-related mortality in people with type 2 diabetes. METHODS: This was a nationwide observational cohort study done with data from the National Diabetes Audit for people with type 2 diabetes and registered with a general practice in England since 2003. Cox regression was used to estimate the hazard ratio (HR) of COVID-19-related mortality in people prescribed each class of glucose-lowering drug, with covariate adjustment with a propensity score to address confounding by demographic, socioeconomic, and clinical factors. FINDINGS: Among the 2 851 465 people with type 2 diabetes included in our analyses, 13 479 (0·5%) COVID-19-related deaths occurred during the study period (Feb 16 to Aug 31, 2020), corresponding to a rate of 8·9 per 1000 person-years (95% CI 8·7-9·0). The adjusted HR associated with recorded versus no recorded prescription was 0·77 (95% CI 0·73-0·81) for metformin and 1·42 (1·35-1·49) for insulin. Adjusted HRs for prescription of other individual classes of glucose-lowering treatment were as follows: 0·75 (0·48-1·17) for meglitinides, 0·82 (0·74-0·91) for SGLT2 inhibitors, 0·94 (0·82-1·07) for thiazolidinediones, 0·94 (0·89-0·99) for sulfonylureas, 0·94 (0·83-1·07) for GLP-1 receptor agonists, 1·07 (1·01-1·13) for DPP-4 inhibitors, and 1·26 (0·76-2·09) for α-glucosidase inhibitors. INTERPRETATION: Our results provide evidence of associations between prescription of some glucose-lowering drugs and COVID-19-related mortality, although the differences in risk are small and these findings are likely to be due to confounding by indication, in view of the use of different drug classes at different stages of type 2 diabetes disease progression. In the context of the COVID-19 pandemic, there is no clear indication to change prescribing of glucose-lowering drugs in people with type 2 diabetes. FUNDING: None.

3.
Nat Med ; 27(3): 471-479, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33707775

RESUMO

Multimorbidity, the simultaneous presence of multiple chronic conditions, is an increasing global health problem and research into its determinants is of high priority. We used baseline untargeted plasma metabolomics profiling covering >1,000 metabolites as a comprehensive readout of human physiology to characterize pathways associated with and across 27 incident noncommunicable diseases (NCDs) assessed using electronic health record hospitalization and cancer registry data from over 11,000 participants (219,415 person years). We identified 420 metabolites shared between at least 2 NCDs, representing 65.5% of all 640 significant metabolite-disease associations. We integrated baseline data on over 50 diverse clinical risk factors and characteristics to identify actionable shared pathways represented by those metabolites. Our study highlights liver and kidney function, lipid and glucose metabolism, low-grade inflammation, surrogates of gut microbial diversity and specific health-related behaviors as antecedents of common NCD multimorbidity with potential for early prevention. We integrated results into an open-access webserver ( https://omicscience.org/apps/mwasdisease/ ) to facilitate future research and meta-analyses.


Assuntos
Metaboloma , Multimorbidade , Doenças não Transmissíveis , Plasma/metabolismo , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
4.
PLoS Med ; 18(3): e1003455, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33711016

RESUMO

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 causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we report that a genetically predicted inflammation-related insulin resistance phenotype (raised fasting insulin (raised fasting insulin (Wald ratio OR = 2.95, 95% C.I, 1.38-6.34, Holm-Bonferroni corrected p-value (p) = 0.035) and lower high-density lipoprotein (Wald ratio OR = 0.55, 95% C.I., 0.36-0.84; p = 0.035)) was associated with schizophrenia. Evidence for these associations attenuated to the null in multivariable MR analyses after adjusting for C-reactive protein, an archetypal inflammatory marker: (fasting insulin Wald ratio OR = 1.02, 95% C.I, 0.37-2.78, p = 0.975), high-density lipoprotein (Wald ratio OR = 1.00, 95% C.I., 0.85-1.16; p = 0.849), suggesting that the associations could be fully explained by inflammation. One potential limitation of the study is that the full range of gene products from the genetic variants we used as proxies for the exposures is unknown, and so we are unable to comment on potential biological mechanisms of association other than inflammation, which may also be relevant. CONCLUSIONS: Our findings support a role for inflammation as a common cause for insulin resistance and schizophrenia, which may at least partly explain why the traits commonly co-occur in clinical practice. Inflammation and immune pathways may represent novel therapeutic targets for the prevention or treatment of schizophrenia and comorbid insulin resistance. Future work is needed to understand how inflammation may contribute to the risk of schizophrenia and insulin resistance.

5.
J Nutr ; 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33693815

RESUMO

BACKGROUND: The consumption of legumes is promoted as part of a healthy diet in many countries but associations of total and types of legume consumption with type 2 diabetes (T2D) are not well established. Analyses across diverse populations are lacking despite the availability of unpublished legume consumption data in prospective cohort studies. OBJECTIVE: To examine the prospective associations of total and types of legume intake with the risk of incident T2D. METHODS: Meta-analyses of associations between total legume, pulse, and soy consumption and T2D were conducted using a federated approach without physical data-pooling. Prospective cohorts were included if legume exposure and T2D outcome data were available and the cohort investigators agreed to participate. We estimated incidence rate ratios (IRRs) and CIs of associations using individual participant data including ≤42,473 incident cases among 807,785 adults without diabetes in 27 cohorts across the Americas, Eastern Mediterranean, Europe, and Western Pacific. Random-effects meta-analysis was used to combine effect estimates and estimate heterogeneity. RESULTS: Median total legume intake ranged from 0-140 g/d across cohorts. We observed a weak positive association between total legume consumption and T2D (IRR = 1.02, 95% CI: 1.01 to 1.04) per 20 g/d higher intake, with moderately high heterogeneity (I2 = 74%). Analysis by region showed no evidence of associations in the Americas, Eastern Mediterranean, and Western Pacific. The positive association in Europe (IRR = 1.05, 95% CI: 1.01 to 1.10, I2 = 82%) was mainly driven by studies from Germany, UK, and Sweden. No evidence of associations was observed for the consumption of pulses or soy. CONCLUSIONS: These findings suggest no evidence of an association of legume intakes with T2D in several world regions. The positive association observed in some European studies warrants further investigation relating to overall dietary contexts in which legumes are consumed, including accompanying foods which may be positively associated with T2D.

6.
Am Heart J ; 2021 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-33626384

RESUMO

BACKGROUND: Recent studies show a mechanistic link between gut microbiota-dependent formation of the atherosclerosis- and thrombosis-promoting metabolite trimethylamine N-oxide (TMAO) and cardiovascular disease (CVD). The clinical utility of TMAO in apparently healthy subjects for predicting incident CVD risks is unclear. METHODS AND RESULTS: In the EPIC-Norfolk community-based study, we examined baseline fasting levels of TMAO and two of its nutrient precursors, choline and betaine, in a case:control design study comparing apparently European healthy middle-aged participants who subsequently develop CVD (Cases, n = 908) vs those who did not (Controls, n = 1,273) over an ensuing average follow-up period of 8 years. In participants who developed CVD vs controls, higher plasma TMAO (3.70 [IQR 2.50-6.41]µM vs 3.25 [IQR 2.19-52,1.15]µM; P < .001) and choline levels (9.09 [IQR 7.87-10.53]µM vs 8.89 [IQR 7.66-10.13]µM; P = .001) were observed. Following adjustments for traditional risk factors, elevated TMAO (adjusted odds ratio (OR) 1.58 [95% confidence interval (CI) 1.21-2.06], P < .001) and choline levels (adjusted OR 1.31 [95%CI 1.00-1.72], P < .05) remained predictive of incident CVD development. The clinical prognostic utility of TMAO remained significant and essentially unchanged regardless of the level of cutoff chosen between 1.5 uM (10%ile) to 10.5 uM (90%ile). CONCLUSION: In apparently healthy participants of the community-based middle-aged EPIC-Norfolk population, elevated plasma levels of the gut microbe-dependent metabolite TMAO, and its nutrient precursor choline, predict incident risk for CVD development independent of traditional risk factors.

7.
BMC Med ; 19(1): 49, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33588846

RESUMO

BACKGROUND: Characteristics of the built environment, such as neighbourhood fast-food outlet exposure, are increasingly recognised as risk factors for unhealthy diet and obesity. Obesity also has a genetic component, with common genetic variants explaining a substantial proportion of population-level obesity susceptibility. However, it is not known whether and to what extent associations between fast-food outlet exposure and body weight are modified by genetic predisposition to obesity. METHODS: We used data from the Fenland Study, a population-based sample of 12,435 UK adults (mean age 48.6 years). We derived a genetic risk score associated with BMI (BMI-GRS) from 96 BMI-associated single nucleotide polymorphisms. Neighbourhood fast-food exposure was defined as quartiles of counts of outlets around the home address. We used multivariable regression models to estimate the associations of each exposure, independently and in combination, with measured BMI, overweight and obesity, and investigated interactions. RESULTS: We found independent associations between BMI-GRS and risk of overweight (RR = 1.34, 95% CI 1.23-1.47) and obesity (RR = 1.73, 95% CI 1.55-1.93), and between fast-food outlet exposure and risk of obesity (highest vs lowest quartile RR = 1.58, 95% CI 1.21-2.05). There was no evidence of an interaction of fast-food outlet exposure and genetic risk on BMI (P = 0.09), risk of overweight (P = 0.51), or risk of obesity (P = 0.27). The combination of higher BMI-GRS and highest fast-food outlet exposure was associated with 2.70 (95% CI 1.99-3.66) times greater risk of obesity. CONCLUSIONS: Our study demonstrated independent associations of both genetic obesity risk and neighbourhood fast-food outlet exposure with adiposity. These important drivers of the obesity epidemic have to date been studied in isolation. Neighbourhood fast-food outlet exposure remains a potential target of policy intervention to prevent obesity and promote the public's health.

8.
Nat Genet ; 53(1): 54-64, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33414548

RESUMO

In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10-10) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with ß-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables the discovery of regulators of human metabolism and translation into clinical insights.


Assuntos
Saúde , Metabolismo/genética , Diabetes Mellitus Tipo 2/genética , Oftalmopatias/genética , Frequência do Gene/genética , Loci Gênicos , Pleiotropia Genética , Genoma Humano , Receptor do Peptídeo Semelhante ao Glucagon 2/genética , Glicina/metabolismo , Humanos , Modelos Lineares , Análise da Randomização Mendeliana , Erros Inatos do Metabolismo/genética , Metaboloma/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Telangiectasia Retiniana/genética , Tamanho da Amostra , Serina/metabolismo
9.
Neurology ; 96(13): e1732-e1742, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33495378

RESUMO

OBJECTIVE: We employed Mendelian randomization to explore the effects of genetic predisposition to type 2 diabetes (T2D), hyperglycemia, insulin resistance, and pancreatic ß-cell dysfunction on risk of stroke subtypes and related cerebrovascular phenotypes. METHODS: We selected instruments for genetic predisposition to T2D (74,124 cases, 824,006 controls), HbA1c levels (n = 421,923), fasting glucose levels (n = 133,010), insulin resistance (n = 108,557), and ß-cell dysfunction (n = 16,378) based on published genome-wide association studies. Applying 2-sample Mendelian randomization, we examined associations with ischemic stroke (60,341 cases, 454,450 controls), intracerebral hemorrhage (1,545 cases, 1,481 controls), and ischemic stroke subtypes (large artery, cardioembolic, small vessel stroke), as well as with related phenotypes (carotid atherosclerosis, imaging markers of cerebral white matter integrity, and brain atrophy). RESULTS: Genetic predisposition to T2D and higher HbA1c levels were associated with higher risk of any ischemic stroke, large artery stroke, and small vessel stroke. Similar associations were also noted for carotid atherosclerotic plaque, fractional anisotropy, a white matter disease marker, and markers of brain atrophy. We further found associations of genetic predisposition to insulin resistance with large artery and small vessel stroke, whereas predisposition to ß-cell dysfunction was associated with small vessel stroke, intracerebral hemorrhage, lower gray matter volume, and total brain volume. CONCLUSIONS: This study supports causal effects of T2D and hyperglycemia on large artery and small vessel stroke. We show associations of genetically predicted insulin resistance and ß-cell dysfunction with large artery and small vessel stroke that might have implications for antidiabetic treatments targeting these mechanisms. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that genetic predisposition to T2D and higher HbA1c levels are associated with a higher risk of large artery and small vessel ischemic stroke.


Assuntos
Hemorragia Cerebral/genética , Diabetes Mellitus Tipo 2/genética , Hiperglicemia/genética , Resistência à Insulina/genética , /genética , Atrofia/epidemiologia , Atrofia/genética , Glicemia/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Doenças das Artérias Carótidas/epidemiologia , Doenças das Artérias Carótidas/genética , Hemorragia Cerebral/epidemiologia , Transtornos Cerebrovasculares/epidemiologia , Transtornos Cerebrovasculares/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Predisposição Genética para Doença , Hemoglobina A Glicada/metabolismo , Humanos , Hiperglicemia/epidemiologia , Hiperglicemia/metabolismo , Células Secretoras de Insulina , Análise da Randomização Mendeliana , Substância Branca/diagnóstico por imagem
10.
Nat Commun ; 12(1): 654, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510174

RESUMO

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Debilidade Muscular/genética , Sarcopenia/genética , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Estudos de Coortes , Europa (Continente) , Feminino , Fator 5 de Diferenciação de Crescimento/genética , Cadeias alfa de HLA-DQ/genética , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular/genética , Força Muscular/fisiologia , Debilidade Muscular/fisiopatologia , Polimorfismo de Nucleotídeo Único , Sarcopenia/fisiopatologia
11.
Health Place ; 67: 102490, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33321456

RESUMO

The environments in which young and middle-aged adults live may influence their physical activity (PA) behaviours. These associations are less clear among older adults. We estimated cross-sectional and prospective associations of population density, junction density, and land use mix and perceived active living environments with accelerometer-assessed PA in a cohort of older adults. Adults living in more dense and mixed neighbourhoods had less optimal activity profiles at baseline and less optimal changes in activity. Better perceptions were associated with more overall PA at baseline. Interventions for older adults may wish to target individuals living in more dense and mixed neighbourhoods.

12.
Stroke ; 52(1): 172-180, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33349021

RESUMO

BACKGROUND AND PURPOSE: B-vitamin supplements lower circulating concentrations of homocysteine and may reduce stroke incidence. Homocysteine concentrations are associated with the incidence of stroke but other sulfur-containing compounds in the related metabolic pathway have not yet been investigated for an association with incident cerebrovascular diseases. METHODS: Nested within the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Norfolk cohort, we established a case-control study with 480 incident cases of cerebrovascular diseases and 480 controls matched by age, sex, and year of baseline examination (1993-1997). Using baseline plasma samples, we assayed sulfur-containing compounds including methionine, homocysteine, cystathionine, cysteine, glutathione, and taurine with liquid chromatography-tandem mass spectrometry. We examined the association of concentrations of each of the compounds and the ratio of methionine to homocysteine (representing activity of one-carbon metabolism) with risk of incident cerebrovascular diseases, adjusted for potential confounders. RESULTS: Plasma methionine and the methionine/homocysteine ratio were inversely associated with risk of cerebrovascular diseases, with odds ratios per 1 SD of 0.83 (95% CI, 0.72-0.96) and 0.82 (95% CI, 0.71-0.95), respectively. The association of methionine remained significant after adjustment for homocysteine. None of the other examined compounds was significantly associated with incident cerebrovascular diseases. CONCLUSIONS: These findings suggest that greater availability of methionine, an essential amino acid, may play a role in the prevention of cerebrovascular diseases and explain the previously recognized link between elevated homocysteine and stroke. Further research is needed to determine causation and the potential of circulating methionine as a target in cerebrovascular disease prevention.


Assuntos
Transtornos Cerebrovasculares/sangue , Metionina/sangue , Idoso , Aminoácidos Sulfúricos/sangue , Estudos de Casos e Controles , Transtornos Cerebrovasculares/epidemiologia , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco
13.
Diabetes Obes Metab ; 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33269535

RESUMO

BACKGROUND: Short-term weight loss may lead to remission of type 2 diabetes but the effect of maintained weight loss on cardiovascular disease (CVD) is unknown. We quantified the associations between changes in weight 5 years following diabetes diagnosis, and incident CVD events and mortality up to 10 years after diagnosis. METHODS: Observational analysis of the ADDITION-Europe trial of 2,730 adults with screen-detected type 2 diabetes from the UK, Denmark, and the Netherlands. We defined weight change based on the maintenance at 5-years of weight loss achieved in the year after diabetes diagnosis, and as 5-year overall change in weight. Incident CVD events (n=229) and all-cause mortality (n=225) from years 5-10 follow-up were ascertained from medical records. FINDINGS: Gaining >2% weight in the year after diabetes diagnosis was associated with higher hazard of all-cause mortality vs maintaining weight [Hazard Ratio(HR)(95%CI): 3.18(1.30-7.82)]. Losing ≥5% weight 1 year after diagnosis was also associated with mortality, whether or not weight loss was maintained at 5 years [2.47(0.99-6.21) and 2.72(1.17-6.30), respectively]. Losing ≥10% weight over 5 years was associated with mortality among those with BMI<30kg/m2 [4.62(1.87-11.42)]. Associations with CVD incidence were inconclusive. INTERPRETATION: Both weight loss and weight gain after screen-detected diabetes diagnosis were associated with higher mortality, but not CVD events, particularly among participants without obesity. The clinical implications of weight loss following diabetes diagnosis are likely to depend on its magnitude and timing, and may differ by BMI status. Personalisation of weight loss advice and support may be warranted. This article is protected by copyright. All rights reserved.

14.
Diabetes Care ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33303636

RESUMO

OBJECTIVE: Islet autoimmunity is associated with diabetes incidence. We investigated whether there was an interaction between dietary fish intake or plasma phospholipid n-3 polyunsaturated fatty acid (PUFA) concentration with the 65-kDa isoform of GAD (GAD65) antibody positivity on the risk of developing adult-onset diabetes. RESEARCH DESIGN AND METHODS: We used prospective data on 11,247 incident cases of adult-onset diabetes and 14,288 noncases from the EPIC-InterAct case-cohort study conducted in eight European countries. Baseline plasma samples were analyzed for GAD65 antibodies and phospholipid n-3 PUFAs. Adjusted hazard ratios (HRs) for incident diabetes in relation to GAD65 antibody status and tertiles of plasma phospholipid n-3 PUFA or fish intake were estimated using Prentice-weighted Cox regression. Additive (proportion attributable to interaction [AP]) and multiplicative interactions between GAD65 antibody positivity (≥65 units/mL) and low fish/n-3 PUFA were assessed. RESULTS: The hazard of diabetes in antibody-positive individuals with low intake of total and fatty fish, respectively, was significantly elevated (HR 2.52 [95% CI 1.76-3.63] and 2.48 [1.79-3.45]) compared with people who were GAD65 antibody negative and had high fish intake, with evidence of additive (AP 0.44 [95% CI 0.16-0.72] and 0.48 [0.24-0.72]) and multiplicative (P = 0.0465 and 0.0103) interactions. Individuals with high GAD65 antibody levels (≥167.5 units/mL) and low total plasma phospholipid n-3 PUFAs had a more than fourfold higher hazard of diabetes (HR 4.26 [2.70-6.72]) and an AP of 0.46 (0.12-0.80) compared with antibody-negative individuals with high n-3 PUFAs. CONCLUSIONS: High fish intake or relative plasma phospholipid n-3 PUFA concentrations may partially counteract the increased diabetes risk conferred by GAD65 antibody positivity.

15.
Artigo em Inglês | MEDLINE | ID: mdl-33318069

RESUMO

INTRODUCTION: To report the observations of point-of-care (POC) glycated hemoglobin (HbA1c) testing in people with non-diabetic hyperglycemia (NDH; HbA1c 42-47 mmol/mol (6.0%-6.4%)), applied in community settings, within the English National Health Service Diabetes Prevention Programme (NHS DPP). RESEARCH DESIGN AND METHODS: A service evaluation assessing prospectively collected national service-level data from the NHS DPP, using data from the first referral received in June 2016-October 2018. Individuals were referred to the NHS DPP with a laboratory-measured HbA1c in the NDH range and had a repeat HbA1c measured at first attendance of the program using one of three POC devices: DCA Vantage, Afinion or A1C Now+. Differences between the referral and POC HbA1c and the SD of the POC HbA1c were calculated. The factors associated with the difference in HbA1c and the association between POC HbA1c result and subsequent attendance of the NHS DPP were also evaluated. RESULTS: Data from 73 703 participants demonstrated a significant mean difference between the referral and POC HbA1c of -2.48 mmol/mol (-0.23%) (t=157, p<0.001) with significant differences in the mean difference between devices (F(2, 73 700)=738, p<0.001). The SD of POC HbA1c was 4.46 mmol/mol (0.41%) with significant differences in SDs between devices (F(2, 73 700)=1542, p<0.001). Participants who were older, from more deprived areas and from Asian, black and mixed ethnic groups were associated with smaller HbA1c differences. Normoglycemic POC HbA1c versus NDH POC HbA1c values were associated with lower subsequent attendance at behavioral interventions (58% vs 67%, p<0.001). CONCLUSION: POC HbA1c testing in community settings was associated with significantly lower HbA1c values when compared with laboratory-measured referrals. Acknowledging effects of regression to the mean, we found that these differences were also associated with POC method, location, individual patient factors and time between measurements. Compared with POC HbA1c values in the NDH range, normoglycemic POC HbA1c values were associated with lower subsequent intervention attendance.

16.
Nat Commun ; 11(1): 6397, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33328453

RESUMO

Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ).


Assuntos
/genética , Interações Hospedeiro-Patógeno/genética , Proteínas/genética , /fisiologia , Sistema ABO de Grupos Sanguíneos/metabolismo , Aptâmeros de Peptídeos/sangue , Aptâmeros de Peptídeos/metabolismo , Coagulação Sanguínea , Sistemas de Liberação de Medicamentos , Feminino , Regulação da Expressão Gênica , Fatores Celulares Derivados do Hospedeiro/metabolismo , Humanos , Internet , Masculino , Pessoa de Meia-Idade , Locos de Características Quantitativas/genética
17.
Sci Data ; 7(1): 393, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188205

RESUMO

Type 2 diabetes (T2D) is a global public health challenge. Whilst the advent of genome-wide association studies has identified >400 genetic variants associated with T2D, our understanding of its biological mechanisms and translational insights is still limited. The EPIC-InterAct project, centred in 8 countries in the European Prospective Investigations into Cancer and Nutrition study, is one of the largest prospective studies of T2D. Established as a nested case-cohort study to investigate the interplay between genetic and lifestyle behavioural factors on the risk of T2D, a total of 12,403 individuals were identified as incident T2D cases, and a representative sub-cohort of 16,154 individuals was selected from a larger cohort of 340,234 participants with a follow-up time of 3.99 million person-years. We describe the results from a genome-wide association analysis between more than 8.9 million SNPs and T2D risk among 22,326 individuals (9,978 cases and 12,348 non-cases) from the EPIC-InterAct study. The summary statistics to be shared provide a valuable resource to facilitate further investigations into the genetics of T2D.

19.
Diabetes Care ; 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203707

RESUMO

OBJECTIVE: Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants. RESULTS: We identified 11 genomic regions associated with plasma vitamin C (P < 5 × 10-8), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1, and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10). CONCLUSIONS: These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.

20.
Maturitas ; 142: 55-63, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33158488

RESUMO

OBJECTIVES: To examine whether anticholinergic medication exposure in middle and late life is associated with physical capability. STUDY DESIGN: We used data from 8477 men and women who had enrolled in the European Prospective Investigation of Cancer-Norfolk study at baseline (1HC; 1993-1997) and who had attended its third health examination (3HC; 2004-2010). Medication history at the 1HC and 3HC was used to score participants according to the Anticholinergic Cognitive Burden (ACB) Scale at baseline and 3HC; participants were categorised as ACB = 0, ACB = 1, ACB>2. MAIN OUTCOME MEASURE: At 3HC, physical capability was objectively measured by: usual walking speed, maximum grip strength, timed chair stands speed (TCSS) and standing balance. Linear and logistic regression models examined prospective and cross-sectional associations between ACB and physical capability, controlling for co-morbidity, sociodemographic and lifestyle factors. RESULTS: The analyses included 3386 men and 4110 women who were 56.4 (SD 7.9) and 55.0 (7.7) years old respectively at baseline and 69.4 (8.1) and 67.9 (8.0) years old at follow-up. Significant cross-sectional and prospective relationships were observed for all physical capability measures in women, except grip strength. For example, women with ACB ≥ 2 compared with ACB = 0 at baseline had 0.07 m/s (95 % CI -0.11, -0.03) slower usual walking speed, 2.61 stands/min (-4.17, -1.05) slower TCSS and higher odds of being unable to complete a tandem stand (odds ratio 2.40, 95 % CI 1.53, 3.76). These trends were observed in men but were less consistent in prospective analyses. CONCLUSION: Exposure to anticholinergic medication predicts poor physical capability and is a potentially reversible risk factor.

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