Publications by authors named "Nicholas J Wareham"

766 Publications

Cardiorespiratory fitness assessment using risk-stratified exercise testing and dose-response relationships with disease outcomes.

Sci Rep 2021 Jul 28;11(1):15315. Epub 2021 Jul 28.

MRC Epidemiology Unit, School of Clinical Medicine, Institute of Metabolic Science, University of Cambridge, Cambridge Biomedical Campus, Box 285, Cambridge, CB2 0QQ, UK.

Cardiorespiratory fitness (CRF) is associated with mortality and cardiovascular disease, but assessing CRF in the population is challenging. Here we develop and validate a novel framework to estimate CRF (as maximal oxygen consumption, VOmax) from heart rate response to low-risk personalised exercise tests. We apply the method to examine associations between CRF and health outcomes in the UK Biobank study, one of the world's largest and most inclusive studies of CRF, showing that risk of all-cause mortality is 8% lower (95%CI 5-11%, 2670 deaths among 79,981 participants) and cardiovascular mortality is 9% lower (95%CI 4-14%, 854 deaths) per 1-metabolic equivalent difference in CRF. Associations obtained with the novel validated CRF estimation method are stronger than those obtained using previous methodology, suggesting previous methods may have underestimated the importance of fitness for human health.
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http://dx.doi.org/10.1038/s41598-021-94768-3DOI Listing
July 2021

Sex-Specific Associations of Genetically-Predicted Circulating Lipoprotein(a) and Hepatic LPA Gene Expression Levels with Cardiovascular Outcomes: Mendelian Randomization and Observational Analyses.

Circ Genom Precis Med 2021 Jul 19. Epub 2021 Jul 19.

Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec & Department of Medicine, Faculty of Medicine, Université Laval, Québec (QC), Canada.

- Elevated Lipoprotein(a) (Lp[a]) levels are associated with coronary artery disease (CAD), ischemic stroke (IS) and calcific aortic valve stenosis (CAVS). Studies investigating the association between Lp(a) levels and these diseases in women have yielded inconsistent results. - To investigate the association of Lp(a) with sex-specific cardiovascular outcomes, we determined the association between genetically-predicted Lp(a) levels (using 27 single nucleotide polymorphisms (SNPs) at the locus) and hepatic expression (using 80 SNPs at the locus associated with mRNA expression in liver samples from the Genotype-Tissue Expression dataset) on CAD, IS and CAVS using individual participant data from the UK Biobank: 408,403 participants of European ancestry (37,102, 4283 and 2574 with prevalent CAD, IS and CAVS, respectively). The long-term association between Lp(a) levels and incident CAD, IS and CAVS in was also investigated in EPIC-Norfolk: 18,721 participants (3964, 846 and 424 with incident CAD, IS and CAVS, respectively). - Genetically-predicted and plasma Lp(a) levels were positively and similarly associated with prevalent and incident CAD and CAVS in men and women. Genetically-predicted and plasma Lp(a) levels was associated with prevalent and incident IS when we studied men and women pooled together, and in men only. Genetically-predicted expression levels was associated with prevalent CAD and CAVS in men and women, but not with IS. - Genetically-predicted blood Lp(a) and hepatic gene expression as well as serum Lp(a) levels predict the risk of CAD and CAVS in men and in women. Whether RNA interference therapies aiming at lowering Lp(a) levels could be useful in reducing cardiovascular disease risk in both men and women with high Lp(a) levels needs to be determined in large-scale cardiovascular outcomes trials.
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http://dx.doi.org/10.1161/CIRCGEN.120.003271DOI Listing
July 2021

Sugar-sweetened Beverage Consumption May Modify Associations between Genetic Variants in the CHREBP Locus and HDL-C and TG Concentrations.

Circ Genom Precis Med 2021 Jul 16. Epub 2021 Jul 16.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

- Carbohydrate responsive element binding protein (ChREBP) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the locus have separately been linked to high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) concentrations. We hypothesized SSB consumption would modify the association between genetic variants in the locus and dyslipidemia. - Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (N=63,599) and the UK Biobank (UKB) (N=59,220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and TG concentrations using linear regression models. A total of 1,606 single-nucleotide polymorphisms (SNPs) within or near were considered. SSB consumption was estimated from validated questionnaires and participants were grouped by their estimated intake. - In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers [β (95% CI) = 2.12 (1.16, 3.07) mg/dl; <0.0002], but not significantly among the lowest SSB consumers (=0.81; <0.0001). Similar results were observed for two additional variants (rs35709627 and rs71556736). For TG, rs55673514 was positively associated with TG concentrations only among the highest SSB consumers [β (95% CI): 0.06 (0.02, 0.09) per allele count for log(mg/dl), =0.001], but not the lowest SSB consumers (=0.84; =0.0005). - Our results identified genetic variants in the locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in TG concentrations.
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http://dx.doi.org/10.1161/CIRCGEN.120.003288DOI Listing
July 2021

GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health.

Nat Commun 2021 07 7;12(1):4178. Epub 2021 Jul 7.

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

Mosaic loss of chromosome Y (LOY) in leukocytes is the most common form of clonal mosaicism, caused by dysregulation in cell-cycle and DNA damage response pathways. Previous genetic studies have focussed on identifying common variants associated with LOY, which we now extend to rarer, protein-coding variation using exome sequences from 82,277 male UK Biobank participants. We find that loss of function of two genes-CHEK2 and GIGYF1-reach exome-wide significance. Rare alleles in GIGYF1 have not previously been implicated in any complex trait, but here loss-of-function carriers exhibit six-fold higher susceptibility to LOY (OR = 5.99 [3.04-11.81], p = 1.3 × 10). These same alleles are also associated with adverse metabolic health, including higher susceptibility to Type 2 Diabetes (OR = 6.10 [3.51-10.61], p = 1.8 × 10), 4 kg higher fat mass (p = 1.3 × 10), 2.32 nmol/L lower serum IGF1 levels (p = 1.5 × 10) and 4.5 kg lower handgrip strength (p = 4.7 × 10) consistent with proposed GIGYF1 enhancement of insulin and IGF-1 receptor signalling. These associations are mirrored by a common variant nearby associated with the expression of GIGYF1. Our observations highlight a potential direct connection between clonal mosaicism and metabolic health.
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http://dx.doi.org/10.1038/s41467-021-24504-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263756PMC
July 2021

Long Term Prognostic Impact of Sex-specific Longitudinal Changes in Blood Pressure. The EPIC-Norfolk Prospective Population Cohort Study.

Eur J Prev Cardiol 2021 Jul 5. Epub 2021 Jul 5.

Aberdeen Diabetes and Cardiovascular Centre, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Room 4:013, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, UK.

Aims: We aimed to determine the sex differences in longitudinal systolic and diastolic blood pressure (SBP and DBP) trajectories in mid-life and delineate the associations between these and mortality (all-cause, cardiovascular, and non-cardiovascular) and incident cardiovascular disease (CVD) in old age.

Methods And Results: Participants were selected from the European Prospective Investigation into Cancer, Norfolk (EPIC-Norfolk) cohort study. Sex-specific trajectories were determined using group-based trajectory models using three clinic BP measurements acquired between 1993 and 2012 (mean exposure ∼12.9 years). Multivariable Cox regressions determined the associations between trajectories and incident outcomes over the follow-up (median follow-up 9.4 years). A total of 2897 men (M) and 3819 women (F) were included. At baseline, women were younger (F-55.5, M-57.1), had a worse cardiometabolic profile and were less likely to receive primary CVD prevention including antihypertensive treatment (F-36.0%, M-42.0%). Over the exposure period, women had lower SBP trajectories while men exhibited more pronounced SBP decreases over this period. Over the follow-up period, women had lower mortality (F-11.9%, M-20.5%) and CVD incidence (F-19.8%, M-29.6%). Compared to optimal SBP (≤120 mmHg) and DBP (≤70 mmHg) trajectories, hypertensive trajectories were associated with increased mortality and incident CVD in both men and women during follow-up at univariable level. These associations were nevertheless not maintained upon extensive confounder adjustment including antihypertensive therapies.

Conclusion: We report sex disparities in CVD prevention which may relate to worse cardiometabolic profiles and less pronounced longitudinal SBP decreases in women. Effective anti-hypertensivetherapy may offset the adverse outcomes associated with prolonged exposure to high blood pressure.
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http://dx.doi.org/10.1093/eurjpc/zwab104DOI Listing
July 2021

Association between serum secretory phospholipase A2 and risk of ischaemic stroke.

Eur J Neurol 2021 Jul 3. Epub 2021 Jul 3.

Ageing Clinical and Experimental Research, Institute of Applied Health Sciences, Aberdeen, UK.

Background And Purpose: Previous literature has demonstrated an association between high serum levels of type II secretory phospholipase A2 (sPLA2) concentration and an increased risk of coronary artery disease. However, such association has not been established in terms of ischaemic stroke risk. The aim was to evaluate the association between both sPLA2 concentration and activity as continuous variables with risk of future ischaemic stroke.

Methods: A nested case-control study was conducted using data from the European Prospective Investigation into Cancer-Norfolk study. Cases (n = 145) in the current study were participants who developed ischaemic stroke during follow-up, with controls (n = 290) matched in a 2:1 ratio based on age and sex. Statistical analyses were performed using SPSS (version 25.0) software. Logistic regression was used to determine odds ratios (OR) and corresponding 95% confidence intervals (95% CIs) for ischaemic stroke.

Results: After adjusting for a wide array of cardiovascular confounders, sPLA2 activity was found to be associated with an increased risk of ischaemic stroke using both multiple imputations with chained equations and complete case analysis: OR 1.20 (95% CI 1.01-1.43) and OR 1.23 (95% CI 1.01-1.49), respectively. However, sPLA2 concentration was not found to be associated with increased risk of ischaemic stroke.

Conclusions: The activity of sPLA2, but not sPLA2 concentration, is associated with an increased risk of future ischaemic stroke. This finding may be significant in risk group stratification, allowing targeted prophylactic treatment, or the development of novel therapeutic agents.
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http://dx.doi.org/10.1111/ene.15004DOI Listing
July 2021

The relationship between alcohol intake and falls hospitalization: Results from the EPIC-Norfolk.

Geriatr Gerontol Int 2021 Jun 22. Epub 2021 Jun 22.

Ageing Clinical & Experimental Research (ACER) Team, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.

Aim: To evaluate the relationship between habitual alcohol consumption and the risk of falls hospitalization.

Methods: The EPIC-Norfolk is a prospective population-based cohort study in Norfolk, UK. In total, 25 637 community dwelling adults aged 40-79 years were recruited. Units of alcohol consumed per week were measured using a validated Food Frequency Questionnaire. The main outcome was the first hospital admission following a fall.

Results: Over a median follow-up period of 11.5 years (299 211 total person years), the cumulative incidence function (95% confidence interval) of hospitalized falls at 121-180 months for non-users, light (>0 to ≤7 units/week), moderate (>7 to ≤28 units/week) and heavy (>28 units/week) were 11.08 (9.94-12.35), 7.53 (7.02-8.08), 5.91 (5.29-6.59) and 8.20 (6.35-10.56), respectively. Moderate alcohol consumption was independently associated with a reduced risk of falls hospitalization after adjustment for most major confounders (hazard ratio = 0.88; 95% confidence interval 0.79-0.99). The relationship between light alcohol consumption and falls hospitalization was attenuated by gender differences. Alcohol intake higher than the recommended threshold of 28 units/week was associated with an increased risk of falls hospitalization (hazard ratio 1.40 [1.14-1.73]).

Conclusions: Moderate alcohol consumption appears to be associated with a reduced risk of falls hospitalization, and intake above the recommended limit is associated with an increased risk. This provides incentive to limit alcohol consumption within the recommended range and has important implications for public health policies for aging populations. Geriatr Gerontol Int 2021; ••: ••-••.
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http://dx.doi.org/10.1111/ggi.14219DOI Listing
June 2021

Variants associated with expression have sex-differential effects on lung function.

Wellcome Open Res 2020 24;5:111. Epub 2021 May 24.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.

Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 ) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV ) (P=3.15x10 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV more in males (untransformed FEV β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( ) gene and was previously associated with lung function and lung expression. We found expression was significantly different between the sexes (P=6.90x10 ), but we could not detect sex differential effects of rs7697189 on expression. We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the gene. Establishing the mechanism by which SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
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http://dx.doi.org/10.12688/wellcomeopenres.15846.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938335.2PMC
May 2021

Prepubertal Dietary and Plasma Phospholipid Fatty Acids Related to Puberty Timing: Longitudinal Cohort and Mendelian Randomization Analyses.

Nutrients 2021 May 30;13(6). Epub 2021 May 30.

MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus Box 285, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK.

Dietary intakes of polyunsaturated, monounsaturated and saturated fatty acids (FAs) have been inconsistently associated with puberty timing. We examined longitudinal associations of prepubertal dietary and plasma phospholipid FAs with several puberty timing traits in boys and girls. In the Avon Longitudinal Study of Parents and Children, prepubertal fat intakes at 3-7.5 years and plasma phospholipid FAs at 7.5 years were measured. Timings of Tanner stage 2 genital or breast development and voice breaking or menarche from repeated reports at 8-17 years, and age at peak height velocity (PHV) from repeated height measurements at 5-20 years were estimated. In linear regression models with adjustment for maternal and infant characteristics, dietary substitution of polyunsaturated FAs for saturated FAs, and higher concentrations of dihomo-γ-linolenic acid (20:3n6) and palmitoleic acid (16:1n7) were associated with earlier timing of puberty traits in girls ( = 3872) but not boys ( = 3654). In Mendelian Randomization models, higher genetically predicted circulating dihomo-γ-linolenic acid was associated with earlier menarche in girls. Based on repeated dietary intake data, objectively measured FAs and genetic causal inference, these findings suggest that dietary and endogenous metabolic pathways that increase plasma dihomo-γ-linolenic acid, an intermediate metabolite of n-6 polyunsaturated FAs, may promote earlier puberty timing in girls.
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http://dx.doi.org/10.3390/nu13061868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228200PMC
May 2021

Heterogeneity of Associations between Total and Types of Fish Intake and the Incidence of Type 2 Diabetes: Federated Meta-Analysis of 28 Prospective Studies Including 956,122 Participants.

Nutrients 2021 Apr 7;13(4). Epub 2021 Apr 7.

Postgraduate Program in Epidemiology Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90040-060, Brazil.

The association between fish consumption and new-onset type 2 diabetes is inconsistent and differs according to geographical location. We examined the association between the total and types of fish consumption and type 2 diabetes using individual participant data from 28 prospective cohort studies from the Americas (6), Europe (15), the Western Pacific (6), and the Eastern Mediterranean (1) comprising 956,122 participants and 48,084 cases of incident type 2 diabetes. Incidence rate ratios (IRRs) for associations of total fish, shellfish, fatty, lean, fried, freshwater, and saltwater fish intake and type 2 diabetes were derived for each study, adjusting for a consistent set of confounders and combined across studies using random-effects meta-analysis. We stratified all analyses by sex due to observed interaction ( = 0.002) on the association between fish and type 2 diabetes. In women, for each 100 g/week higher intake the IRRs (95% CIs) of type 2 diabetes were 1.02 (1.01-1.03, = 61%) for total fish, 1.04 (1.01-1.07, = 46%) for fatty fish, and 1.02 (1.00-1.04, = 33%) for lean fish. In men, all associations were null. In women, we observed variation by geographical location: IRRs for total fish were 1.03 (1.02-1.04, = 0%) in the Americas and null in other regions. In conclusion, we found evidence of a neutral association between total fish intake and type 2 diabetes in men, but there was a modest positive association among women with heterogeneity across studies, which was partly explained by geographical location and types of fish intake. Future research should investigate the role of cooking methods, accompanying foods and environmental pollutants, but meanwhile, existing dietary regional, national, or international guidelines should continue to guide fish consumption within overall healthy dietary patterns.
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http://dx.doi.org/10.3390/nu13041223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068031PMC
April 2021

Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies.

Nat Commun 2021 04 22;12(1):2329. Epub 2021 Apr 22.

MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.
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http://dx.doi.org/10.1038/s41467-021-22370-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062567PMC
April 2021

Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.

medRxiv 2021 Apr 7. Epub 2021 Apr 7.

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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http://dx.doi.org/10.1101/2021.04.01.21254789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043484PMC
April 2021

Prescription of glucose-lowering therapies and risk of COVID-19 mortality in people with type 2 diabetes: a nationwide observational study in England.

Lancet Diabetes Endocrinol 2021 05 30;9(5):293-303. Epub 2021 Mar 30.

National Diabetes Audit Programme, NHS England & Improvement, London, UK; NHS England and NHS Improvement, London, UK; Department of Diabetes and Endocrinology, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK; Division of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.

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.
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http://dx.doi.org/10.1016/S2213-8587(21)00050-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009618PMC
May 2021

Reply to Unreliability of genotyping arrays for detecting very rare variants in human genetic studies: Example from a recent study of MC4R.

Cell 2021 Apr;184(7):1652-1653

University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK. Electronic address:

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http://dx.doi.org/10.1016/j.cell.2021.03.014DOI Listing
April 2021

The potential shared role of inflammation in insulin resistance and schizophrenia: A bidirectional two-sample mendelian randomization study.

PLoS Med 2021 03 12;18(3):e1003455. Epub 2021 Mar 12.

Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, England.

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.
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http://dx.doi.org/10.1371/journal.pmed.1003455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954314PMC
March 2021

Plasma metabolites to profile pathways in noncommunicable disease multimorbidity.

Nat Med 2021 03 11;27(3):471-479. Epub 2021 Mar 11.

MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.

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.
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http://dx.doi.org/10.1038/s41591-021-01266-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127079PMC
March 2021

Associations of Total Legume, Pulse, and Soy Consumption with Incident Type 2 Diabetes: Federated Meta-Analysis of 27 Studies from Diverse World Regions.

J Nutr 2021 May;151(5):1231-1240

School of Public Health, Physiotherapy & Sports Science, University College Dublin, Dublin, Ireland.

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.
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http://dx.doi.org/10.1093/jn/nxaa447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112771PMC
May 2021

Plasma trimethylamine N-oxide (TMAO) levels predict future risk of coronary artery disease in apparently healthy individuals in the EPIC-Norfolk prospective population study.

Am Heart J 2021 Jun 21;236:80-86. Epub 2021 Feb 21.

Center for Microbiome and Human Health, Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland, OH; Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland, OH.

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.
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http://dx.doi.org/10.1016/j.ahj.2021.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085024PMC
June 2021

Independent and combined associations between fast-food outlet exposure and genetic risk for obesity: a population-based, cross-sectional study in the UK.

BMC Med 2021 Feb 15;19(1):49. Epub 2021 Feb 15.

UKCRC Centre for Diet and Activity Research (CEDAR), MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.

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.
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http://dx.doi.org/10.1186/s12916-021-01902-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885578PMC
February 2021

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Nat Commun 2021 01 28;12(1):654. Epub 2021 Jan 28.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

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), arthritis (GDF5 p = 4 × 10), 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.
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http://dx.doi.org/10.1038/s41467-021-20918-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844411PMC
January 2021

Diabetes Mellitus, Glycemic Traits, and Cerebrovascular Disease: A Mendelian Randomization Study.

Neurology 2021 03 25;96(13):e1732-e1742. Epub 2021 Jan 25.

From the Institute for Stroke and Dementia Research (M.K.G., R.M., M.D.), Department of Neurology (M.K.G), University Hospital, and Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-University, Munich, Germany; Stroke Research Group, Department of Clinical Neurosciences (E.L.H., H.S.M.), and MRC Epidemiology Unit (C.L., N.J.W.), University of Cambridge, UK; Department of Epidemiology (N.F.), UNC Gillings Global School of Public Health, Chapel Hill, NC; Munich Cluster for Systems Neurology (SyNergy) (M.D.); and German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany.

Objective: We employed Mendelian randomization to explore the effects of genetic predisposition to type 2 diabetes (T2D), hyperglycemia, insulin resistance, and pancreatic β-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 β-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 β-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 β-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.
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http://dx.doi.org/10.1212/WNL.0000000000011555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055310PMC
March 2021

A cross-platform approach identifies genetic regulators of human metabolism and health.

Nat Genet 2021 01 7;53(1):54-64. Epub 2021 Jan 7.

Metabolic Research Laboratories, University of Cambridge, Cambridge, UK.

In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 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 β-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.
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http://dx.doi.org/10.1038/s41588-020-00751-5DOI Listing
January 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Plasma Sulfur Amino Acids and Risk of Cerebrovascular Diseases: A Nested Case-Control Study in the EPIC-Norfolk Cohort.

Stroke 2021 01 22;52(1):172-180. Epub 2020 Dec 22.

Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, United Kingdom (N.J.W., N.G.F., F.I.).

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.
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http://dx.doi.org/10.1161/STROKEAHA.120.029177DOI Listing
January 2021

Genetic architecture of host proteins involved in SARS-CoV-2 infection.

Nat Commun 2020 12 16;11(1):6397. Epub 2020 Dec 16.

MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.

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/ ).
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http://dx.doi.org/10.1038/s41467-020-19996-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744536PMC
December 2020

Cross-sectional and prospective associations between active living environments and accelerometer-assessed physical activity in the EPIC-Norfolk cohort.

Health Place 2021 01 13;67:102490. Epub 2020 Dec 13.

Medical Research Council (MRC) Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.

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.
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http://dx.doi.org/10.1016/j.healthplace.2020.102490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883217PMC
January 2021

Experience of point-of-care HbA1c testing in the English National Health Service Diabetes Prevention Programme: an observational study.

BMJ Open Diabetes Res Care 2020 12;8(2)

Division of Metabolism, Digestion & Reproduction, Faculty of Medicine, Imperial College London, London, UK.

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.
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http://dx.doi.org/10.1136/bmjdrc-2020-001703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737024PMC
December 2020
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