| 21. |
- Berry, Sarah E., et al.
(författare)
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Human postprandial responses to food and potential for precision nutrition
- 2020
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 26:6, s. 964-973
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic responses to food influence risk of cardiometabolic disease, but large-scale high-resolution studies are lacking. We recruited n = 1,002 twins and unrelated healthy adults in the United Kingdom to the PREDICT 1 study and assessed postprandial metabolic responses in a clinical setting and at home. We observed large inter-individual variability (as measured by the population coefficient of variation (s.d./mean, %)) in postprandial responses of blood triglyceride (103%), glucose (68%) and insulin (59%) following identical meals. Person-specific factors, such as gut microbiome, had a greater influence (7.1% of variance) than did meal macronutrients (3.6%) for postprandial lipemia, but not for postprandial glycemia (6.0% and 15.4%, respectively); genetic variants had a modest impact on predictions (9.5% for glucose, 0.8% for triglyceride, 0.2% for C-peptide). Findings were independently validated in a US cohort (n = 100 people). We developed a machine-learning model that predicted both triglyceride (r = 0.47) and glycemic (r = 0.77) responses to food intake. These findings may be informative for developing personalized diet strategies. The ClinicalTrials.gov registration identifier is NCT03479866.
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| 22. |
- Bizzotto, Roberto, et al.
(författare)
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Processes Underlying Glycemic Deterioration in Type 2 Diabetes : An IMI DIRECT Study
- 2021
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 44:2, s. 511-518
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped over 3 years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS), and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA1c deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression. RESULTS: Faster HbA1c progression was independently associated with faster deterioration of OGIS and GS and increasing CLIm; visceral or liver fat, HDL-cholesterol, and triglycerides had further independent, though weaker, roles (R2 = 0.38). A subgroup of patients with a markedly higher progression rate (fast progressors) was clearly distinguishable considering these variables only (discrimination capacity from area under the receiver operating characteristic = 0.94). The proportion of fast progressors was reduced from 56% to 8-10% in subgroups in which only one trait among OGIS, GS, and CLIm was relatively stable (odds ratios 0.07-0.09). T2D polygenic risk score and baseline pancreatic fat, glucagon-like peptide 1, glucagon, diet, and physical activity did not show an independent role. CONCLUSIONS: Deteriorating insulin sensitivity and β-cell function, increasing insulin clearance, high visceral or liver fat, and worsening of the lipid profile are the crucial factors mediating glycemic deterioration of patients with T2D in the initial phase of the disease. Stabilization of a single trait among insulin sensitivity, β-cell function, and insulin clearance may be relevant to prevent progression.
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| 23. |
- Bonander, Carl, et al.
(författare)
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A regression discontinuity analysis of the social distancing recommendations for older adults in Sweden during COVID-19.
- 2022
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Ingår i: European Journal of Public Health. - : Oxford University Press. - 1101-1262 .- 1464-360X. ; 32:5, s. 799-806
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: This paper investigates the impact of a non-mandatory and age-specific social distancing recommendation on isolation behaviors and disease outcomes in Sweden during the first wave of the COVID-19 pandemic (March to July, 2020). The policy stated that people aged 70 years or older should avoid crowded places and contact with people outside the household.METHODS: We used a regression discontinuity design-in combination with self-reported isolation data from COVID Symptom Study Sweden (n = 96,053; age range: 39-79 years) and national register data (age range: 39-100+ years) on severe COVID-19 disease (hospitalization or death, n = 21,804) and confirmed cases (n = 48,984)-to estimate the effects of the policy.RESULTS: Our primary analyses showed a sharp drop in the weekly number of visits to crowded places (-13%) and severe COVID-19 cases (-16%) at the 70-year-threshold. These results imply that the age-specific recommendations prevented approximately 1,800 to 2,700 severe COVID-19 cases, depending on model specification.CONCLUSION: It seems that the non-mandatory, age-specific recommendations helped control COVID-19 disease during the first wave of the pandemic in Sweden, as opposed to not implementing a social distancing policy aimed at older adults. Our study provides empirical data on how populations may react to non-mandatory, age-specific social distancing policies in the face of a novel virus.SUPPLEMENTARY MATERIAL: Online appendix with figures, tables, extra methods and results.
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| 24. |
- Cai, Lina, et al.
(författare)
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Genome-wide association analysis of type 2 diabetes in the EPIC-InterAct study
- 2020
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Ingår i: Scientific Data. - : Nature Publishing Group. - 2052-4463. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 25. |
- Chan, Andrew T., et al.
(författare)
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The COronavirus Pandemic Epidemiology (COPE) Consortium: A Call to Action
- 2020
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Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1538-7755. ; 29:7, s. 1283-1289
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Tidskriftsartikel (refereegranskat)abstract
- The rapid pace of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) pandemic presents challenges to the real-time collection of population-scale data to inform near-term public health needs as well as future investigations. We established the COronavirus Pandemic Epidemiology (COPE) consortium to address this unprecedented crisis on behalf of the epidemiology research community. As a central component of this initiative, we have developed a COVID Symptom Study (previously known as the COVID Symptom Tracker) mobile application as a common data collection tool for epidemiologic cohort studies with active study participants. This mobile application collects information on risk factors, daily symptoms, and outcomes through a user-friendly interface that minimizes participant burden. Combined with our efforts within the general population, data collected from nearly 3 million participants in the United States and United Kingdom are being used to address critical needs in the emergency response, including identifying potential hot spots of disease and clinically actionable risk factors. The linkage of symptom data collected in the app with information and biospecimens already collected in epidemiology cohorts will position us to address key questions related to diet, lifestyle, environmental, and socioeconomic factors on susceptibility to COVID-19, clinical outcomes related to infection, and long-term physical, mental health, and financial sequalae. We call upon additional epidemiology cohorts to join this collective effort to strengthen our impact on the current health crisis and generate a new model for a collaborative and nimble research infrastructure that will lead to more rapid translation of our work for the betterment of public health. ©2020 American Association for Cancer Research.
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| 26. |
- Chikowore, Tinashe, et al.
(författare)
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GWAS transethnic meta-analysis of BMI in similar to 700k individuals reveals novel gene-smoking interaction in African populations
- 2020
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Ingår i: Genetic Epidemiology. - : John Wiley & Sons. - 0741-0395 .- 1098-2272. ; 44:5, s. 475-476
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Sixty two percent of the 1.12 billion obese people globally reside in low‐middle income countries, 77% of which are in Africa. There is paucity of data on gene‐lifestyle interactions associated with the increasing prevalence of obesity among Africans. We hypothesised that gene‐environment interacting (GEI) variants exhibit heterogenous effects on obesity in transethnic meta‐analysis of marginal SNP associations as a result of modification by an unknown exposure that varies across populations.Body mass index (BMI) genome‐wide association study (GWAS) summary statistics for 678,671 individuals representative of the major global ancestries were aggregated at 21,338,816 SNPs via fixed‐effects meta‐analysis. Lead SNPs attaining genome‐wide significance (P < 5 × 10−8) were tested for heterogeneity in effects between GWAS. Lead SNPs with significant evidence of heterogeneity after Bonferroni correction were then selected for interaction analysis with selected lifestyle factors in an independent AWI‐Gen study of 10,500 African participants. Significant interaction findings were then replicated in 3,177 individuals of African ancestry in the UK Biobank.Of 881 lead SNPs, five had significant heterogenous effects on BMI (P < 5.7 × 10−5). Rs471094, at the CDKAL1 locus had significant interaction with smoking status, which reduced the effect of the BMI raising allele in current smokers (Betaint = −0.949 kg/m2; P int = .002) compared with non‐smokers in AWI‐Gen. This finding was validated in the UK Biobank (Betaint = −1.471 kg/m2, P int = .020; meta‐analysis Betaint = −1.050 kg/m2, P int = .0002). Our results highlight the first gene‐lifestyle interaction on BMI in Africans and demonstrate the utility of transethnic meta‐analysis of GWAS for identifying GEI effects.
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| 27. |
- Chung, Wendy K., et al.
(författare)
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Precision medicine in diabetes : a Consensus Report from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)
- 2020
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 63:9, s. 1671-1693
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Tidskriftsartikel (refereegranskat)abstract
- The convergence of advances in medical science, human biology, data science and technology has enabled the generation of new insights into the phenotype known as ‘diabetes’. Increased knowledge of this condition has emerged from populations around the world, illuminating the differences in how diabetes presents, its variable prevalence and how best practice in treatment varies between populations. In parallel, focus has been placed on the development of tools for the application of precision medicine to numerous conditions. This Consensus Report presents the American Diabetes Association (ADA) Precision Medicine in Diabetes Initiative in partnership with the European Association for the Study of Diabetes (EASD), including its mission, the current state of the field and prospects for the future. Expert opinions are presented on areas of precision diagnostics and precision therapeutics (including prevention and treatment) and key barriers to and opportunities for implementation of precision diabetes medicine, with better care and outcomes around the globe, are highlighted. Cases where precision diagnosis is already feasible and effective (i.e. monogenic forms of diabetes) are presented, while the major hurdles to the global implementation of precision diagnosis of complex forms of diabetes are discussed. The situation is similar for precision therapeutics, in which the appropriate therapy will often change over time owing to the manner in which diabetes evolves within individual patients. This Consensus Report describes a foundation for precision diabetes medicine, while highlighting what remains to be done to realise its potential. This, combined with a subsequent, detailed evidence-based review (due 2022), will provide a roadmap for precision medicine in diabetes that helps improve the quality of life for all those with diabetes.
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| 28. |
- Chung, Wendy K., et al.
(författare)
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Precision Medicine in Diabetes : A Consensus Report From the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)
- 2020
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 43:7, s. 1617-1635
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Forskningsöversikt (refereegranskat)abstract
- The convergence of advances in medical science, human biology, data science, and technology has enabled the generation of new insights into the phenotype known as "diabetes." Increased knowledge of this condition has emerged from populations around the world, illuminating the differences in how diabetes presents, its variable prevalence, and how best practice in treatment varies between populations. In parallel, focus has been placed on the development of tools for the application of precision medicine to numerous conditions. This Consensus Report presents the American Diabetes Association (ADA) Precision Medicine in Diabetes Initiative in partnership with the European Association for the Study of Diabetes (EASD), including its mission, the current state of the field, and prospects for the future. Expert opinions are presented on areas of precision diagnostics and precision therapeutics (including prevention and treatment), and key barriers to and opportunities for implementation of precision diabetes medicine, with better care and outcomes around the globe, are highlighted. Cases where precision diagnosis is already feasible and effective (i.e., monogenic forms of diabetes) are presented, while the major hurdles to the global implementation of precision diagnosis of complex forms of diabetes are discussed. The situation is similar for precision therapeutics, in which the appropriate therapy will often change over time owing to the manner in which diabetes evolves within individual patients. This Consensus Report describes a foundation for precision diabetes medicine, while highlighting what remains to be done to realize its potential. This, combined with a subsequent, detailed evidence-based review (due 2022), will provide a roadmap for precision medicine in diabetes that helps improve the quality of life for all those with diabetes.
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| 29. |
- Coral, Daniel
(författare)
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Characterisation of the genetic discordance between body mass index and type 2 diabetes: a phenome-wide analysis : No 111
- 2020
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 63
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Konferensbidrag (refereegranskat)abstract
- Background and aims: Obesity is on the rise globally, and is a leading risk factor for T2D. However, it is very heterogeneous, with varying degrees of T2D risk within the same levels of BMI. Better classification may lead to improve outcomes of current preventive and therapeutic strategies. Moreover, by elucidating the mechanisms uncoupling obesity from T2D risk, new possible therapeutic targets may emerge. Leveraging the vast amount of genetic data produced to date may contribute to reach these goals while overcoming the obstacles imposed by common assumptions, biases and confounders present in observational studies. Our aim is to compare the phenome-wide association patterns of BMI-increasing genetic profiles that either concordantly increase or discordantly decrease T2D risk. Materials and methods: Highly concordant and highly discordant SNPs between BMI and T2D were obtained from the latest GWAS for both conditions. Their standardized effect sizes (SES) across multiple traits in the phenome, metabolome, proteinome and transcriptome were retrieved from the online genomic repositories. After alignment to the BMI-increasing allele, these effects were organized into a SNP x Trait matrix. A hierarchical clustering technique, combining PCA and Random Forest algorithms was applied, retrieving the optimal number of clusters of traits, organized in order of importance, useful to distinguish a discordant from a concordant SNP. Posterior probabilities of colocalization with T2D were calculated for each gene using transcriptome results. Tissue, biological process, molecular mechanism and cellular component enrichments were evaluated. The predictive potential of GRSs informed by these findings were assessed in the UK Biobank dataset. Results: 121 SNPs were found to be significantly associated with BMI and T2D. 18 were discordant and 104 concordant. A total of 1372 variables were included in the analyses (Phenome = 546, Metabolome = 233, Proteinome = 593). The most important difference between discordant and concordant SNPs in the phenome matrix was found in a cluster of traits led by hypertension (Mean discordant SES = -1.59, Mean concordant SES = 2.56), highly correlated with two clusters led by coronary heart disease and overall health status, respectively. The second most important cluster was led by physical activity-adjusted WHR (Mean discordant SES = -2.69, Mean concordant SES = 0.24). The model obtained from the phenome matrix had the highest classification performance (Matthews Correlation Coefficient, MCC = 0.79). Metabolome results showed differences in polyunsaturated fatty acids and lipid contents in VLDL, but with lower performance (MCC = 0.67). The model from the proteinome matrix was unable to correctly classify SNPs (MCC = -0.03). Two genes (CCDC92 and DNAH10) showed the strongest association within the discordant set in adipose tissue, both involved in cilia formation. A GRS of these 121 SNPs with weights derived from the clusters with high classification performance was highly associated with T2D in both the general and obese populations in UK Biobank (p < 1x1016). Conclusion: The main difference between BMI-increasing genetic profiles that either discordantly decrease or concordantly increase T2D risk is found in hypertension risk and physical activity-adjusted WHR. These traits can be used to inform GRSs to better classify T2D risk in obesity. Molecular mechanisms behind the discordant profile appear to involve cilia formation in the adipose tissue.
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| 30. |
- Coral, Daniel E, et al.
(författare)
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A phenome-wide comparative analysis of genetic discordance between obesity and type 2 diabetes
- 2023
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Ingår i: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 5:2, s. 237-247
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Tidskriftsartikel (refereegranskat)abstract
- Obesity and type 2 diabetes are causally related, yet there is considerable heterogeneity in the consequences of both conditions and the mechanisms of action are poorly defined. Here we show a genetic-driven approach defining two obesity profiles that convey highly concordant and discordant diabetogenic effects. We annotate and then compare association signals for these profiles across clinical and molecular phenotypic layers. Key differences are identified in a wide range of traits, including cardiovascular mortality, fat distribution, liver metabolism, blood pressure, specific lipid fractions and blood levels of proteins involved in extracellular matrix remodelling. We find marginal differences in abundance of Bacteroidetes and Firmicutes bacteria in the gut. Instrumental analyses reveal prominent causal roles for waist-to-hip ratio, blood pressure and cholesterol content of high-density lipoprotein particles in the development of diabetes in obesity. We prioritize 17 genes from the discordant signature that convey protection against type 2 diabetes in obesity, which may represent logical targets for precision medicine approaches.
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