| 1. |
- Atabaki Pasdar, Naeimeh, et al.
(author)
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Predicting and elucidating the etiology of fatty liver disease: A machine learning modeling and validation study in the IMI DIRECT cohorts
- 2020
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In: PLoS Medicine. - San Francisco : Public Library of Science (PLoS). - 1549-1676 .- 1549-1277. ; 17:6, s. 1003149-1003149
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Journal article (peer-reviewed)abstract
- BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in individuals with and without type 2 diabetes (T2D). Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and, ultimately, hepatocellular carcinomas. We sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning. METHODS AND FINDINGS: We utilized the baseline data from IMI DIRECT, a multicenter prospective cohort study of 3,029 European-ancestry adults recently diagnosed with T2D (n = 795) or at high risk of developing the disease (n = 2,234). Multi-omics (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI-image-derived liver fat content (
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| 2. |
- Bergwall, Sara, et al.
(author)
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Leisure-time physical activities and the risk of cardiovascular mortality in the Malmö diet and Cancer study
- 2021
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In: BMC Public Health. - : Springer Science and Business Media LLC. - 1471-2458. ; 21:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: The association between leisure-time physical activity and cardiovascular mortality has been previously studied, but few studies have focused on specific activities and intensities.METHODS: The association between different leisure-time physical activities and cardiovascular mortality was investigated among 25,876 individuals without diabetes or cardiovascular disease from the population-based Malmö Diet and Cancer Study cohort. The individuals estimated the average duration spent on 17 physical activities at baseline in 1991-1996 and after 5 years. Cardiovascular mortality was obtained from a register during a mean of 20 years of follow-up.RESULTS: A total leisure-time physical activity of 15-25 metabolic equivalent task (MET) hours/week was associated with a decreased risk of cardiovascular mortality (HR 15-25 vs < 7.5 MET-h/week =0.80, 95% CI 0.69-0.93), with no further risk reduction at higher levels. Several high-intensity activities (i.e., lawn tennis and running) and moderate-intensity activities (i.e., golf, cycling and gardening) were associated with a reduced risk. Individuals who engaged in high-intensity physical activity for an average of 2.29 MET h/week (30 min/week) had an 18% (95% CI 0.72-0.93) reduced risk of cardiovascular mortality compared with non-participants, and no further risk reductions were observed at higher levels. Decreased risk was observed among individuals who had started (HR 0.56, 95% CI 0.32-0.97) or continued (HR 0.49, 95% CI 0.36-0.66) high-intensity activities at the five-year follow-up.CONCLUSIONS: Moderate- and high-intensity leisure-time physical activities reduced the risk of cardiovascular mortality. With regard to total leisure-time physical activity, the largest risk reduction was observed for 15-25 MET-h/week (equivalent to walking for approximately 5 h/week).
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| 3. |
- Coral, Daniel E, et al.
(author)
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A phenome-wide comparative analysis of genetic discordance between obesity and type 2 diabetes
- 2023
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In: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 5:2, s. 237-247
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Journal article (peer-reviewed)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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| 4. |
- Herdenberg, Carl, et al.
(author)
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LRIG proteins regulate lipid metabolism via BMP signaling and affect the risk of type 2 diabetes
- 2021
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In: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 4
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Journal article (peer-reviewed)abstract
- Leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins have been implicated as regulators of growth factor signaling; however, the possible redundancy among mammalian LRIG1, LRIG2, and LRIG3 has hindered detailed elucidation of their physiological functions. Here, we show that Lrig-null mouse embryonic fibroblasts (MEFs) are deficient in adipogenesis and bone morphogenetic protein (BMP) signaling. In contrast, transforming growth factor-beta (TGF-β) and receptor tyrosine kinase (RTK) signaling appeared unaltered in Lrig-null cells. The BMP signaling defect was rescued by ectopic expression of LRIG1 or LRIG3 but not by expression of LRIG2. Caenorhabditis elegans with mutant LRIG/sma-10 variants also exhibited a lipid storage defect. Human LRIG1 variants were strongly associated with increased body mass index (BMI) yet protected against type 2 diabetes; these effects were likely mediated by altered adipocyte morphology. These results demonstrate that LRIG proteins function as evolutionarily conserved regulators of lipid metabolism and BMP signaling and have implications for human disease.
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| 5. |
- Johansson, Anna, et al.
(author)
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Components of a healthy diet and different types of physical activity and risk of atherothrombotic ischemic stroke : A prospective cohort study
- 2022
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In: Frontiers in Cardiovascular Medicine. - : Frontiers Media SA. - 2297-055X. ; 9
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Journal article (peer-reviewed)abstract
- Background: Diet and physical activity (PA) are modifiable risk factors thought to influence the risk of ischemic stroke (IS). However, few studies have examined their effect on different subtypes of IS. Aim: To examine components of overall diet quality and different types of PA in relation to the risk of atherothrombotic IS (aIS). Materials and methods: The study population included 23,797 participants (mean age 58 years; 63% women) from the Malmö Diet and Cancer Study cohort. Participants were enrolled between 1991 and 1996 and followed until end of 2016 (median follow-up 21.5 years). Incident aIS events were identified using national registries (total cases 1,937). Measures of PA (total, leisure-time, occupational, and domestic) were assessed using a baseline questionnaire and dietary intakes were estimated using a modified diet history method. Overall diet quality was assessed using a diet quality index. Intake of key food groups and beverages associated with overall diet quality were investigated separately. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariable Cox regression models adjusting for confounders. Results: A high diet quality with high intake of fruit and vegetables, fish and shellfish and low intake of sugar-sweetened beverages and red and processed meat compared to a low diet quality was associated with lower risk of aIS (HR = 0.82, 95% CI = 0.69–0.97; p = 0.015). Leisure-time PA was associated with reduced risk of aIS (HR = 0.95 per SD increase in MET-hours/week, 95% CI = 0.91–0.99; p = 0.028) with null associations observed for total, occupational and domestic PA level. We observed no significant interaction between diet and PA on the risk of aIS. The standardized 20-year risk of aIS among subjects with low leisure-time PA and low diet quality was 8.1% compared to 6.1% among those with high leisure-time PA and high diet quality. Conclusion: Several components of a healthy diet and being physically active may reduce the risk of aIS, however, the absolute risk reduction observed was modest. A high diet quality seemed to have a risk reducing effect regardless of level of PA suggesting that individuals with a sedentary lifestyle may still gain some positive health benefits through a healthy diet.
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| 6. |
- Mutie, Pascal
(author)
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Elucidating causal relationships between energy homeostasis and cardiometabolic outcomes
- 2022
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Doctoral thesis (other academic/artistic)abstract
- Energy metabolism dyshomeostasis is associated with multiple health problems. For example, abundant epidemiological data show that obesity and overweight increase the risk of cardiometabolic diseases and early mortality. Type 2 diabetes (T2D), characterized by chronically elevated blood glucose, is also associated with debilitating complications, high healthcare costs and mortality, with cardiovascular complications accounting for more than half of T2D-related deaths. Prediabetes, which is defined as elevated blood glucose below the diagnostic threshold for T2D, affects approximately 350M people worldwide, with about 35-50% developing T2D within 5 years. Further, non-alcoholic fatty liver disease, a form of ectopic fat deposition as a result of energy imbalance, is associated with increased risk of T2D, CVD and hepatocellular carcinoma. Determination of causal relationships between phenotypes related to positive energy balance and disease outcomes, as well as elucidation of the nature of these relationships, may help inform public health intervention policies. In addition, utilizing big data and machine learning (ML) approaches can improve prediction of outcomes related to excess adiposity both for research purposes and eventual validation and clinical translation. AimsIn paper 1, I set out to summarize observational evidence and further determine the causal relationships between prediabetes and common vascular complications associated with T2D i.e., coronary artery disease (CAD), stroke and renal disease. In paper 2, I studied the association between LRIG1 genetic variants and BMI, T2D and lipid biomarkers. In paper 3, we used ML to identify novel molecular features associated with non-alcoholic fatty liver disease (NAFLD). In paper 4, I elucidate the nature of causal relationships between BMI and cardiometabolic traits and investigate sex differences within the causal framework.ResultsPrediabetes was associated with CAD and stroke but not renal disease in observational analyses, whilst in the causal inference analyses, prediabetes was only associated with CAD. Common LRIG1 variant (rs4856886) was associated with increased BMI and lipid hyperplasia but a decreased risk of T2D. In paper 3, models using common clinical variables showed strong NAFLD prediction ability (ROCAUC = 0.73, p < 0.001); addition of hepatic and glycemic biomarkers and omics data to these models strengthened predictive power (ROCAUC = 0.84, p < 0.001). Finally, there was evidence of non-linearity in the causal effect of BMI on T2D and CAD, biomarkers and blood pressure. The causal effects BMI on CAD were different in men and women, though this difference did no hold after Bonferroni correction. ConclusionWe show that derangements in energy homeostasis are causally associated with increased risk of cardiometabolic outcomes and that early intervention on perturbed glucose control and excess adiposity may help prevent these adverse health outcomes. In addition, effects of novel LRIG1 genetic variants on BMI and T2D might enrich our understanding of lipid metabolism and T2D and thus warrant further investigations. Finally, application of ML to multidimensional data improves prediction of NAFLD; similar approaches could be used in other disease research.
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| 7. |
- Mutie, Pascal, et al.
(author)
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Lifestyle precision medicine : the next generation in type 2 diabetes prevention?
- 2017
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In: BMC Medicine. - : BIOMED CENTRAL LTD. - 1741-7015. ; 15
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Research review (peer-reviewed)abstract
- The driving force behind the current global type 2 diabetes epidemic is insulin resistance in overweight and obese individuals. Dietary factors, physical inactivity, and sedentary behaviors are the major modifiable risk factors for obesity. Nevertheless, many overweight/obese people do not develop diabetes and lifestyle interventions focused on weight loss and diabetes prevention are often ineffective. Traditionally, chronically elevated blood glucose concentrations have been the hallmark of diabetes; however, many individuals will either remain 'prediabetic' or regress to normoglycemia. Thus, there is a growing need for innovative strategies to tackle diabetes at scale. The emergence of biomarker technologies has allowed more targeted therapeutic strategies for diabetes prevention (precision medicine), though largely confined to pharmacotherapy. Unlike most drugs, lifestyle interventions often have systemic health-enhancing effects. Thus, the pursuance of lifestyle precision medicine in diabetes seems rational. Herein, we review the literature on lifestyle interventions and diabetes prevention, describing the biological systems that can be characterized at scale in human populations, linking them to lifestyle in diabetes, and consider some of the challenges impeding the clinical translation of lifestyle precision medicine.
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| 8. |
- Mutie, Pascal M., et al.
(author)
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An investigation of causal relationships between prediabetes and vascular complications
- 2020
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- Prediabetes is a state of glycaemic dysregulation below the diagnostic threshold of type 2 diabetes (T2D). Globally, ~352 million people have prediabetes, of which 35–50% develop full-blown diabetes within five years. T2D and its complications are costly to treat, causing considerable morbidity and early mortality. Whether prediabetes is causally related to diabetes complications is unclear. Here we report a causal inference analysis investigating the effects of prediabetes in coronary artery disease, stroke and chronic kidney disease, complemented by a systematic review of relevant observational studies. Although the observational studies suggest that prediabetes is broadly associated with diabetes complications, the causal inference analysis revealed that prediabetes is only causally related with coronary artery disease, with no evidence of causal effects on other diabetes complications. In conclusion, prediabetes likely causes coronary artery disease and its prevention is likely to be most effective if initiated prior to the onset of diabetes.
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| 9. |
- Mutie, Pascal M., et al.
(author)
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Different domains of self-reported physical activity and risk of type 2 diabetes in a population-based Swedish cohort : the Malmö diet and Cancer study
- 2020
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In: BMC Public Health. - : Springer Science and Business Media LLC. - 1471-2458. ; 20:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: While a dose-response relationship between physical activity and risk of diabetes has been demonstrated, few studies have assessed the relative importance of different measures of physical activity on diabetes risk. The aim was to examine the association between different self-reported measures of physical activity and risk of type 2 diabetes in a prospective cohort study. METHODS: Out of 26,615 adults (45-74 years, 60% women) in the population-based Swedish Malmö Diet and Cancer Study cohort, 3791 type 2 diabetes cases were identified from registers during 17 years of follow-up. Leisure-time (17 activities), occupational and domestic physical activity were assessed through a questionnaire, and these and total physical activity were investigated in relation to type 2 diabetes risk. RESULTS: All physical activity measures showed weak to modest associations with type 2 diabetes risk. The strongest association was found in the lower end of leisure-time physical activity in dose-response analysis at levels approximately below 22 MET-hrs/week (300 min/week) representing around 40% of the population. Compared with the lowest quintile, the moderate leisure-time physical activity category had a 28% (95% CI: 0.71, 0.87) decreased risk of type 2 diabetes. Total physical activity showed a similar, but weaker, association with diabetes risk as to that of leisure-time physical activity. Domestic physical activity was positively and linearly related to diabetes risk, HR = 1.11 (95% CI: 0.99, 1.25) comparing highest to lowest quintile. There was no association between occupational physical activity and diabetes risk. CONCLUSION: A curvilinear association was observed between leisure-time physical activity and risk of diabetes. Beyond a threshold level of approximately 22 MET-hrs/week or 300 min/week, no additional risk reduction was observed with increase in physical activity.
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| 10. |
- Mutie, Pascal M, et al.
(author)
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Investigating the causal relationships between excess adiposity and cardiometabolic health in men and women
- 2023
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 66:2, s. 321-335
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Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS: Excess adiposity is differentially associated with increased risk of cardiometabolic disease in men and women, according to observational studies. Causal inference studies largely assume a linear relationship between BMI and cardiometabolic outcomes, which may not be the case. In this study, we investigated the shapes of the causal relationships between BMI and cardiometabolic diseases and risk factors. We further investigated sex differences within the causal framework.METHODS: To assess causal relationships between BMI and the outcomes, we used two-stage least-squares Mendelian randomisation (MR), with a polygenic risk score for BMI as the instrumental variable. To elucidate the shapes of the causal relationships, we used a non-linear MR fractional polynomial method, and used piecewise MR to investigate threshold relationships and confirm the shapes.RESULTS: BMI was associated with type 2 diabetes (OR 3.10; 95% CI 2.73, 3.53), hypertension (OR 1.53; 95% CI 1.44, 1.62) and coronary artery disease (OR 1.20; 95% CI 1.08, 1.33), but not chronic kidney disease (OR 1.08; 95% CI 0.67, 1.72) or stroke (OR 1.08; 95% CI 0.92, 1.28). The data suggest that these relationships are non-linear. For cardiometabolic risk factors, BMI was positively associated with glucose, HbA1c, triacylglycerol levels and both systolic and diastolic BP. BMI had an inverse causal relationship with total cholesterol, LDL-cholesterol and HDL-cholesterol. The data suggest a non-linear causal relationship between BMI and BP and other biomarkers (p<0.001) except lipoprotein A. The piecewise MR results were consistent with the fractional polynomial results. The causal effect of BMI on coronary artery disease, total cholesterol and LDL-cholesterol was different in men and women, but this sex difference was only significant for LDL-cholesterol after controlling for multiple testing (p<0.001). Further, the causal effect of BMI on coronary artery disease varied by menopause status in women.CONCLUSIONS/INTERPRETATION: We describe the shapes of causal effects of BMI on cardiometabolic diseases and risk factors, and report sex differences in the causal effects of BMI on LDL-cholesterol. We found evidence of non-linearity in the causal effect of BMI on diseases and risk factor biomarkers. Reducing excess adiposity is highly beneficial for health, but there is greater need to consider biological sex in the management of adiposity.
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| 11. |
- Wilman, H. R., et al.
(author)
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Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration
- 2019
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In: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 71:3, s. 594-602
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Journal article (peer-reviewed)abstract
- Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10−8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Lay summary: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.
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