| 1. |
- van de Luitgaarden, Inge A T, et al.
(författare)
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Alcohol consumption in relation to cardiovascular diseases and mortality : a systematic review of Mendelian randomization studies
- 2022
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 37:7, s. 655-669
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Forskningsöversikt (refereegranskat)abstract
- The causal effects of alcohol-in-moderation on cardiometabolic health are continuously debated. Mendelian randomization (MR) is an established method to address causal questions in observational studies. We performed a systematic review of the current evidence from MR studies on the association between alcohol consumption and cardiometabolic diseases, all-cause mortality and cardiovascular risk factors. We performed a systematic search of the literature, including search terms on type of design and exposure. We assessed methodological quality based on key elements of the MR design: use of a full instrumental variable analysis and validation of the three key MR assumptions. We additionally looked at exploration of non-linearity. We reported the direction of the studied associations. Our search yielded 24 studies that were eligible for inclusion. A full instrumental variable analysis was performed in 17 studies (71%) and 13 out of 24 studies (54%) validated all three key assumptions. Five studies (21%) assessed potential non-linearity. In general, null associations were reported for genetically predicted alcohol consumption with the primary outcomes cardiovascular disease (67%) and diabetes (75%), while the only study on all-cause mortality reported a detrimental association. Considering the heterogeneity in methodological quality of the included MR studies, it is not yet possible to draw conclusions on the causal role of moderate alcohol consumption on cardiometabolic health. As MR is a rapidly evolving field, we expect that future MR studies, especially with recent developments regarding instrument selection and non-linearity methodology, will further substantiate this discussion.
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| 2. |
- Oort, Sabine van, et al.
(författare)
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Modifiable lifestyle factors and heart failure : A Mendelian randomization study
- 2020
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 227, s. 64-73
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Tidskriftsartikel (refereegranskat)abstract
- Background Lifestyle factors may be important targets in the prevention of heart failure. The current knowledge on the relationship between lifestyle factors and heart failure originates mostly from observational studies. The objective of this study was to investigate causal associations of multiple lifestyle factors with heart failure risk by using Mendelian randomization. Methods We obtained summary statistics data for single nucleotide polymorphisms associated with the following 5 lifestyle factors at genome-wide significance in genome-wide association studies of European-descent individuals: smoking, alcohol consumption, coffee consumption, physical activity, and sleep duration. The corresponding data for heart failure were acquired from a genome-wide association study comprising 47,309 cases and 930,014 controls of European ancestry. For the primary analyses, we used the inverse-variance weighted method. Results Genetic predisposition to smoking initiation (ever smoked regularly) was robustly associated with a higher odds of heart failure (odds ratio: 1.28; 99% CI: 1.21-1.35). Genetically predicted longer sleep duration was associated with a lower odds of heart failure (odds ratio per hour/day: 0.73; 99% CI: 0.60-0.89). We found no associations of alcohol consumption, coffee consumption, and physical activity with heart failure. Conclusions This Mendelian randomization study showed that smoking initiation increases heart failure risk, whereas longer sleep duration decreases the risk of heart failure. Sleep duration should be regarded as novel risk factor in heart failure prevention guidelines. The potential causal role of alcohol and coffee consumption and physical activity for heart failure warrants further investigation in future larger Mendelian randomization analyses.
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| 3. |
- van Oort, Sabine, et al.
(författare)
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Association of Cardiovascular Risk Factors and Lifestyle Behaviors With Hypertension : A Mendelian Randomization Study
- 2020
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Ingår i: Hypertension. - 0194-911X .- 1524-4563. ; 76:6, s. 1971-1979
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Tidskriftsartikel (refereegranskat)abstract
- Hypertension is a major risk factor for cardiovascular disease and mortality. To identify targets for the prevention of hypertension and its associated disease burden, we used the 2-sample Mendelian randomization method to investigate the causal associations of 18 cardiovascular risk factors and lifestyle behaviors with hypertension. From European-descent genome-wide association studies, we selected genetic variants (P<5×10−8) for type 2 diabetes, fasting glucose, lipids, body mass index, smoking, alcohol and coffee consumption, physical activity, sleep duration, insomnia, and educational level. We extracted the genetic associations with hypertension from 2 European cohorts: the FinnGen Study (15 870 cases and 74 345 controls) and UK Biobank (54 358 cases and 408 652 controls). The inverse-variance weighted method was used as main analysis method. Genetically predicted triglycerides (pooled odds ratio [OR] per 1 SD, 1.17 [1.10–1.25]), body mass index (OR per 1 SD, 1.42 [1.37–1.48]), alcohol dependence (OR, 1.10 [1.06–1.13]), and insomnia (OR, 1.17 [1.13–1.20]) were associated with a higher odds of hypertension. Higher genetically predicted high-density lipoprotein cholesterol (OR per 1 SD, 0.88 [0.83–0.94]) and educational level (OR per 1 SD, 0.56 [0.54–0.59]) were associated with a lower odds of hypertension. Suggestive evidence was obtained for type 2 diabetes, smoking initiation and alcohol consumption with a higher hypertension odds, and longer sleep duration with a lower hypertension odds. This Mendelian randomization study identified high-density lipoprotein cholesterol, triglycerides, body mass index, alcohol dependence, insomnia, and educational level as causal risk factors for hypertension. This implicates that these modifiable risk factors are important targets in the prevention of hypertension.
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| 4. |
- van Oort, Sabine, et al.
(författare)
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Cardiovascular risk factors and lifestyle behaviours in relation to longevity : a Mendelian randomization study.
- 2020
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 289:2, s. 232-243
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The American Heart Association introduced the Life's Simple 7 initiative to improve cardiovascular health by modifying cardiovascular risk factors and lifestyle behaviours. It is unclear whether these risk factors are causally associated with longevity.OBJECTIVES: This study aimed to investigate causal associations of Life's Simple 7 modifiable risk factors, as well as sleep and education, with longevity using the two-sample Mendelian randomization design.METHODS: Instrumental variables for the modifiable risk factors were obtained from large-scale genome-wide association studies. Data on longevity beyond the 90th survival percentile were extracted from a genome-wide association meta-analysis with 11,262 cases and 25,483 controls whose age at death or last contact was ≤ the 60th survival percentile.RESULTS: Risk factors associated with a lower odds of longevity included the following: genetic liability to type 2 diabetes (OR 0.88; 95% CI: 0.84;0.92), genetically predicted systolic and diastolic blood pressure (per 1-mmHg increase: 0.96; 0.94;0.97 and 0.95; 0.93;0.97), body mass index (per 1-SD increase: 0.80; 0.74;0.86), low-density lipoprotein cholesterol (per 1-SD increase: 0.75; 0.65;0.86) and smoking initiation (0.75; 0.66;0.85). Genetically increased high-density lipoprotein cholesterol (per 1-SD increase: 1.23; 1.08;1.41) and educational level (per 1-SD increase: 1.64; 1.45;1.86) were associated with a higher odds of longevity. Fasting glucose and other lifestyle factors were not significantly associated with longevity.CONCLUSION: Most of the Life's Simple 7 modifiable risk factors are causally related to longevity. Prevention strategies should focus on modifying these risk factors and reducing education inequalities to improve cardiovascular health and longevity.
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| 5. |
- Allesøe, Rosa Lundbye, et al.
(författare)
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Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models
- 2023
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Ingår i: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 41:3, s. 399-408
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Tidskriftsartikel (refereegranskat)abstract
- The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.
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| 6. |
- Atabaki-Pasdar, Naeimeh, et al.
(författare)
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Inferring causal pathways between metabolic processes and liver fat accumulation: an IMI DIRECT study
- 2021
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) often co-occur. Defining causal pathways underlying this relationship may help optimize the prevention and treatment of both diseases. Thus, we assessed the strength and magnitude of the putative causal pathways linking dysglycemia and fatty liver, using a combination of causal inference methods.Measures of glycemia, insulin dynamics, magnetic resonance imaging (MRI)-derived abdominal and liver fat content, serological biomarkers, lifestyle, and anthropometry were obtained in participants from the IMI DIRECT cohorts (n=795 with new onset T2D and 2234 individuals free from diabetes). UK Biobank (n=3641) was used for modelling and replication purposes. Bayesian networks were employed to infer causal pathways, with causal validation using two-sample Mendelian randomization.Bayesian networks fitted to IMI DIRECT data identified higher basal insulin secretion rate (BasalISR) and MRI-derived excess visceral fat (VAT) accumulation as the features of dysmetabolism most likely to cause liver fat accumulation; the unconditional probability of fatty liver (>5%) increased significantly when conditioning on high levels of BasalISR and VAT (by 23%, 32% respectively; 40% for both). Analyses in UK Biobank yielded comparable results. MR confirmed most causal pathways predicted by the Bayesian networks.Here, BasalISR had the highest causal effect on fatty liver predisposition, providing mechanistic evidence underpinning the established association of NAFLD and T2D. BasalISR may represent a pragmatic biomarker for NAFLD prediction in clinical practice.Competing Interest StatementHR is an employee and shareholder of Sanofi. MIM: The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. MIM has served on advisory panels for Pfizer, NovoNordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, MIM is an employee of Genentech, and a holder of Roche stock. AM is a consultant for Lilly and has received research grants from several diabetes drug companies. PWF has received research grants from numerous diabetes drug companies and fess as consultant from Novo Nordisk, Lilly, and Zoe Global Ltd. He is currently the Scientific Director in Patient Care at the Novo Nordisk Foundation. Other authors declare non competing interests.Funding StatementThe work leading to this publication has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement 115317 (DIRECT) resources of which are composed of financial contribution from the European Union Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. NAP is supported in part by Henning och Johan Throne-Holsts Foundation, Hans Werthen Foundation, an IRC award from the Swedish Foundation for Strategic Research and a European Research Council award ERC-2015-CoG - 681742_NASCENT. HPM is supported by an IRC award from the Swedish Foundation for Strategic Research and a European Research Council award ERC-2015-CoG - 681742_NASCENT. AGJ is supported by an NIHR Clinician Scientist award (17/0005624). RK is funded by the Novo Nordisk Foundation (NNF18OC0031650) as part of a postdoctoral fellowship, an IRC award from the Swedish Foundation for Strategic Research and a European Research Council award ERC-2015-CoG - 681742_NASCENT. AK, PM, HF, JF and GNG are supported by an IRC award from the Swedish Foundation for Strategic Research and a European Research Council award ERC-2015-CoG - 681742_NASCENT. TJM is funded by an NIHR clinical senior lecturer fellowship. S.Bru acknowledges support from the Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001). ATH is a Wellcome Trust Senior Investigator and is also supported by the NIHR Exeter Clinical Research Facility. JMS acknowledges support from Science for Life Laboratory (Plasma Profiling Facility), Knut and Alice Wallenberg Foundation (Human Protein Atlas) and Erling-Persson Foundation (KTH Centre for Precision Medicine). MIM is supported by the following grants; Wellcome (090532, 098381, 106130, 203141, 212259); NIH (U01-DK105535). PWF is supported by an IRC award from the Swedish Foundation for Strategic Research and a European Research Council award ERC-2015-CoG - 681742_NASCENT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Approval for the study protocol was obtained from each of the regional research ethics review boards separately (Lund, Sweden: 20130312105459927, Copenhagen, Denmark: H-1-2012-166 and H-1-2012-100, Amsterdam, Netherlands: NL40099.029.12, Newcastle, Dundee and Exeter, UK: 12/NE/0132), and all participants provided written informed consent at enrolment. The research conformed to the ethical principles for medical research involving human participants outlined in the Declaration of Helsinki.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAuthors agree to make data and materials supporting the results or analyses presented in their paper available upon reasonable request
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| 7. |
- Menichetti, Lorenzo, et al.
(författare)
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Increase in soil stable carbon isotope ratio relates to loss of organic carbon : results from five long-term bare fallow experiments
- 2015
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Ingår i: Oecologia. - New York : Springer Verlag. - 0029-8549 .- 1432-1939. ; 177:3, s. 811-821
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Tidskriftsartikel (refereegranskat)abstract
- Changes in the 12C/13C ratio (expressed as δ13C) of soil organic C (SOC) has been observed over long time scales and with depth in soil profiles. The changes are ascribed to the different reaction kinetics of 12C and 13C isotopes and the different isotopic composition of various SOC pool components. However, experimental verification of the subtle isotopic shifts associated with SOC turnover under field conditions is scarce. We determined δ13C and SOC in soil sampled during 1929–2009 in the Ap-horizon of five European long-term bare fallow experiments kept without C inputs for 27–80 years and covering a latitudinal range of 11°. The bare fallow soils lost 33–65 % of their initial SOC content and showed a mean annual δ13C increase of 0.008–0.024 ‰. The 13C enrichment could be related empirically to SOC losses by a Rayleigh distillation equation. A more complex mechanistic relationship was also examined. The overall estimate of the fractionation coefficient (ε) was −1.2 ± 0.3 ‰. This coefficient represents an important input to studies of long-term SOC dynamics in agricultural soils that are based on variations in 13C natural abundance. The variance of ε may be ascribed to site characteristics not disclosed in our study, but the very similar kinetics measured across our five experimental sites suggest that overall site-specific factors (including climate) had a marginal influence and that it may be possible to isolate a general mechanism causing the enrichment, although pre-fallow land use may have some impact on isotope abundance and fractionation.
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