| 1. |
- Surendran, Praveen, et al.
(författare)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 2. |
- Erzurumluoglu, A. Mesut, et al.
(författare)
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Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
- 2020
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:10, s. 2392-2409
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Tidskriftsartikel (refereegranskat)abstract
- Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
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| 3. |
- Behravesh, Masoud, et al.
(författare)
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A prospective study of the relationships between movement and glycemic control during day and night in pregnancy
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Both disturbed sleep and lack of exercise can disrupt metabolism in pregnancy. Accelerometery was used to objectively assess movement during waking (physical activity) and movement during sleeping (sleep disturbance) periods and evaluated relationships with continuous blood glucose variation during pregnancy. Data was analysed prospectively. 15-women without pre-existing diabetes mellitus wore continuous glucose monitors and triaxial accelerometers from February through June 2018 in Sweden. The relationships between physical activity and sleep disturbance with blood glucose rate of change were assessed. An interaction term was fitted to determine difference in the relationship between movement and glucose variation, conditional on waking/sleeping. Total movement was inversely related to glucose rate of change (p < 0.001, 95% CI (− 0.037, − 0.026)). Stratified analyses showed total physical activity was inversely related to glucose rate of change (p < 0.001, 95% CI (− 0.040, − 0.028)), whereas sleep disturbance was not related to glucose rate of change (p = 0.07, 95% CI (< − 0.001, 0.013)). The interaction term was positively related to glucose rate of change (p < 0.001, 95% CI (0.029, 0.047)). This study provides temporal evidence of a relationship between total movement and glycemic control in pregnancy, which is conditional on time of day. Movement is beneficially related with glycemic control while awake, but not during sleep.
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| 4. |
- Varga, Tibor V, et al.
(författare)
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Acute and Long-Term Changes in Blood-Borne Biomarkers in Response to Dynamic Standing in Nonambulant Children With Cerebral Palsy
- 2024
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Ingår i: Pediatric Exercise Science. - Champaign, IL : Human Kinetics. - 0899-8493 .- 1543-2920. ; 36:1, s. 15-22
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To investigate acute and long-term changes in hormonal and inflammatory biomarkers in nonambulant children with cerebral palsy in response to dynamic standing exercise.Methods: Fourteen children with severe cerebral palsy were recruited. Anthropometrics and body composition measures were obtained. Physical activity levels before the study were assessed using hip-worn accelerometry. All children underwent a 30-minute dynamic standing exercise using the Innowalk standing aid. Respiratory data during exercise were collected using indirect calorimetry. Blood samples were collected before and after exercise. Blood samples were also obtained after two 16-week exercise protocols, in a resting state. Hormonal and inflammatory metabolites were measured from blood serum/plasma, and acute and long-term changes in biomarker levels were assessed using Wilcoxon signed-rank tests.Results: Of the 14 children at baseline, all had slightly/moderately/severely elevated C-reactive protein and cortisol levels. C-reactive protein levels were decreased following a 30-minute bout of dynamic standing (before exercise: 53 mg/L [interquartile range: 40-201]; after exercise: 39 mg/L [interquartile range: 20-107]; P = .04).Conclusions: We show that several hormonal and inflammatory biomarkers are dysregulated in children with cerebral palsy. Our preliminary results from a small, but deep-phenotyped prospective cohort indicate acute and long-term alterations of several biomarkers in response to exercise. ©2023 The Authors.
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| 5. |
- Varga, Tibor V., et al.
(författare)
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Association is not prediction : A landscape of confused reporting in diabetes – A systematic review
- 2020
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Ingår i: Diabetes Research and Clinical Practice. - : Elsevier BV. - 0168-8227. ; 170
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Appropriate analysis of big data is fundamental to precision medicine. While statistical analyses often uncover numerous associations, associations themselves do not convey predictive value. Confusion between association and prediction harms clinicians, scientists, and ultimately, the patients. We analyzed published papers in the field of diabetes that refer to “prediction” in their titles. We assessed whether these articles report metrics relevant to prediction. Methods: A systematic search was undertaken using NCBI PubMed. Articles with the terms “diabetes” and “prediction” were selected. All abstracts of original research articles, within the field of diabetes epidemiology, were searched for metrics pertaining to predictive statistics. Simulated data was generated to visually convey the differences between association and prediction. Results: The search-term yielded 2,182 results. After discarding non-relevant articles, 1,910 abstracts were evaluated. Of these, 39% (n = 745) reported metrics of predictive statistics, while 61% (n = 1,165) did not. The top reported metrics of prediction were ROC AUC, sensitivity and specificity. Using the simulated data, we demonstrated that biomarkers with large effect sizes and low P values can still offer poor discriminative utility. Conclusions: We demonstrate a landscape of confused reporting within the field of diabetes epidemiology where the term “prediction” is often incorrectly used to refer to association statistics. We propose guidelines for future reporting, and two major routes forward in terms of main analytic procedures and research goals: the explanatory route, which contributes to precision medicine, and the prediction route which contributes to personalized medicine.
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| 6. |
- Varga, Tibor V, et al.
(författare)
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Lipidomic profiles, lipid trajectories and clinical biomarkers in female elite endurance athletes
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- We assessed whether blood lipid metabolites and their changes associate with various cardiometabolic, endocrine, bone- and energy-related comorbidities of Relative Energy Deficiency in Sport (RED-S) in female elite endurance athletes. Thirty-eight Scandinavian female elite athletes underwent a day-long exercise test. Five blood samples were obtained during the day - at fasting state and before and after two standardized exercise tests. Clinical biomarkers were assessed at fasting state, while untargeted lipidomics was undertaken using all blood samples. Linear and logistic regression was used to assess associations between lipidomic features and clinical biomarkers. Overrepresentations of findings with P < 0.05 from these association tests were assessed using Fisher's exact tests. Self-organizing maps and a trajectory clustering algorithm were utilized to identify informative clusters in the population. Twenty associations PFDR < 0.05 were detected between lipidomic features and clinical biomarkers. Notably, cortisol demonstrated an overrepresentation of associations with P < 0.05 compared to other traits (PFisher = 1.9×10-14). Mean lipid trajectories were created for 201 named features for the cohort and subsequently by stratifying participants by their energy availability and menstrual dysfunction status. This exploratory analysis of lipid trajectories indicates that participants with menstrual dysfunction might have decreased adaptive response to exercise interventions.
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| 7. |
- Varga, Tibor V., et al.
(författare)
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Organizational Justice and Long-term Metabolic Trajectories : A 25-Year Follow-up of the Whitehall II Cohort
- 2022
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 107:2, s. 398-409
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Tidskriftsartikel (refereegranskat)abstract
- Context: Organizational justice has been linked to lower risk of several chronic conditions among employees, but less is known about the long-term mechanisms underlying this risk reduction.Objective: To assess whether self-reported organizational justice is associated with individual and composite long-term metabolic trajectories.Design: Twenty-five-year follow-up of the Whitehall II prospective cohort study.Setting: Middle-aged public servants from the United Kingdom.Participants: Data on 8182 participants were used.Main Outcome Measures: Levels of 11 anthropometric, glycemic, lipid, and blood pressure biomarkers were measured at 5 timepoints (1991–2013). We used generalized estimating equations and group-based trajectory modeling to investigate the relationship between organizational justice and biomarker trajectories.Results: High vs low organizational justice were associated with lower waist (−1.7 cm) and hip (−1 cm) circumference, body mass index (−0.6 kg/m2), triglycerides (−1.07 mmol/L), and fasting insulin (−1.08 µIU/mL) trajectories. Two latent metabolic trajectory clusters were identified: a high- and a low-risk cluster. High organizational justice (vs low) were associated with belonging to the low-risk cluster (pooled odds ratio = 1.47). The low-risk cluster demonstrated lower baseline levels of most biomarkers and better glycemic control, whereas the high-risk cluster showed higher baseline levels of most biomarkers, glycemic deterioration, but also greater improvements in lipid levels over time.Conclusions: People with high organizational justice had more favorable long-term cardiometabolic biomarker patterns than those with low organizational justice, indicating a potential mechanism contributing to the lower risk of chronic diseases in the first group. Further intervention studies are warranted to determine whether improvement of organizational justice might improve long-term health.
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| 8. |
- Varga, Tibor V., et al.
(författare)
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Predictive utilities of lipid traits, lipoprotein subfractions and other risk factors for incident diabetes : A machine learning approach in the Diabetes Prevention Program
- 2021
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Ingår i: BMJ Open Diabetes Research and Care. - : BMJ. - 2052-4897. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Although various lipid and non-lipid analytes measured by nuclear magnetic resonance (NMR) spectroscopy have been associated with type 2 diabetes, a structured comparison of the ability of NMR-derived biomarkers and standard lipids to predict individual diabetes risk has not been undertaken in larger studies nor among individuals at high risk of diabetes. Research design and methods Cumulative discriminative utilities of various groups of biomarkers including NMR lipoproteins, related non-lipid biomarkers, standard lipids, and demographic and glycemic traits were compared for short-term (3.2 years) and long-term (15 years) diabetes development in the Diabetes Prevention Program, a multiethnic, placebo-controlled, randomized controlled trial of individuals with pre-diabetes in the USA (N=2590). Logistic regression, Cox proportional hazards model and six different hyperparameter-tuned machine learning algorithms were compared. The Matthews Correlation Coefficient (MCC) was used as the primary measure of discriminative utility. Results Models with baseline NMR analytes and their changes did not improve the discriminative utility of simpler models including standard lipids or demographic and glycemic traits. Across all algorithms, models with baseline 2-hour glucose performed the best (max MCC=0.36). Sophisticated machine learning algorithms performed similarly to logistic regression in this study. Conclusions NMR lipoproteins and related non-lipid biomarkers were associated but did not augment discrimination of diabetes risk beyond traditional diabetes risk factors except for 2-hour glucose. Machine learning algorithms provided no meaningful improvement for discrimination compared with logistic regression, which suggests a lack of influential latent interactions among the analytes assessed in this study. Trial registration number Diabetes Prevention Program: NCT00004992; Diabetes Prevention Program Outcomes Study: NCT00038727.
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| 9. |
- Zheng, Yan, et al.
(författare)
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Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood
- 2020
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 1573-7284 .- 0393-2990. ; 35:7, s. 685-697
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = − 0.76, 95% CI − 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = − 0.06, 95% CI − 0.93 to 0.87 mmHg), or pulse pressure (β = − 0.65, 95% CI − 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses. © 2020, Springer Nature B.V.
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