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- 2019
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Mahajan, Anubha, et al.
(författare)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Tidskriftsartikel (refereegranskat)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 3. |
- Birney, Ewan, et al.
(författare)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Tidskriftsartikel (refereegranskat)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 4. |
- Wessel, Jennifer, et al.
(författare)
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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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| 5. |
- Ademuyiwa, Adesoji O., et al.
(författare)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 6. |
- Ivanics, Tommy, et al.
(författare)
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Outcomes after liver transplantation using deceased after circulatory death donors : A comparison of outcomes in the UK and the US
- 2023
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Ingår i: Liver international. - : Wiley-Blackwell. - 1478-3223 .- 1478-3231. ; 43:5, s. 1107-1119
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Identifying international differences in utilization and outcomes of liver transplantation (LT) after donation after circulatory death (DCD) donation provides a unique opportunity for benchmarking and population-level insight.Methods: Adult (>= 18 years) LT data between 2008 and 2018 from the UK and US were used to assess mortality and graft failure after DCD LT. We used time-dependent Cox-regression methods to estimate hazard ratios (HR) for risk-adjusted short-term (0-90 days) and longer-term (90 days-5 years) outcomes.Results: One-thousand five-hundred-and-sixty LT receipts from the UK and 3426 from the US were included. Over the study period, the use of DCD livers increased from 15.7% to 23.9% in the UK compared to 5.1% to 7.6% in the US. In the UK, DCD donors were older (UK:51 vs. US:33 years) with longer cold ischaemia time (UK: 437 vs. US: 333 min). Recipients in the US had higher Model for End-stage Liver Disease (MELD) scores, higher body mass index, higher proportions of ascites, encephalopathy, diabetes and previous abdominal surgeries. No difference in the risk-adjusted short-term mortality or graft failure was observed between the countries. In the longer-term (90 days-5 years), the UK had lower mortality and graft failure (adj.mortality HR:UK: 0.63 (95% CI: 0.49-0.80); graft failure HR: UK: 0.72, 95% CI: 0.58-0.91). The cumulative incidence of retransplantation was higher in the UK (5 years: UK: 11.9% vs. 4.6%; p < .001).Conclusions: For those receiving a DCD LT, longer-term post-transplant outcomes in the UK are superior to the US, however, significant differences in recipient illness, graft quality and access to retransplantation were seen between the two countries.
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| 7. |
- Benson, Tyler W, et al.
(författare)
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Glycoprotein VI is Critical for the Detection and Progression of Abdominal Aortic Aneurysms.
- 2023
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Ingår i: bioRxiv : the preprint server for biology.
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Tidskriftsartikel (refereegranskat)abstract
- UNLABELLED: A common feature in patients with abdominal aortic aneurysms (AAA) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation impacts the pathogenesis of AAA. Using RNA-sequencing, we identify that the platelet-associated transcripts are significantly enriched in the ILT compared to the adjacent aneurysm wall and healthy control aortas. We found that the platelet specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of AAA patients. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in two independent AAA patient cohorts is highly predictive of a AAA diagnosis and associates more strongly with aneurysm growth rate when compared to D-dimer in humans. Finally, intervention with the anti-GPVI antibody (J) in mice with established aneurysms blunted the progression of AAA in two independent mouse models. In conclusion, we show that levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, where none currently exist.KEY POINTS: Soluble glycoprotein VI, which is a platelet-derived blood biomarker, predicts a diagnosis of AAA, with high sensitivity and specificity in distinguishing patients with fast from slow-growing AAA.Blockade of glycoprotein VI in mice with established aneurysms reduces AAA progression and mortality, indicating therapeutic potential.
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| 8. |
- Benson, Tyler W., et al.
(författare)
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Soluble glycoprotein VI predicts abdominal aortic aneurysm growth rate and is a novel therapeutic target
- 2024
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020.
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Tidskriftsartikel (refereegranskat)abstract
- A common feature in patients with abdominal aortic aneurysms (AAAs) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA-associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation affects the pathogenesis of AAA. Using RNA sequencing, we identified that the platelet-associated transcripts are significantly enriched in the ILT compared with the adjacent aneurysm wall and healthy control aortas. We found that the platelet-specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of patients with AAAs. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in 2 independent cohorts of patients with AAAs is highly predictive of an AAA diagnosis and associates more strongly with aneurysm growth rate than D-dimer in humans. Finally, intervention with the anti-GPVI antibody (JAQ1) in mice with established aneurysms blunted the progression of AAA in 2 independent mouse models. In conclusion, we show that the levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, for which none currently exists.
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| 9. |
- Bowes, Heather M, et al.
(författare)
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Scaling the peak and steady-state aerobic power of running and walking humans.
- 2021
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Ingår i: European Journal of Applied Physiology. - : Springer Nature. - 1439-6319 .- 1439-6327. ; 121:10, s. 2925-2938
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The first aim of this experiment was to evaluate the appropriateness of linear and non-linear (allometric) models to scale peak aerobic power (oxygen consumption) against body mass. The possibilities that oxygen consumption would scale allometrically across the complete metabolic range, and that the scaling exponents would differ significantly between basal and maximal-exercise states, were then evaluated. It was further hypothesised that the scaling exponent would increase in a stepwise manner with elevations in exercise intensity. Finally, the utility of applying the scaling exponent derived for peak aerobic power to another population sample was evaluated.METHODS: Basal, steady-state walking and peak (treadmill) oxygen-consumption data were measured using 60 relatively homogeneous men (18-40 year; 56.0-117.1 kg), recruited across five mass classes. Linear and allometric regressions were applied, with the utility of each scaling method evaluated.RESULTS: Oxygen consumption scaled allometrically with body mass across the complete metabolic range, and was always superior to both ratiometric analysis and linear regression. The scaling exponent increased significantly from rest (mass0.57) to maximal exercise (mass0.75; P < 0.05), but not between steady-state walking (mass0.87) and maximal exercise (P > 0.05). When used with an historical database, the maximal-exercise exponent successfully removed the mass bias.CONCLUSION: It has been demonstrated that the oxygen consumption of healthy humans scales allometrically with body mass across the entire metabolic range. Moreover, only two scaling exponents (rest and exercise) were required to produce mass-independent outcomes from those data. Accordingly, ratiometric and linear regression analyses are not recommended as scaling methods.
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| 10. |
- Bowes, Heather M., et al.
(författare)
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The scaling of human basal and resting metabolic rates
- 2021
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Ingår i: European Journal of Applied Physiology. - : Springer Science and Business Media LLC. - 1439-6319 .- 1439-6327. ; 121:1
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: In tachymetabolic species, metabolic rate increases disproportionately with body mass, and that inter-specific relationship is typically modelled allometrically. However, intra-specific analyses are less common, particularly for healthy humans, so the possibility that human metabolism would also scale allometrically was investigated.METHODS: Basal metabolic rate was determined (respirometry) for 68 males (18-40 years; 56.0-117.1 kg), recruited across five body-mass classes. Data were collected during supine, normothermic rest from well-rested, well-hydrated and post-absorptive participants. Linear and allometric regressions were applied, and three scaling methods were assessed. Data from an historical database were also analysed (2.7-108.9 kg, 4811 males; 2.0-96.4 kg, 2364 females).RESULTS: Both linear and allometric functions satisfied the statistical requirements, but not the biological pre-requisite of an origin intercept. Mass-independent basal metabolic data beyond the experimental mass range were not achieved using linear regression, which yielded biologically impossible predictions as body mass approached zero. Conversely, allometric regression provided a biologically valid, powerful and statistically significant model: metabolic rate = 0.739 * body mass0.547 (P < 0.05). Allometric analysis of the historical male data yielded an equivalent, and similarly powerful model: metabolic rate = 0.873 * body mass0.497 (P < 0.05).CONCLUSION: It was established that basal and resting metabolic rates scale allometrically with body mass in humans from 10-117 kg, with an exponent of 0.50-0.55. It was also demonstrated that ratiometric scaling yielded invalid metabolic predictions, even within the relatively narrow experimental mass range. Those outcomes have significant physiological implications, with applications to exercising states, modelling, nutrition and metabolism-dependent pharmacological prescriptions.
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