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- 2019
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 4. |
- de Vries, Paul S., et al.
(författare)
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Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
- 2019
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Ingår i: American Journal of Epidemiology. - : Oxford University Press. - 0002-9262 .- 1476-6256. ; 188:6, s. 1033-1054
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Tidskriftsartikel (refereegranskat)abstract
- A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 x 10(-6)) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 x 10(-8) using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
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- Smith, Caren E., et al.
(författare)
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Genome-Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent
- 2018
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Ingår i: Molecular Nutrition & Food Research. - : Wiley. - 1613-4125. ; 62:3
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Tidskriftsartikel (refereegranskat)abstract
- Scope: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption. Methods and results: A genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction <10−7), and six independent variants (LINC01512-rs7751666, PALM2/AKAP2-rs914359, ACTA2-rs1388, PPP1R12A-rs7961195, LINC00333-rs9635058, AC098847.1-rs1791355) were evaluated meta-analytically for replication of interaction in up to 17 675 individuals. Variant rs9635058 (128 kb 3’ of LINC00333) was replicated (p-interaction = 0.004). In the discovery cohorts, rs9635058 interacted with dairy (p-interaction = 7.36 × 10−8) such that each serving of low-fat dairy was associated with 0.225 kg m−2 lower BMI per each additional copy of the effect allele (A). A second genetic variant (ACTA2-rs1388) approached interaction replication significance for low-fat dairy exposure. Conclusion: Body weight responses to dairy intake may be modified by genotype, in that greater dairy intake may protect a genetic subgroup from higher body weight.
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- Taylor, Carolyn, et al.
(författare)
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Estimating the Risks of Breast Cancer Radiotherapy : Evidence From Modern Radiation Doses to the Lungs and Heart and From Previous Randomized Trials
- 2017
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Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 35:15, s. 1641-1649
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Radiotherapy reduces the absolute risk of breast cancer mortality by a few percentage points in suitable women but can cause a second cancer or heart disease decades later. We estimated the absolute long-term risks of modern breast cancer radiotherapy. Methods First, a systematic literature review was performed of lung and heart doses in breast cancer regimens published during 2010 to 2015. Second, individual patient data meta-analyses of 40,781 women randomly assigned to breast cancer radiotherapy versus no radiotherapy in 75 trials yielded rate ratios (RRs) for second primary cancers and cause-specific mortality and excess RRs (ERRs) per Gy for incident lung cancer and cardiac mortality. Smoking status was unavailable. Third, the lung or heart ERRs per Gy in the trials and the 2010 to 2015 doses were combined and applied to current smoker and nonsmoker lung cancer and cardiac mortality rates in population-based data. Results Average doses from 647 regimens published during 2010 to 2015 were 5.7 Gy for whole lung and 4.4 Gy for whole heart. The median year of irradiation was 2010 (interquartile range [IQR], 2008 to 2011). Meta-analyses yielded lung cancer incidence ≥ 10 years after radiotherapy RR of 2.10 (95% CI, 1.48 to 2.98; P < .001) on the basis of 134 cancers, indicating 0.11 (95% CI, 0.05 to 0.20) ERR per Gy whole-lung dose. For cardiac mortality, RR was 1.30 (95% CI, 1.15 to 1.46; P < .001) on the basis of 1,253 cardiac deaths. Detailed analyses indicated 0.04 (95% CI, 0.02 to 0.06) ERR per Gy whole-heart dose. Estimated absolute risks from modern radiotherapy were as follows: lung cancer, approximately 4% for long-term continuing smokers and 0.3% for nonsmokers; and cardiac mortality, approximately 1% for smokers and 0.3% for nonsmokers. Conclusion For long-term smokers, the absolute risks of modern radiotherapy may outweigh the benefits, yet for most nonsmokers (and ex-smokers), the benefits of radiotherapy far outweigh the risks. Hence, smoking can determine the net effect of radiotherapy on mortality, but smoking cessation substantially reduces radiotherapy risk.
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| 7. |
- Chen, Cheng, et al.
(författare)
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Performance of multiple satellite precipitation estimates over a typical arid mountainous area of China : Spatiotemporal patterns and extremes
- 2020
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Ingår i: Journal of Hydrometeorology. - 1525-755X. ; 21:3, s. 533-550
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Tidskriftsartikel (refereegranskat)abstract
- Precipitation in arid mountainous areas is characterized by low rainfall intensity and large spatial heterogeneity, which challenges satellite-based monitoring by the spaceborne sensors. This study aims to comparatively evaluate the detection ability of spatiotemporal patterns and extremes of rainfall by a range of mainstream satellite precipitation products [TMPA, Climate Hazards Group Infrared Precipitation with Station Data (CHIRPS), and PERSIANN-Climate Data Record (PERSIANN-CDR)] over a typical arid mountainous basin of China, benchmarking against rain gauge data from 2000 to 2015. Results showed that satellite precipitation estimates had relatively low accuracy at the daily scale, while a significant improvement of correlation coefficient (CC;>0.6) and a significant reduction of relative root-mean-square error (RRMSE;, 1.0) were found as time scale increases beyond the monthly scale. CHIRPS tended to overestimate the gauge precipitation with positive relative bias (RB), while the negative RBvalues for TMPAand PERSIANN-CDR indicated there was an underestimation. CHIRPS had the most similar spatial pattern and slope trends of the seasonal precipitation and interannual variations of annual precipitation with gauge observations. With the increase in rainfall rates, the probability of detection (POD) and critical success index (CSI) were reduced and the false alarm ratio (FAR) was increased significantly, demonstrating the limited capability for all the three satellite products for detecting heavy rainfall events. CHIRPS showed the best performance in detecting rainfall extremes compared to TMPA and PERSIANN-CDR, evidenced by the largerCSI values and similar extreme rainfall indices obtained from gauge records. This study provides valuable guidance for choosing satellite precipitation products instead of gauge observations for rainfall monitoring (especially rainfall extremes) and agricultural production management over arid mountainous area.
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| 8. |
- Chen, Cheng, et al.
(författare)
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Triple collocation-based error estimation and data fusion of global gridded precipitation products over the Yangtze River basin
- 2022
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Ingår i: Journal of Hydrology. - : Elsevier BV. - 0022-1694. ; 605
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Tidskriftsartikel (refereegranskat)abstract
- Error estimation and data fusion are critical to improving the accuracy of global model- and satellite-based precipitation products for practical applications. However, they face challenges over vast areas of the world due to limited ground observations. Triple collocation (TC) method can overcome this limitation and provide an efficient way for error estimation without the “ground truth” and thus also for data fusion, by leveraging multi-source observations and model outputs, which have been increasingly available in recent years. In this work, we conducted a comprehensive study on error estimation and data fusion of a number of global gridded precipitation products over the Yangtze River basin from 2015 to 2018 using TC and multiplicative TC (MTC) methods. We use three satellite-based precipitation products such as the IMERG Final (IMERG-F), PERSIANN-CDR (PCDR) and SM2RAIN-ASCAT (SM2R), and one reanalysis dataset ERA5 which contains precipitation estimates. They were grouped into two TC triplets based on different combinations: IMERG-F + SM2R + ERA5 and PCDR + SM2R + ERA5. For performance evaluation, the TC-based error estimation methods were compared to the traditional method using rain gauge data, and the TC-based data fusion methods were compared with two widely-used data fusion methods Bayesian Model Averaging (BMA) and Random Forest based MErging Procedure (RF-MEP). Results showed that ERA5 had the best performance with the largest correlation coefficient (CC, 0.435), while PCDR had the worst accuracy with the smallest CC (0.304) and the largest absolute relative bias (RB, 0.365). TC tended to underestimate the root mean square error (RMSE) with respect to the traditional gauged-based method, but MTC showed a consistent result owing to the employment of a multiplicative error model. The performance of TC-based data fusion methods had no significant difference from BMA and RF-MEP. All data fusion results were better than the original triplets, as the mean CC value increased from 0.38 to 0.47 and the mean RMSE decreased from 15.0 to 13.5 mm/day. In addition, we found that the zero value replacement in MTC had great influence on error estimation, while had limited impacts on data fusion.
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| 9. |
- Guo, Xiaoxian, et al.
(författare)
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Understand the genomic diversity and evolution of fungal pathogen Candida glabrata by genome-wide analysis of genetic variations
- 2020
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Ingår i: Methods. - : Elsevier BV. - 1095-9130 .- 1046-2023. ; 176, s. 82-90
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Tidskriftsartikel (refereegranskat)abstract
- The yeast Candida glabrata, an opportunistic human fungal pathogen, is the second most prevalent cause of candidiasis worldwide, with an infection incidence that has been increasing in the past decades. The completion of the C. glabrata reference genome made fundamental contributions to the understanding of the molecular basis of its pathogenic phenotypes. However, knowledge of genome-wide genetic variations among C. glabrata strains is limited. In this study, we present a population genomic study of C. glabrata based on whole genome re-sequencing of 47 clinical strains to an average coverage of ∼63×. Abundant genetic variations were identified in these strains, including single nucleotide polymorphisms (SNPs), small insertion/deletions (indels) and copy number variations (CNVs). The observed patterns of variations revealed clear population structure of these strains. Using population genetic tests, we detected fast evolution of several genes involved in C. glabrata adherence ability, such as EPA9 and EPA10. We also located genome structural variations, including aneuploidies and large fragment CNVs, in regions that are functionally related to virulence. Subtelometric regions were hotspots of CNVs, which may contribute to variation in expression of adhesin genes that are important for virulence. We further conducted a genome-wide association study that identified two SNPs in the 5′UTR region of CST6 that were associated with fluconazole susceptibility. These observations provide convincing evidence for the highly dynamic nature of the C. glabrata genome with potential adaptive evolution to clinical environments, and offer valuable resources for investigating the mechanisms underlying drug resistance and virulence in this fungal pathogen. (249 words)
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| 10. |
- Han, Fenghui, et al.
(författare)
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Energy analysis and multi-objective optimization of waste heat and cold energy recovery process in LNG-fueled vessels based on a triple organic Rankine cycle
- 2019
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Ingår i: Energy Conversion and Management. - : Elsevier BV. - 0196-8904. ; 195, s. 561-572
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Tidskriftsartikel (refereegranskat)abstract
- Due to the high level of pollutant emissions from traditional marine diesel engines, Liquefied Natural Gas (LNG) as clean energy is becoming a better choice for main engines to replace the traditional fuels. Meanwhile, in order to improve the energy efficiency of the marine power system, the Organic Rankine Cycle (ORC) has been regarded as the most suitable solution to recover the waste heat for the power generation of vessels. In this paper, both the waste heat of the main engine and the cold energy of LNG have been fully considered, and a novel triple ORC process has been proposed for the waste heat and cold energy recovery of LNG-fueled vessels. It adopts the exhaust gas of the main engine and the cooling water from the engine jacket as heat sources, and uses the cold energy of LNG and the sea water as cold sources. Based on the 15 optional working fluid conditions, the heat source utilization rate, system exergy efficiency, net output power, and system cost are, respectively, combined as two objectives, and the multi-objective adaptive firefly algorithm is used to optimize the thermodynamic performance of the system. The optimization results of different heat and cold sources as well as the design parameters have been discussed. Finally, the system's exergy loss has been analyzed to make suggestions for further improvement. The results show that this novel ORC system can better meet the energy recovery requirements of LNG-fueled vessels, with higher net output power, lower cost, and greater energy recovery efficiency. The largest exergy loss of the system exists in the condensers of the stages 2 and 3, and the expanders in the various stages. Therefore, subsequent cooling energy recovery and the use of Stirling engines can be considered to further improve the system efficiency.
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