| 1. |
- 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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| 2. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 3. |
- Takeuchi, Fumihiko, et al.
(författare)
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Interethnic analyses of blood pressure loci in populations of East Asian and European descent
- 2018
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.
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| 4. |
- Liu, Chaolong, et al.
(författare)
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A Ruthenium(II) complex-based probe for colorimetric and luminescent detection and imaging of hydrogen sulfide in living cells and organisms
- 2021
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Ingår i: Analytica Chimica Acta. - : Elsevier BV. - 0003-2670 .- 1873-4324. ; 1145, s. 114-123
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Tidskriftsartikel (refereegranskat)abstract
- The development of reliable bioanalytical probes for sensitive and specific detection of hydrogen sulfide (H2S) plays important role for better understanding the roles of this biomolecule in living cells and or-ganisms. Taking advantages of unique photophysical properties of ruthenium(II) (Ru(II)) complex, this work presents the development of a responsive Ru(II) complex probe, Ru-PNBD, for colorimetric and luminescent analysis of H2S in living cells and organisms. In aqueous solution, Ru-PNBD is yellow color and non-luminescent because of the photoinduced electron transfer (PET) process from Ru(II) complex luminophore to NBD moiety. The H2S-triggered specific nucleophilic substitution reaction with Ru-PNBD cleaves the NBD moiety to form pink NBD-SH and highly luminescent Ru-PH. The color of the solution thus changes from yellow to pink for colorimetric analysis and the emission intensity is about 65-fold increased for luminescent analysis. Ru-PNBD has high sensitivity and selectivity for H2S detection, low cytotoxicity and good permeability to cell membrane, which allow the application of this probe for H2S imaging in living cells, Daphnia magna, and larval zebrafish. Collectively, this work provides a useful tool for H2S analysis and expands the scope of transition metal complex probes.
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| 5. |
- Liu, Chaolong, et al.
(författare)
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"Two Birds with One Stone" Ruthenium(II) Complex Probe for Biothiols Discrimination and Detection In Vitro and In Vivo
- 2020
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Ingår i: Advanced Science. - : Wiley. - 2198-3844. ; 7:14
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Tidskriftsartikel (refereegranskat)abstract
- In this work, a two birds with one stone ruthenium(II) complex probe, Ru-NBD, is proposed as an effective tool for biothiols detection and discrimination in vitro and in vivo. Ru-NBD is nonluminescent due to the quenching of Ru(II) complex emission by photoinduced electron transfer (PET) from Ru(II) center to NBD and the quenching of NBD emission through 4-substitution with O ether bond. Ru-NBD is capable of reacting with Cys/Hcy to form long-lived red-emitting Ru-OH and short-lived green-emitting NBD-NR, while reacting with GSH to produce Ru-OH and nonemissive NBD-SR. The long lifetime emission of Ru(II) complex allows elimination of short lifetime background and NBD-NR fluorescence for total biothiols detection (bird one) by time-gated luminescence (TGL) analysis, and the remarkable difference in luminescence color response allows discrimination GSH and Cys/Hcy (bird two) through steady-state luminescence analysis. Ru-NBD features high sensitivity and selectivity, rapid luminescence response, and low cytotoxicity, which enables it to be used as the probe for luminescence and background-free TGL detection and visualization of biothiols in live cells, zebrafish, and mice. The successful development of this probe is anticipated to contribute to the future biological studies of biothiols roles in various diseases.
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| 6. |
- Zhang, Wenzhu, et al.
(författare)
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Responsive ruthenium complex probe for phosphorescence and time-gated luminescence detection of bisulfite
- 2020
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Ingår i: Dalton Transactions. - : Royal Society of Chemistry (RSC). - 1477-9226 .- 1477-9234. ; 49:17, s. 5531-5538
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Tidskriftsartikel (refereegranskat)abstract
- Sensitive and selective quantification of specific analytes is of great significance in analytical and environmental sciences, as well as in the food industry. Herein, we report the design, synthesis, characterization, and application of a responsive ruthenium(ii) complex probe, Ru-azo, for phosphorescence and time-gated luminescence (TGL) detection of bisulfite, an important additive in the food industry. Upon a specific nucleophilic addition reaction between bisulfite and the azo group of Ru-azo, a new ruthenium(ii) complex, Ru-SO3, was obtained, which resulted in a remarkable increase in phosphorescence intensity, allowing the bisulfite detection to be achieved. In addition, long-lived emissions of Ru-azo (tau = 258 ns) and Ru-SO3 (tau = 261 ns) also enabled the TGL detection of bisulfite in autofluorescence-rich food samples. Through theoretical computations, the photoinduced electron transfer (PET) process within the ruthenium(ii) complex was validated, which unveiled the rationality of the luminescence off-on response of Ru-azo to bisulfite. The probe showed advantages of good water solubility, and high sensitivity, selectivity and accuracy for responding to bisulfite, facilitating its application in phosphorescence and TGL detection of bisulfite in aqueous and food samples.
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