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| 32. |
- Glicksberg, Benjamin S., et al.
(författare)
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Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits
- 2019
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Ingår i: BMC Medical Genomics. - : BMC. - 1755-8794. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundGenetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene.ResultsWe identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight.ConclusionIn sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.
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| 36. |
- Lindehammer, Sabina, et al.
(författare)
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Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk
- 2008
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Ingår i: Acta Diabetologica. - : Springer Science and Business Media LLC. - 0940-5429 .- 1432-5233. ; 45:4, s. 231-5
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to compare the frequency of human leukocyte antigen (HLA) genotypes in 1-18-year-old patients with type 1 diabetes newly diagnosed in 1986-1987 (n = 430), 1996-2000 (n = 342) and in 2003-2005 (n = 171). We tested the hypothesis that the HLA DQ genotype distribution changes over time. Swedish type 1 diabetes patients and controls were typed for HLA using polymerase chain reaction amplification and allele specific probes for DQ A1* and B1* alleles. The most common type 1 diabetes HLA DQA1*-B1*genotype 0501-0201/0301-0302 was 36% (153/430) in 1986-1987 and 37% (127/342) in 1996-2000, but decreased to 19% (33/171) in 2003-2005 (P \ 0.0001). The 0501-0201/0501-0201 genotype increased from 1% in 1986-1987 to 7% in 1996-2000 (P = 0.0047) and to 5% in 2003-2005 (P > 0.05). This study in 1-18-year-old Swedish type 1 diabetes patients supports the notion that there is a temporal change in HLA risk.
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| 38. |
- Lukes, D. J., et al.
(författare)
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Ischemic preconditioning can overcome the effect of moderate to severe cold ischemia on concordant mouse xeno-heart transplants
- 2005
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Ingår i: Transplantation proceedings. - 0041-1345. ; 37:8, s. 3332-4
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Concordant mouse xeno-heart transplants are relatively sensitive to ischemia-reperfusion injury. We investigated the effect of an ischemic preconditioning (IPC) protocol on the functional and biochemical outcome of mouse xenohearts transplanted to the Lewis rat. MATERIAL AND METHODS: NMRI mice (30 to 40 g) were anesthetized, intubated, and mechanically ventilated. They were subjected either to a IPC protocol leading to an SaO(2) of 70% for 5 minutes followed by normoxia (defined as SaO(2) >90%) for 10 minutes (n = 9) or normoxia only (n = 11). The hearts were then heterotopically transplanted to Lewis rats (220 g). The frequencies of immediate onset and early dysfunction and late dysfunction were registered. The hearts surviving for 6 hours were explanted and the absolute concentrations of phosphocreatine and adenosine triphosphate (ATP) were determined in micromole per gram of heart tissue with high-pressure liquid chromatography. The phosphorylation ratio, PCr/ATP, a known correlate to biochemical and functional outcome, was calculated. RESULTS: Four of 11 (36.4%) of control hearts experienced immediate onset and early dysfunction versus 0% (0/9) in M hearts subjected to IPC (P = .01). Furthermore, the IPC protocol increased the PCr concentration, 15.08 +/- 1.00 versus 9.04 +/- 2.04 micromol/g in controls (P = .01), and the PCr/ATP ratio, 1.80 +/- 0.17 versus 1.27 +/- 0.21 (NS; P = .06). CONCLUSIONS: IPC provides a protective PCr overshoot overcoming the short-term effects of moderate to severe ischemic injury on mouse xeno-heart transplants.
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| 39. |
- Lukes, D. J., et al.
(författare)
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Singlet oxygen energy illumination during moderate cold ischemia prolongs the survival of concordant hamster xeno-heart transplants
- 2005
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Ingår i: Transplantation proceedings. - 0041-1345. ; 37:1, s. 518-20
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Singlet oxygen energy (SOE) is a potent inhibitor of reactive oxygen species (ROS) in vitro and in vivo in certain dose ranges and can improve the levels of high-energy phosphates (HEP) in concordant hamster xeno-heart transplants. Some data indicate that a certain degree of cold ischemia (CI) might be beneficial to xenotransplants. We investigated if SOE illumination of hamster xeno-hearts during moderate cold ischemia (CI) improved graft survival. MATERIALS AND METHODS: Eighteen hearts from Golden Syrian hamsters (70 to 80 g) were subjected to 8 hours of CI in cold (+4 degrees C) saline solution (NaCL, 0.9%) before heterotopic cervical transplantation to Lewis rats (220 g). Among the treatment group (n = 8), SOE was produced by illuminating the hearts for 10 minutes every 30 minutes with photons at lambda 634 nm with the Oxylight equipment. Graft function was evaluated every 6 hours after transplantation with digital exam until cessation of heart beats. RESULTS: The graft survival of SOE-illuminated ischemic hamster xenografts was 2.34 +/- 0.56 versus 1.15 +/- 0.37 days in the control group (P < .05). All hearts displayed immediate graft function versus 70% in the controls (NS). CONCLUSIONS: SOE illumination at lambda 634 nm during moderate cold ischemia (+4 degrees C) can improve the survival of concordant hamster xeno-heart transplants. The exact mechanism(s) are currently unknown, but the effect might in part be exerted by a combination of reduced production of ROS and increased oxidative phosphorylation.
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