| 1. |
- Kanoni, Stavroula, et al.
(author)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Journal article (peer-reviewed)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. |
- Williamson, Alice, et al.
(author)
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Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake
- 2023
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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:6, s. 973-983
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Journal article (peer-reviewed)abstract
- Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.
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| 3. |
- Broadaway, K Alaine, et al.
(author)
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Loci for insulin processing and secretion provide insight into type 2 diabetes risk.
- 2023
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In: American Journal of Human Genetics. - : Elsevier. - 0002-9297 .- 1537-6605. ; 110:2, s. 284-299
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Journal article (peer-reviewed)abstract
- Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
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| 6. |
- Rossignol, P, et al.
(author)
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NT-proBNP and stem cell factor plasma concentrations are independently associated with cardiovascular outcomes in end-stage renal disease hemodialysis patients
- 2022
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In: European Heart Journal Open. - : Oxford University Press. - 2752-4191. ; 2:6
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Journal article (peer-reviewed)abstract
- Aimas: End-stage renal disease (ESRD) treated by chronic hemodialysis (HD) is associated with poor cardiovascular (CV) outcomes, with no available evidence-based therapeutics. A multiplexed proteomic approach may identify new pathophysiological pathways associated with CV outcomes, potentially actionable for precision medicine.Methods and Results: The AURORA trial was an international, multicentre, randomized, double-blind trial involving 2776 patients undergoing maintenance HD. Rosuvastatin vs. placebo had no significant effect on the composite primary endpoint of death from CV causes, nonfatal myocardial infarction or nonfatal stroke. We first compared CV risk-matched cases and controls (n = 410) to identify novel biomarkers using a multiplex proximity extension immunoassay (276 proteomic biomarkers assessed with OlinkTM). We replicated our findings in 200 unmatched cases and 200 controls. External validation was conducted from a multicentre real-life Danish cohort [Aarhus-Aalborg (AA), n = 331 patients] in which 92 OlinkTM biomarkers were assessed. In AURORA, only N-terminal pro-brain natriuretic peptide (NT-proBNP, positive association) and stem cell factor (SCF) (negative association) were found consistently associated with the trial's primary outcome across exploration and replication phases, independently from the baseline characteristics. Stem cell factor displayed a lower added predictive ability compared with NT-ProBNP. In the AA cohort, in multivariable analyses, BNP was found significantly associated with major CV events, while higher SCF was associated with less frequent CV deaths.Conclusions: Our findings suggest that NT-proBNP and SCF may help identify ESRD patients with respectively high and low CV risk, beyond classical clinical predictors and also point at novel pathways for prevention and treatment.
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| 8. |
- Hanke, Michael, et al.
(author)
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A reliable direct numerical treatment of differential–algebraic equations by overdetermined collocation : An operator approach
- 2021
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In: Journal of Computational and Applied Mathematics. - : Elsevier BV. - 0377-0427 .- 1879-1778. ; 387
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Journal article (peer-reviewed)abstract
- Recently reported experiments and theoretical contributions concerning overdetermined polynomial collocation applied to higher-index differential–algebraic equations give rise to the conjecture that next to the existing derivative-array based methods there is further potential toward a reliable direct numerical treatment of DAEs. By analyzing first-order differential–algebraic operators and their special approximations in detail, we contribute to justify the overdetermined polynomial collocation applied to first-order higher-index differential–algebraic equations and fill the hitherto existing gap between the theoretical convergence results and its practical realization. Moreover, we shortly touch related questions for higher-order DAEs. We discuss several practical aspects of higher-order differential–algebraic operators and the associated equations which may be important for the application of collocation methods.
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| 9. |
- Hanke, Michael, et al.
(author)
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Convergence analysis of least-squares collocation methods for nonlinear higher-index differential–algebraic equations
- 2021
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In: Journal of Computational and Applied Mathematics. - : Elsevier BV. - 0377-0427 .- 1879-1778. ; 387
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Journal article (peer-reviewed)abstract
- We approach a direct numerical treatment of nonlinear higher-index differential–algebraic equations by means of overdetermined polynomial least-squares collocation. The procedure is not much more computationally expensive than standard collocation methods for regular ordinary differential equations and the numerical experiments show promising results. Nevertheless, the theoretical basic concept turns out to be considerably challenging. So far, quite recently, convergence proofs have been published for linear problems. In the present paper we come up with a first basic qualitative convergence result for nonlinear problems.
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| 10. |
- Hanke, Michael, et al.
(author)
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Towards a reliable implementation of least-squares collocation for higher index differential-algebraic equations—Part 1 : basics and ansatz function choices
- 2022
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In: Numerical Algorithms. - : Springer Nature. - 1017-1398 .- 1572-9265. ; 89:3, s. 931-963
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Journal article (peer-reviewed)abstract
- In the two parts of the present note we discuss several questions concerning the implementation of overdetermined least-squares collocation methods for higher index differential-algebraic equations (DAEs). Since higher index DAEs lead to ill-posed problems in natural settings, the discrete counterparts are expected to be very sensitive, which attaches particular importance to their implementation. In the present Part 1, we provide a robust selection of basis functions and collocation points to design the discrete problem. We substantiate a procedure for its numerical solution later in Part 2. Additionally, in Part 1, a number of new error estimates are proven that support some of the design decisions.
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