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- Teumer, A, et al.
(författare)
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Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4130-
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Tidskriftsartikel (refereegranskat)abstract
- Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
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- 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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- Gorski, Mathias, et al.
(författare)
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Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
- 2022
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Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 102:3, s. 624-639
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Tidskriftsartikel (refereegranskat)abstract
- Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genomewide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR- baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant- by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with agedependency of genetic cross- section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in- silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03- 1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
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- Kato, Norihiro, et al.
(författare)
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Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation
- 2015
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 47:11, s. 1282-1293
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Tidskriftsartikel (refereegranskat)abstract
- We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
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- Pashchenko, V. P., et al.
(författare)
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Structural and magnetic inhomogeneity and the NMR of Mn-55 and La-139 in the magnetoresistive ceramics La0.7Ba0.3-xSnxMnO3 -> La0.7-xBa0.3-xMnO3+0.5xLa(2)Sn(2)O(7)
- 2003
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Ingår i: Low temperature physics (Woodbury, N.Y., Print). - : AIP Publishing. - 1063-777X .- 1090-6517. ; 29:11, s. 910-916
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Tidskriftsartikel (refereegranskat)abstract
- The effects of substitution of barium by tin on the phase composition, structural imperfection, and properties of lanthanum manganite perovskites La0.7Ba0.3-xSnxMnO3 (X=0, 0.1, 0.15, 0.2, 0.3) are established by comprehensive studies done by x-ray diffraction, resistive, and magnetic (including NMR on Mn-55 and La-139) methods. It is shown that the introduction of Sn leads to the formation of a pyrochloric phase La2Sn2O7, to an increase in the density of lattice defects of the manganese-enriched main lanthanum manganite phase, and to a substantial decrease of the magnetoresistive effect. The smearing of the metal-semiconductor phase transition temperature is explained by an increase in the inhomogeneity and imperfection of the perovskite structure. The low activation energy is confirmed by a high degree of inhomogeneity and imperfection of the crystal lattice of the samples studied. The broad, asymmetric NMR spectra of Mn-55 and La-139 attest to high-frequency electron exchange between Mn3+ and Mn4+ and nonequivalence of the environment of those ions and La3+ due both to heterovalent ions and to vacancies and clusters.
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- Schaap, M., et al.
(författare)
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Standardized evaluation methodology and reference database for evaluating coronary artery centerline extraction algorithms
- 2009
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Ingår i: Medical Image Analysis. - : Elsevier. - 1361-8415 .- 1361-8423. ; 13:5, s. 701-714
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Tidskriftsartikel (refereegranskat)abstract
- Efficiently obtaining a reliable coronary artery centerline from computed tomography angiography data is relevant in clinical practice. Whereas numerous methods have been presented for this purpose, up to now no standardized evaluation methodology has been published to reliably evaluate and compare the performance of the existing or newly developed coronary artery centerline extraction algorithms. This paper describes a standardized evaluation methodology and reference database for the quantitative evaluation of coronary artery centerline extraction algorithms. The contribution of this work is fourfold: (1) a method is described to create a consensus centerline with multiple observers, (2) well-defined measures are presented for the evaluation of coronary artery centerline extraction algorithms, (3) a database containing 32 cardiac CTA datasets with corresponding reference standard is described and made available, and (4) 13 coronary artery centerline extraction algorithms, implemented by different research groups, are quantitatively evaluated and compared. The presented evaluation framework is made available to the medical imaging community for benchmarking existing or newly developed coronary centerline extraction algorithms.
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