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1.
  • Ellinghaus, David, et al. (författare)
  • Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies
  • 2013
  • Ingår i: Gastroenterology. - 0016-5085 .- 1528-0012. ; 145:2, s. 339-347
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 x 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 x 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor kappa B activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.
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3.
  • Boeckel, Jes-Niels, et al. (författare)
  • Adjusted Troponin I for Improved Evaluation of Patients with Chest Pain
  • 2018
  • Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322 .- 2045-2322. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • The use of cardiac troponins (cTn) is the gold standard for diagnosing myocardial infarction. Independent of myocardial infarction (MI), however, sex, age and kidney function affect cTn levels. Here we developed a method to adjust cTnI levels for age, sex, and renal function, maintaining a unified cut-off value such as the 99th percentile. A total of 4587 individuals enrolled in a prospective longitudinal study were used to develop a model for adjustment of cTn. cTnI levels correlated with age and estimated glomerular filtration rate (eGFR) in males/females with r(age) = 0.436/0.518 and with (r)(eGFR) = -0.142/-0.207. For adjustment, these variables served as covariates in a linear regression model with cTnl as dependent variable. This adjustment model was then applied to a real-world cohort of 1789 patients with suspected acute MI (AMI) (N = 407). Adjusting cTnI showed no relevant loss of diagnostic information, as evidenced by comparable areas under the receiver operator characteristic curves, to identify AMI in males and females for adjusted and unadjusted cTnI. In specific patients groups such as in elderly females, adjusting cTnI improved specificity for AMI compared with unadjusted cTnI. Specificity was also improved in patients with renal dysfunction by using the adjusted cTnI values. Thus, the adjustments improved the diagnostic ability of cTnI to identify AMI in elderly patients and in patients with renal dysfunction. Interpretation of cTnI values in complex emergency cases is facilitated by our method, which maintains a single diagnostic cut-off value in all patients.
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4.
  • Stoldt, Stefan, et al. (författare)
  • Mic60 exhibits a coordinated clustered distribution along and across yeast and mammalian mitochondria
  • 2019
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 116:20, s. 9853-9858
  • Tidskriftsartikel (refereegranskat)abstract
    • Mitochondria are tubular double-membrane organelles essential for eukaryotic life. They form extended networks and exhibit an intricate inner membrane architecture. The MICOS (mitochondrial contact site and cristae organizing system) complex, crucial for proper architecture of the mitochondrial inner membrane, is localized primarily at crista junctions. Harnessing superresolution fluorescence microscopy, we demonstrate that Mic60, a subunit of the MICOS complex, as well as several of its interaction partners are arranged into intricate patterns in human and yeast mitochondria, suggesting an ordered distribution of the crista junctions. We show that Mic60 forms clusters that are preferentially localized in the inner membrane at two opposing sides of the mitochondrial tubules so that they form extended opposing distribution bands. These Mic60 distribution bands can be twisted, resulting in a helical arrangement. Focused ion beam milling-scanning electron microscopy showed that in yeast the twisting of the opposing distribution bands is echoed by the folding of the inner membrane. We show that establishment of the Mic60 distribution bands is largely independent of the cristae morphology. We suggest that Mic60 is part of an extended multiprotein interaction network that scaffolds mitochondria.
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5.
  • Wild, Philipp S., et al. (författare)
  • A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease
  • 2011
  • Ingår i: Circulation: Cardiovascular Genetics. - : American Heart Association. - 1942-325X .- 1942-3268. ; 4:4, s. 203-403
  • Tidskriftsartikel (refereegranskat)abstract
    • Background-eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). Methods and Results-In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7 x 10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3 x 10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4 x 10(-3)). Conclusions-The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD. (Circ Cardiovasc Genet. 2011;4:403-412.)
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