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227 Publications visible to you, out of a total of 227
Genome-Wide Association Analysis for Severity of Coronary Artery Disease Using the Gensini Scoring System
Genetical Statistics and Systems Biology

Abstract (Expand)

Coronary artery disease (CAD) has a complex etiology involving numerous environmental and genetic factors of disease risk. To date, the genetic 9p21 locus represents the most robust genetic finding for … prevalent and incident CAD. However, limited information is available on the genetic background of the severity and distribution of CAD. CAD manifests itself as stable CAD or acute coronary syndrome. The Gensini score quantifies the extent CAD but requires coronary angiography. Here, we aimed to identify novel genetic variants associated with Gensini score severity and distribution of CAD. A two-stage approach including a discovery and a replication stage was used to assess genetic variants. In the discovery phase, a meta-analysis of genome-wide association data of 4,930 CAD-subjects assessed by the Gensini score was performed. Selected single nucleotide polymorphisms (SNPs) were replicated in 2,283 CAD-subjects by de novo genotyping. We identified genetic loci located on chromosome 2 and 9 to be associated with Gensini score severity and distribution of CAD in the discovery stage. Although the loci on chromosome 2 could not be replicated in the second stage, the known CAD-locus on chromosome 9p21, represented by rs133349, was identified and, thus, was confirmed as risk locus for CAD severity.

Authors: Tanja Zeller, Moritz Seiffert, Christian Müller, Markus Scholz, Anna Schäffer, Francisco Ojeda, Heinz Drexel, Axel Mündlein, Marcus E. Kleber, Winfried März, Christoph Sinning, Fabian J. Brunner, Christoph Waldeyer, Till Keller, Christoph H. Saely, Karsten Sydow, Joachim Thiery, Daniel Teupser, Stefan Blankenberg, Renate Schnabel

Date Published: 20th Sep 2017

Publication Type: Journal article

Increased Level of Interleukin 6 Associates With Increased 90-Day and 1-Year Mortality in Patients With End-Stage Liver Disease.
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND & AIMS: Organ allocation for liver transplantation is based on prognosis, using the model for end-stage liver disease (MELD) or MELD including serum sodium (MELD-Na) score. These scores … do not consider systemic inflammation and septic complications. Blood level of C-reactive protein (CRP), in addition to the MELD score, associates with mortality in patients with end-stage liver disease, whereas levels of interleukin 6 (IL6) have not been systematically studied. METHODS: We performed a retrospective observational cohort study of 474 patients with end-stage liver disease (63.5% male; median age, 56.9 years), evaluated for liver transplantation in Germany, with at least 1 year of follow up. Data were collected on blood levels of CRP, IL6, and white blood cell count (WBC). Findings were analyzed in relation to mortality and compared with patients' MELD scores and MELD-Na scores. For survival analysis, the cohort was divided into quartiles of IL6, CRP, and WBC levels, as well as MELD scores. Log-rank test and the Cox proportional hazards regression model were used to compare the groups, and area under the receiver operating characteristic (AUROC) values were calculated. RESULTS: Blood levels of IL6 and MELD scores associated with mortality: none of the patients with levels of IL6 below the first quartile (below 5.3 pg/mL) died within 1 year. In contrast, 67.7% of the patients in the highest quartile of IL6 level (37.0 pg/mL or more) died within 1 year. MELD score also correlated with mortality: among patients with MELD scores below 8.7, 0.9% died within 1 year, whereas in patients with MELD scores of 18.0 or more, 67.4% died within 1 year. The predictive value of level of IL6 (AUROC, 0.940) was higher than level of CRP (AUROC, 0.866) (P = .009) or WBC (AUROC, 0.773) (P < .001) for 90-day mortality. MELD scores associated with 90-day mortality (AUROC, 0.933) (P = .756) as did MELD-Na score (AUROC, 0.946) (P = .771). Level of IL6 associated with 1-year mortality (AUROC, 0.916) to a greater extent than liver synthesis or detoxification markers international normalized ratio (AUROC, 0.839) (P = .007) or bilirubin (AUROC 0.846) (P = .007). Level of IL6 was an independent, significant risk factor for mortality after adjustment for MELD score, MELD-Na score, level of CRP, or WBC. CONCLUSIONS: In a retrospective analysis, we found high blood levels of IL6 to associate with 90-day and 1-year mortality in patients with end-stage liver disease; its predictive value was comparable to that of MELD or MELD-Na score, and was higher than that of level of CRP or WBC. Further studies should be performed to confirm the results in different cohorts.

Authors: J. Remmler, C. Schneider, T. Treuner-Kaueroff, M. Bartels, D. Seehofer, M. Scholz, T. Berg, T. Kaiser

Date Published: 19th Sep 2017

Publication Type: Journal article

Validity and reliability of three-dimensional scanning compared with conventional anthropometry for children and adolescents-response to the rebuttal by Sabour
Genetical Statistics and Systems Biology

Abstract

Pediatric Research accepted article preview online, 29 March 2017. doi:10.1038/pr.2017.76.

Authors: Fabian Glock, Markus Scholz, Andreas Kuehnapfel, Wieland Kiess

Date Published: 1st Aug 2017

Publication Type: Journal article

Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis.
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE: Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic … chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus. DESIGN: 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used. RESULTS: We replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk. CONCLUSION: An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.

Authors: J. Rosendahl, H. Kirsten, E. Hegyi, P. Kovacs, F. U. Weiss, H. Laumen, P. Lichtner, C. Ruffert, J. M. Chen, E. Masson, S. Beer, C. Zimmer, K. Seltsam, H. Algul, F. Buhler, M. J. Bruno, P. Bugert, R. Burkhardt, G. M. Cavestro, H. Cichoz-Lach, A. Farre, J. Frank, G. Gambaro, S. Gimpfl, H. Grallert, H. Griesmann, R. Grutzmann, C. Hellerbrand, P. Hegyi, M. Hollenbach, S. Iordache, G. Jurkowska, V. Keim, F. Kiefer, S. Krug, O. Landt, M. D. Leo, M. M. Lerch, P. Levy, M. Loffler, M. Lohr, M. Ludwig, M. Macek, N. Malats, E. Malecka-Panas, G. Malerba, K. Mann, J. Mayerle, S. Mohr, R. H. M. Te Morsche, M. Motyka, S. Mueller, T. Muller, M. M. Nothen, S. Pedrazzoli, S. P. Pereira, A. Peters, R. Pfutzer, F. X. Real, V. Rebours, M. Ridinger, M. Rietschel, E. Rosmann, A. Saftoiu, A. Schneider, H. U. Schulz, N. Soranzo, M. Soyka, P. Simon, J. Skipworth, F. Stickel, K. Strauch, M. Stumvoll, P. A. Testoni, A. Tonjes, L. Werner, J. Werner, N. Wodarz, M. Ziegler, A. Masamune, J. Mossner, C. Ferec, P. Michl, J. P H Drenth, H. Witt, M. Scholz, M. Sahin-Toth

Date Published: 30th Jul 2017

Publication Type: Journal article

Validity and intraobserver reliability of three-dimensional scanning compared with conventional anthropometry for children and adolescents from a population-based cohort study
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Conventional anthropometric measurements are time consuming and require well trained medical staff. To use three-dimensional whole body laser scanning in daily clinical work, validity, and …d reliability have to be confirmed. METHODS We compared a whole body laser scanner with conventional anthropometry in a group of 473 children and adolescents from the Leipzig Research Centre for Civilization Diseases (LIFE-Child). Concordance correlation coefficients (CCC) were calculated separately for sex, weight, and age to assess validity. Overall CCC (OCCC) was used to analyze intraobserver reliability. RESULTS Body height and the circumferences of waist, hip, upper arm, and calf had an \textquotedblexcellent\textquotedbl (CCC ≥0.9); neck and thigh circumference, a \textquotedblgood\textquotedbl (CCC ≥0.7); and head circumference, a \textquotedbllow\textquotedbl (CCC \textless 0.5) degree of concordance over the complete study population. We observed dependencies of validity on sex, weight, and age. Intraobserver reliability of both techniques is \textquotedblexcellent\textquotedbl (OCCC ≥0.9). CONCLUSION Scanning is faster, requires less intensive staff training and provides more information. It can be used in an epidemiologic setting with children and adolescents but some measurements should be considered with caution due to reduced agreement with conventional anthropometry.

Authors: Fabian Glock, Mandy Vogel, Stephanie Naumann, Andreas Kuehnapfel, Markus Scholz, Andreas Hiemisch, Toralf Kirsten, Kristin Rieger, Antje Koerner, Markus Loeffler, Wieland Kiess

Date Published: 1st May 2017

Publication Type: Journal article

Dyslexia risk gene relates to representation of sound in the auditory brainstem
Genetical Statistics and Systems Biology

Abstract (Expand)

Dyslexia is a reading disorder with strong associations with KIAA0319 and DCDC2. Both genes play a functional role in spike time precision of neurons. Strikingly, poor readers show an imprecise encoding … of fast transients of speech in the auditory brainstem. Whether dyslexia risk genes are related to the quality of sound encoding in the auditory brainstem remains to be investigated. Here, we quantified the response consistency of speech-evoked brainstem responses to the acoustically presented syllable [da] in 159 genotyped, literate and preliterate children. When controlling for age, sex, familial risk and intelligence, partial correlation analyses associated a higher dyslexia risk loading with KIAA0319 with noisier responses. In contrast, a higher risk loading with DCDC2 was associated with a trend towards more stable responses. These results suggest that unstable representation of sound, and thus, reduced neural discrimination ability of stop consonants, occurred in genotypes carrying a higher amount of KIAA0319 risk alleles. Current data provide the first evidence that the dyslexia-associated gene KIAA0319 can alter brainstem responses and impair phoneme processing in the auditory brainstem. This brain-gene relationship provides insight into the complex relationships between phenotype and genotype thereby improving the understanding of the dyslexia-inherent complex multifactorial condition.

Authors: Nicole E. Neef, Bent Müller, Johanna Liebig, Gesa Schaadt, Maren Grigutsch, Thomas C. Gunter, Arndt Wilcke, Holger Kirsten, Michael A. Skeide, Indra Kraft, Nina Kraus, Frank Emmrich, Jens Brauer, Johannes Boltze, Angela D. Friederici

Date Published: 1st Apr 2017

Publication Type: Journal article

Low sphingosine-1-phosphate plasma levels are predictive for increased mortality in patients with liver cirrhosis
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND & AIM: The association of circulating sphingosine-1-phosphate (S1P), a bioactive lipid involved in various cellular processes, and related metabolites such as sphinganine-1-phosphate … (SA1P) and sphingosine (SPH) with mortality in patients with end-stage liver disease is investigated in the presented study. S1P as a bioactive lipid mediator, is involved in several cellular processes, however, in end-stage liver disease its role is not understood. METHODS: The study cohort consisted of 95 patients with end-stage liver disease and available information on one-year outcome. The median MELD (Model for end-stage liver disease) score was 12.41 (Range 6.43-39.63). The quantification of sphingolipids in citrated plasma specimen was performed after methanolic protein precipitation followed by hydrophilic interaction liquid chromatography and tandem mass spectrometric detection. RESULTS: S1P and SA1P displayed significant correlations with the MELD score. Patients with circulating S1P levels below the lowest tertile (110.68 ng/ml) showed the poorest one-year survival rate of only 57.1%, whereas one-year survival rate in patients with S1P plasma levels above 165.67 ng/ml was 93.8%. In a multivariate cox regression analysis including platelet counts, concentrations of hemoglobin and MELD score, S1P remained a significant predictor for three-month and one-year mortality. CONCLUSIONS: Low plasma S1P concentrations are highly significantly associated with prognosis in end-stage liver disease. This association is independent of the stage of liver disease. Further studies should be performed to investigate S1P, its role in the pathophysiology of liver diseases and its potential for therapeutic interventions.

Authors: Susen Becker, Benedict Kinny-Koster, Michael Bartels, Markus Scholz, Daniel Seehofer, Thomas Berg, Cornelius Engelmann, Joachim Thiery, Uta Ceglarek, Thorsten Kaiser

Date Published: 23rd Mar 2017

Publication Type: Journal article

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