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190 Publications visible to you, out of a total of 190
Genome-wide analysis of carotid plaque burden suggests a role of IL5 in men.
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: Carotid artery plaque is an established marker of subclinical atherosclerosis with pronounced sex-dimorphism. Here, we aimed to identify genetic variants associated with carotid plaque … burden (CPB) and to examine potential sex-specific genetic effects on plaque sizes. METHODS AND RESULTS: We defined six operationalizations of CPB considering plaques in common carotid arteries, carotid bulb, and internal carotid arteries. We performed sex-specific genome-wide association analyses for all traits in the LIFE-Adult cohort (n = 727 men and n = 550 women) and tested significantly associated loci for sex-specific effects. In order to identify causal genes, we analyzed candidate gene expression data for correlation with CPB traits and corresponding sex-specific effects. Further, we tested if previously reported SNP associations with CAD and plaque prevalence are also associated with CBP. We found seven loci with suggestive significance for CPB (p<3.33x10-7), explaining together between 6 and 13% of the CPB variance. Sex-specific analysis showed a genome-wide significant hit for men at 5q31.1 (rs201629990, beta = -0.401, p = 5.22x10-9), which was not associated in women (beta = -0.127, p = 0.093) with a significant difference in effect size (p = 0.008). Analyses of gene expression data suggested IL5 as the most plausible candidate, as it reflected the same sex-specific association with CPBs (p = 0.037). Known plaque prevalence or CAD loci showed no enrichment in the association with CPB. CONCLUSIONS: We showed that CPB is a complementary trait in analyzing genetics of subclinical atherosclerosis. We detected a novel locus for plaque size in men only suggesting a role of IL5. Several estrogen response elements in this locus point towards a functional explanation of the observed sex-specific effect.

Authors: J. Pott, F. Beutner, K. Horn, H. Kirsten, K. Olischer, K. Wirkner, M. Loeffler, M. Scholz

Date Published: 30th May 2020

Publication Type: Journal article

Human Diseases: cardiovascular system disease, atherosclerosis

Alemtuzumab plus CHOP versus CHOP in elderly patients with peripheral T-cell lymphoma: the DSHNHL2006-1B/ACT-2 trial.
GLA - German Lymphoma Alliance

Abstract (Expand)

PTCL patients exhibit poor survival with existing treatments. We investigated the efficacy of CHOP combined with alemtuzumab in 116 PTCL patients age 61-80 in an open-label, randomized phase 3 trial. … Alemtuzumab was given on day 1, to a total of 360 mg in 21 patients, or 120 mg in 37. Hematotoxicity was increased with A-CHOP resulting in more grade >/=3 infections (40% versus 21%) and 4 versus 1 death due to infections, respectively. CR/CRu rate was 60% for A-CHOP and 43% for CHOP, and OR rate was 72% and 66%, respectively. Three-year-EFS, PFS and OS were 27% [15%-39%], 28% [15%-40%], and 37% ([23%-50%] for A-CHOP, and 24% [12%-35%], 29% [17%-41%], and 56% [44%-69%] for CHOP, respectively, showing no significant differences. Multivariate analyses, adjusted for strata and sex confirmed these results (hazard ratio HREFS: 0.7 ([95% CI: 0.5-1.1]; p = 0.094), HRPFS: 0.8 ([95% CI: 0.5-1.2]; p = 0.271), HROS: 1.4 ([95% CI: 0.9-2.4]; p = 0.154). The IPI score was validated, and male sex (HREFS 2.5) and bulky disease (HREFS 2.2) were significant risk factors for EFS, PFS, and OS. Alemtuzumab added to CHOP increased response rates, but did not improve survival due to treatment-related toxicity.

Authors: G. G. Wulf, B. Altmann, M. Ziepert, F. D'Amore, G. Held, R. Greil, O. Tournilhac, T. Relander, A. Viardot, M. Wilhelm, C. Wilhelm, A. Pezzutto, J. M. Zijlstra, E. V. D. Neste, P. J. Lugtenburg, J. K. Doorduijn, M. V. Gelder, G. W. van Imhoff, F. Zettl, F. Braulke, M. Nickelsen, B. Glass, A. Rosenwald, P. Gaulard, M. Loeffler, M. Pfreundschuh, N. Schmitz, L. Trumper

Date Published: 10th May 2020

Publication Type: Journal article

Human Diseases: lymphoma, peripheral T-cell lymphoma

The aging human body shape.
LIFE Adult

Abstract (Expand)

Body shape and composition are heterogeneous among humans with possible impact for health. Anthropometric methods and data are needed to better describe the diversity of the human body in human … populations, its age dependence, and associations with health risk. We applied whole-body laser scanning to a cohort of 8499 women and men of age 40-80 years within the frame of the LIFE (Leipzig Research Center for Civilization Diseases) study aimed at discovering health risk in a middle European urban population. Body scanning delivers multidimensional anthropometric data, which were further processed by machine learning to stratify the participants into body types. We here applied this body typing concept to describe the diversity of body shapes in an aging population and its association with physical activity and selected health and lifestyle factors. We find that aging results in similar reshaping of female and male bodies despite the large diversity of body types observed in the study. Slim body shapes remain slim and partly tend to become even more lean and fragile, while obese body shapes remain obese. Female body shapes change more strongly than male ones. The incidence of the different body types changes with characteristic Life Course trajectories. Physical activity is inversely related to the body mass index and decreases with age, while self-reported incidence for myocardial infarction shows overall the inverse trend. We discuss health risks factors in the context of body shape and its relation to obesity. Body typing opens options for personalized anthropometry to better estimate health risk in epidemiological research and future clinical applications.

Authors: A. Frenzel, H. Binder, N. Walter, K. Wirkner, M. Loeffler, H. Loeffler-Wirth

Date Published: 29th Mar 2020

Publication Type: Not specified

Association of proteome and metabolome signatures with severity in patients with community-acquired pneumonia
Genetical Statistics and Systems Biology

Abstract (Expand)

A combined OMICS screening approach of human plasma and serum was used to characterize protein and metabolome signatures displaying association to severity of Community-acquired pneumonia (CAP). 240 … serum and BD P100 EDTA plasma samples from patients diagnosed with CAP, collected during the day of enrolment to the hospital, were analyzed by a metabolomic and proteomic approach, respectively. Disease severity of CAP patients was stratified using the Sequential Organ Failure Assessment (SOFA) score. Quantitative proteome and metabolome data, derived by LC-MS/MS, were associated to SOFA and specific parameters of SOFA using linear regression models adjusted for age, BMI, sex, smoking and technical variables. Both proteome and metabolome profiling revealed remarkable strong changes in plasma and serum composition in relation to severity of CAP. Proteins and metabolites displaying SOFA associated levels are involved in immune response, particularly in processes of lipid metabolism. Proteins, which show an association to SOFA score, are involved in acute phase response, coagulation, complement activation and inflammation. Many of these metabolites and proteins displayed not only associations to SOFA, but also to parameters of SOFA score, which likely reflect the strong influence of lung-, liver-, kidney- and heart-dysfunction on the metabolome and proteome patterns. SIGNIFICANCE: Community-acquired pneumonia is the most frequent infection disease with high morbidity and mortality. So far, only few studies focused on the identification of proteins or metabolites associated to severity of CAP, often based on smaller sample sets. A screening for new diagnostic markers requires extensive sample collections in combination with high quality clinical data. To characterize the proteomic and metabolomics pattern associated to severity of CAP we performed a combined metabolomics and proteomic approach of serum and plasma sample from a multi-center clinical study focused on patients with CAP, requiring hospitalization. The results of this association study of omics data to the SOFA score enable not only an interpretation of changes in molecular patterns with severity of CAP but also an assignment of altered molecules to dysfunctions of respiratory, renal, coagulation, cardiovascular systems as well as liver.

Authors: Manuela Gesell Salazar, Sophie Neugebauer, Tim Kacprowski, Stephan Michalik, Peter Ahnert, Petra Creutz, Maciej Rosolowski, Markus Löffler, Michael Bauer, Norbert Suttorp, Michael Kiehntopf, Uwe Völker

Date Published: 1st Mar 2020

Publication Type: Journal article

HLA Class II Allele Analyses Implicate Common Genetic Components in Type 1 and Non-Insulin-Treated Type 2 Diabetes
Genetical Statistics and Systems Biology

Abstract (Expand)

CONTEXT Common genetic susceptibility may underlie the frequently observed co-occurrence of type 1 and type 2 diabetes in families. Given the role of HLA class II genes in the pathophysiology of type …e 1 diabetes, the aim of the present study was to test the association of high density imputed human leukocyte antigen (HLA) genotypes with type 2 diabetes. OBJECTIVES AND DESIGN Three cohorts (Ntotal = 10 413) from Leipzig, Germany were included in this study: LIFE-Adult (N = 4649), LIFE-Heart (N = 4815) and the Sorbs (N = 949) cohort. Detailed metabolic phenotyping and genome-wide single nucleotide polymorphism (SNP) data were available for all subjects. Using 1000 Genome imputation data, HLA genotypes were imputed on 4-digit level and association tests for type 2 diabetes, and related metabolic traits were conducted. RESULTS In a meta-analysis including all 3 cohorts, the absence of HLA-DRB5 was associated with increased risk of type 2 diabetes (P = 0.001). In contrast, HLA-DQB*06:02 and HLA-DQA*01:02 had a protective effect on type 2 diabetes (P = 0.005 and 0.003, respectively). Both alleles are part of the well-established type 1 diabetes protective haplotype DRB1*15:01~DQA1*01:02~DQB1*06:02, which was also associated with reduced risk of type 2 diabetes (OR 0.84; P = 0.005). On the contrary, the DRB1*07:01~DQA1*02:01~DQB1*03:03 was identified as a risk haplotype in non-insulin-treated diabetes (OR 1.37; P = 0.002). CONCLUSIONS Genetic variation in the HLA class II locus exerts risk and protective effects on non-insulin-treated type 2 diabetes. Our data suggest that the genetic architecture of type 1 diabetes and type 2 diabetes might share common components on the HLA class II locus.

Authors: Thomas Jacobi, Lucas Massier, Nora Klöting, Katrin Horn, Alexander Schuch, Peter Ahnert, Christoph Engel, Markus Löffler, Ralph Burkhardt, Joachim Thiery, Anke Tönjes, Michael Stumvoll, Matthias Blüher, Ilias Doxiadis, Markus Scholz, Peter Kovacs

Date Published: 1st Mar 2020

Publication Type: Journal article

Markov State Modelling of Disease Courses and Mortality Risks of Patients with Community-Acquired Pneumonia
Genetical Statistics and Systems Biology

Abstract (Expand)

Community-acquired pneumonia (CAP) is one of the most frequent infectious diseases worldwide, with high lethality. Risk evaluation is well established at hospital admission, and re-evaluation is advised … for patients at higher risk. However, severe disease courses may develop from all levels of severity. We propose a stochastic continuous-time Markov model describing daily development of time courses of CAP severity. Disease states were defined based on the Sequential Organ Failure Assessment (SOFA) score. Model calibration was based on longitudinal data from 2838 patients with a primary diagnosis of CAP from four clinical studies (PROGRESS, MAXSEP, SISPCT, VISEP). We categorized CAP severity into five disease states and estimated transition probabilities for CAP progression between these states and corresponding sojourn times. Good agreement between model predictions and clinical data was observed. Time courses of mortality were correctly predicted for up to 28 days, including validation with patient data not used for model calibration. We conclude that CAP disease course follows a Markov process, suggesting the necessity of daily monitoring and re-evaluation of patient’s risk. Our model can be used for regular updates of risk assessments of patients and could improve the design of clinical trials by estimating transition rates for different risk groups.

Authors: Jens Przybilla, Peter Ahnert, Holger Bogatsch, Frank Bloos, Frank M. Brunkhorst, Critical Care Trials Group SepNet, Study Group Progress, Michael Bauer, Markus Loeffler, Martin Witzenrath, Norbert Suttorp, Markus Scholz

Date Published: 1st Feb 2020

Publication Type: Journal article

Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial.
GLA - German Lymphoma Alliance

Abstract (Expand)

BACKGROUND: Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, … we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis. METHODS: This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7.5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m(2)), doxorubicin (50 mg/m(2)), and vincristine (1.4 mg/m(2), with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m(2) of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5.5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421. FINDINGS: Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy. INTERPRETATION: In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population. FUNDING: Deutsche Krebshilfe.

Authors: V. Poeschel, G. Held, M. Ziepert, M. Witzens-Harig, H. Holte, L. Thurner, P. Borchmann, A. Viardot, M. Soekler, U. Keller, C. Schmidt, L. Truemper, R. Mahlberg, R. Marks, H. G. Hoeffkes, B. Metzner, J. Dierlamm, N. Frickhofen, M. Haenel, A. Neubauer, M. Kneba, F. Merli, A. Tucci, P. de Nully Brown, M. Federico, E. Lengfelder, A. di Rocco, R. Trappe, A. Rosenwald, C. Berdel, M. Maisenhoelder, O. Shpilberg, J. Amam, K. Christofyllakis, F. Hartmann, N. Murawski, S. Stilgenbauer, M. Nickelsen, G. Wulf, B. Glass, N. Schmitz, B. Altmann, M. Loeffler, M. Pfreundschuh

Date Published: 21st Dec 2019

Publication Type: Journal article

Human Diseases: lymphoma, diffuse large B-cell lymphoma

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