TY - JOUR AB - BACKGROUND: Visceral adipose tissue (VAT) is well established as a pathogenic fat depot, whereas superficial subcutaneous adipose tissue (SAT) is associated with either an improved or neutral cardiovascular state. However, it is unclear to what extent VAT area (VATcm2) and its proportion of total abdominal adipose tissue (VAT%) are distinguished in predicting cardiometabolic status and clinical outcomes during weight loss. METHODS: We integrated magnetic resonance imaging (MRI) measurements of VAT, deep-SAT, and superficial-SAT from two 18-month lifestyle weight loss clinical trials, CENTRAL and DIRECT PLUS (n = 572). RESULTS: At baseline, the mean VATcm2 was 144.8cm2 and VAT% = 28.2%; over 18 months, participants lost 28cm2 VATcm2 (- 22.5%), and 1.3 VAT% units. Baseline VATcm2 and VAT% were similarly associated with metabolic syndrome, hypertension, and diabetes status, while VAT% better classified hypertriglyceridemia. Conversely, higher VATcm2 was associated with elevated high-sensitivity C-reactive protein (hsCRP), while VAT% was not. After 18 months of lifestyle intervention, both VATcm2 and VAT% loss were significantly associated with decreased triglycerides, HbA1c, ferritin, and liver enzymes, and increased HDL-c levels beyond weight loss (FDR < 0.05). Only VATcm2 loss was correlated with decreased HOMA-IR, chemerin, and leptin levels. CONCLUSIONS: MRI follow-up of 572 participants over 18 months of weight loss intervention suggests that although increased VATcm2 and VAT% exhibit similar clinical manifestations, it might be preferable to examine VAT% when exploring lipid status, while VATcm2 may better reflect inflammatory and glycemic states. TRIAL REGISTRATION: CENTRAL (Clinical-trials-identifier: NCT01530724); DIRECT PLUS (Clinical-trials-identifier: NCT03020186). AU - Klein, H.* AU - Zelicha, H.* AU - Yaskolka Meir, A.* AU - Rinott, E.* AU - Tsaban, G.* AU - Kaplan, A.* AU - Chassidim, Y.* AU - Gepner, Y.* AU - Blüher, M. AU - Ceglarek, U.* AU - Isermann, B.* AU - Stumvoll, M.* AU - Shelef, I.* AU - Qi, L.* AU - Li, J.* AU - Hu, F.B.* AU - Stampfer, M.J.* AU - Shai, I.* C1 - 73283 C2 - 56980 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Visceral adipose tissue area and proportion provide distinct reflections of cardiometabolic outcomes in weight loss; pooled analysis of MRI-assessed CENTRAL and DIRECT PLUS dietary randomized controlled trials. JO - BMC Med. VL - 23 IS - 1 PB - Bmc PY - 2025 SN - 1741-7015 ER - TY - JOUR AB - Following the publication of the original article [1], the authors wish to note that in the sentence, '[…] high-sensitivity C-reactive protein (hsCRP) (tau = 0.0.16, FDR < 0.001)' in the Results section, '0.0.16' should instead read '0.16'. AU - Klein, H.* AU - Zelicha, H.* AU - Meir, A.Y.* AU - Rinott, E.* AU - Tsaban, G.* AU - Kaplan, A.* AU - Chassidim, Y.* AU - Gepner, Y.* AU - Blüher, M. AU - Ceglarek, U.* AU - Isermann, B.* AU - Stumvoll, M.* AU - Shelef, I.* AU - Qi, L.* AU - Li, J.* AU - Hu, F.B.* AU - Stampfer, M.J.* AU - Shai, I.* C1 - 73423 C2 - 57058 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Correction: Visceral adipose tissue area and proportion provide distinct reflections of cardiometabolic outcomes in weight loss; pooled analysis of MRI-assessed CENTRAL and DIRECT PLUS dietary randomized controlled trials. JO - BMC Med. VL - 23 IS - 1 PB - Bmc PY - 2025 SN - 1741-7015 ER - TY - JOUR AB - BACKGROUND: Dysbiotic microbial colonization predisposes to severe outcomes of prematurity, including mortality and severe morbidities like necrotizing enterocolitis (NEC), late-onset infection (LOI) and bronchopulmonary dysplasia (BPD). Here, we studied the variations in the bacterial signatures in the amniotic fluid (AF) of very preterm deliveries < 32 weeks with severe acute and longer-term outcomes within a prospective cohort study. METHODS: One hundred twenty-six AF samples were available for 16S rRNA gene metabarcoding to describe bacterial community structure and diversity in connection to intraventricular haemorrhage (IVH), LOI, focal intestinal perforation (FIP), NEC, retinopathy of prematurity (ROP) and the 2-year cognitive (MDI) and motor (PDI) outcome. RESULTS: Diversity and overall bacterial community composition did not differ between the studied outcomes. But disparities in sequences assigned to single bacterial taxa were observed for the acute outcomes LOI and ROP and the longer-term impairments of MDI and PDI. Enrichments associated with a poor acute outcome were particularly detected in the Escherichia-Shigella cluster, while the predominance of Ureaplasma and Enterococcus species was associated with unrestricted acute and longer-term outcomes. Analysis for FIP did not reach any significance. IVH and NEC constituted rare events, prohibiting the analyses. CONCLUSIONS: Our data provide evidence that microbiota patterns at birth might allow the early identification of infants at risk for the severe outcomes of prematurity and argue against morbidity-specific associations. The data support the early origins hypothesis and relevant contribution of prenatal factors. The partly existing disparities between acute and longer-term outcomes might be traced back to the relevant impact of the diverse longitudinal exposures and socioeconomic factors. AU - Staude, B.* AU - Gschwendtner, S. AU - Frodermann, T.* AU - Oehmke, F.* AU - Kohl, T.* AU - Walch, S. AU - Schloter, M. AU - Ehrhardt, H.* C1 - 75182 C2 - 57843 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Association of specific microbiota taxa in the amniotic fluid at birth with severe acute and longer-term outcomes of very preterm infants: A prospective observational study. JO - BMC Med. VL - 23 IS - 1 PB - Bmc PY - 2025 SN - 1741-7015 ER - TY - JOUR AB - BACKGROUND: In humans, uric acid is a product of purine metabolism that impacts the vascular system. In addition to effects on arterial vascular tone, associations between serum uric acid concentrations-even in the physiological range-and arterial hypertension and vascular-mediated end-organ damage due to an impact on vascular stiffness have been postulated. METHODS: Therefore, we aim to investigate a possible cross-sectional association between serum uric acid concentrations in the physiological range and differences in arterial pulse wave velocity (PWV), an indicator of vascular remodeling, with a focus on possible differences between female and male individuals. We analyzed cross-sectional phenotypic and laboratory parameters, including PWV from 70,649 individuals in the population-based German National Cohort (NAKO) in a sex-specific manner. In parallel, we applied a machine learning approach to identify and quantify factors associated with PWV in a hypothesis-free manner. RESULTS: Our analysis uncovered a positive association between serum uric and PWV which was detected even if only individuals with urate values in the physiological range were included (n = 64,095). This correlation was more pronounced in women than in men. In multivariable linear regression models, we observed an association of uric acid (mmol/l) with PWV (m/s) of β = 1.12 (95% confidence interval (CI): 0.78; 1.45) in males and β = 1.35 (1.05; 1.66) in females, independent of other factors known to affect vascular stiffness. In addition, the machine learning approach identified uric acid as a major factor associated with PWV. The positive association was not restricted to hyperuricemia but evident even in the physiological concentration range. Based on the data from studies on the impact of aging on PWV, it is estimated that an increase in serum uric acid concentration by 0.1 mmol/l corresponds to an increase of approx. 7 years of age in females and of 4 years in males. CONCLUSIONS: Already in the physiological concentration range, uric acid is positively associated with parameters of arterial stiffness. This association is more pronounced in females as compared to males. This finding provides a mechanistic explanation for the increased risk of vascular end-organ damage associated with higher serum uric acid concentrations and supports the observed greater benefit of therapeutic uric acid lowering in female. Future intervention studies have to address the mechanistic causality of the observed effect. AU - Thews, O.* AU - Schmid, T.* AU - Kluttig, A.* AU - Wienke, A.* AU - Zinkhan, M.* AU - Ahrens, W.* AU - Barnighausen, T.* AU - Brenner, H.* AU - Castell, S.* AU - Lange, B.* AU - Lieb, W.* AU - Greiser, K.H.* AU - Dörr, M.* AU - Krist, L.* AU - Willich, S.N.* AU - Harth, V.* AU - Obi, N.* AU - Leitzmann, M.* AU - Peters, A. AU - Schmidt, B.* AU - Schulze, M.B.* AU - Völzke, H.* AU - Nauck, M.* AU - Zylla, S.* AU - Hannemann, A.* AU - Pischon, T.* AU - Velásquez, I.M.* AU - Girndt, M.* AU - Grossmann, C.* AU - Gekle, M.* C1 - 75055 C2 - 57735 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Physiological serum uric acid concentrations correlate with arterial stiffness in a sex-dependent manner. JO - BMC Med. VL - 23 IS - 1 PB - Bmc PY - 2025 SN - 1741-7015 ER - TY - JOUR AB - BACKGROUND: Protein biomarkers may contribute to the identification of vulnerable subgroups for premature mortality. This study aimed to investigate the association of plasma proteins with all-cause and cause-specific mortality among individuals with and without baseline type 2 diabetes (T2D) and evaluate their impact on the prediction of all-cause mortality in two prospective Cooperative Health Research in the Region of Augsburg (KORA) studies. METHODS: The discovery cohort comprised 1545 participants (median follow-up 15.6 years; 244 with T2D: 116 total, 62 cardiovascular, 31 cancer-related and 23 other-cause deaths; 1301 without T2D: 321 total, 114 cardiovascular, 120 cancer-related and 87 other-cause deaths). The validation cohort comprised 1031 participants (median follow-up 6.9 years; 203 with T2D: 76 total, 45 cardiovascular, 19 cancer-related and 12 other-cause deaths; 828 without T2D: 169 total, 74 cardiovascular, 39 cancer-related and 56 other-cause deaths). We used Cox regression to examine associations of 233 plasma proteins with all-cause and cause-specific mortality and Lasso regression to construct prediction models for all-cause mortality stratifying by baseline T2D. C-index, category-free net reclassification index (cfNRI), and integrated discrimination improvement (IDI) were conducted to evaluate the predictive performance of built prediction models. RESULTS: Thirty-five and 62 proteins, with 29 overlapping, were positively associated with all-cause mortality in the group with and without T2D, respectively. Out of these, in the group with T2D, 35, eight, and 26 were positively associated with cardiovascular, cancer-related, and other-cause mortality, while in the group without T2D, 55, 41, and 47 were positively associated with respective cause-specific outcomes in the pooled analysis of both cohorts. Regulation of insulin-like growth factor (IGF) transport and uptake by IGF-binding proteins emerged as a unique pathway enriched for all-cause and cardiovascular mortality in individuals with T2D. The combined model containing the selected proteins (five and 12 proteins, with four overlapping, in the group with and without T2D, respectively) and clinical risk factors improved the prediction of all-cause mortality by C-index, cfNRI, and IDI. CONCLUSIONS: This study uncovered shared and unique mortality-related proteins in persons with and without T2D and emphasized the role of proteins in improving the prediction of mortality in different T2D subgroups. AU - Luo, H. AU - Petrera, A. AU - Hauck, S.M. AU - Rathmann, W.* AU - Herder, C.* AU - Gieger, C. AU - Hoyer, A.* AU - Peters, A. AU - Thorand, B. C1 - 71870 C2 - 56242 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Association of plasma proteomics with mortality in individuals with and without type 2 diabetes: Results from two population-based KORA cohort studies. JO - BMC Med. VL - 22 IS - 1 PB - Bmc PY - 2024 SN - 1741-7015 ER - TY - JOUR AB - Background: IMCY-0098, a synthetic peptide developed to halt disease progression via elimination of key immune cells in the autoimmune cascade, has shown a promising safety profile for the treatment of type 1 diabetes (T1D) in a recent phase 1b trial. This exploratory analysis of data from that trial aimed to identify the patient biomarkers at baseline associated with a positive response to treatment and examined the associations between immune response parameters and clinical efficacy endpoints (as surrogates for mechanism of action endpoints) using an artificial intelligence-based approach of unsupervised explainable machine learning. Methods: We conducted an exploratory analysis of data from a phase 1b, dose-escalation, randomized, placebo-controlled study of IMCY-0098 in patients with recent-onset T1D. Here, a panel of markers of T cell activation, memory T cells, and effector T cell response were analyzed via descriptive statistics. Artificial intelligence-based analyses of associations between all variables, including immune responses and clinical responses, were performed using the Knowledge Extraction and Management (KEM®) v 3.6.2 analytical platform. Results: The relationship between all available patient data was investigated using unsupervised machine learning implemented in the KEM® environment. Of 15 associations found for the dose C group (450 μg subcutaneously followed by 3 × 225 μg subcutaneously), seven involved human leukocyte antigen (HLA) type, all of which identified improvement/absence of worsening of disease parameters in DR4+ patients and worsening/absence of improvement in DR4− patients. This association with DR4+ and non-DR3 was confirmed using the endpoints normalized area under the curve C-peptide from mixed meal tolerance tests where presence of DR4 HLA haplotype was associated with an improvement in both endpoints. Exploratory immune analysis showed that IMCY-0098 dose B (150 μg subcutaneously followed by 3 × 75 μg subcutaneously) and dose C led to an increase in presumed/potentially protective antigen-specific cytolytic CD4+ T cells and a decrease in pathogenic CD8+ T cells, consistent with the expected mechanism of action of IMCY-0098. The analysis identified significant associations between immune and clinical responses to IMCY-0098. Conclusions: Promising preliminary efficacy results support the design of a phase 2 study of IMCY-0098 in patients with recent-onset T1D. Trial registration: ClinicalTrials.gov NCT03272269; EudraCT: 2016–003514-27. AU - Van Rampelbergh, J.* AU - Achenbach, P. AU - Leslie, R.D.* AU - Kindermans, M.* AU - Parmentier, F.* AU - Carlier, V.* AU - Bovy, N.* AU - Vanderelst, L.* AU - Van Mechelen, M.* AU - Vandepapeliere, P.* AU - Boitard, C.* C1 - 70893 C2 - 55799 CY - Campus, 4 Crinan St, London N1 9xw, England TI - First-in-human, double-blind, randomized phase 1b study of peptide immunotherapy IMCY-0098 in new-onset type 1 diabetes: an exploratory analysis of immune biomarkers. JO - BMC Med. VL - 22 IS - 1 PB - Bmc PY - 2024 SN - 1741-7015 ER - TY - JOUR AB - BACKGROUND: The potential impact of specific food additives, common in Western diets, on the risk of developing type 2 diabetes is not well understood. This study focuses on carrageenan, a widely used food additive known to induce insulin resistance and gut inflammation in animal models, and its effects on human health. METHODS: In a randomised, double-blind, placebo-controlled, cross-over trial conducted at a university hospital metabolic study centre, 20 males (age 27.4 ± 4.3 years, BMI 24.5 ± 2.5 kg/m2) participated. The intervention involved oral intake of carrageenan (250 mg) or placebo in the morning and in the evening and each intervention lasted 2 weeks. The primary outcome measured was insulin sensitivity (using oral glucose tolerance test [OGTT] and hyperinsulinaemic-euglycaemic clamp). Additional end-points included whole body and hepatic insulin sensitivity, MRI-measured brain inflammation and insulin resistance, intestinal permeability (via lactulose-mannitol test and plasma zonulin levels), and gut microbiome composition. Immune-cell activation and pro-inflammatory cytokine release from peripheral blood mononuclear cells were measured. RESULTS: Overall insulin sensitivity did not show significant differences between the treatments. However, interactions between BMI and treatment were observed (OGTT-based insulin sensitivity index: p=0.04, fasting insulin resistance: p=0.01, hepatic insulin sensitivity index: p=0.04). In overweight participants, carrageenan exposure resulted in lower whole body and hepatic insulin sensitivity, a trend towards increased brain inflammation, and elevated C-reactive protein (CRP) and IL-6 levels compared to placebo. Additionally, carrageenan was associated with increased intestinal permeability. In vitro natural killer (NK-)cell activation and increased pro-inflammatory cytokine release were found after carrageenan exposure in the participant's peripheral blood mononuclear cells. CONCLUSIONS: These findings suggest that carrageenan, a common food additive, may contribute to insulin resistance and subclinical inflammation in overweight individuals through pro-inflammatory mechanisms in the gut. Further investigation into the long-term health impacts of carrageenan and other food additives is warranted. TRIAL REGISTRATION: NCT02629705. AU - Wagner, R. AU - Buettner, J.* AU - Heni, M. AU - Fritsche, L. AU - Kullmann, S. AU - Wagmüller, M.* AU - Peter, A. AU - Preissl, H. AU - Machann, J. AU - Jumpertz von Schwartzenberg, R. AU - Birkenfeld, A.L. AU - Pape, U.F.* AU - van Hall, G.* AU - Plomgaard, P.* AU - Häring, H.-U. AU - Fritsche, A. AU - Thompson, K.N.* AU - Klein, R.* AU - Stefan, N. C1 - 72546 C2 - 56620 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Carrageenan and insulin resistance in humans: A randomised double-blind cross-over trial. JO - BMC Med. VL - 22 IS - 1 PB - Bmc PY - 2024 SN - 1741-7015 ER - TY - JOUR AB - BACKGROUND: The specific microbiota and associated metabolites linked to non-alcoholic fatty liver disease (NAFLD) are still controversial. Thus, we aimed to understand how the core gut microbiota and metabolites impact NAFLD. METHODS: The data for the discovery cohort were collected from the Guangzhou Nutrition and Health Study (GNHS) follow-up conducted between 2014 and 2018. We collected 272 metadata points from 1546 individuals. The metadata were input into four interpretable machine learning models to identify important gut microbiota associated with NAFLD. These models were subsequently applied to two validation cohorts [the internal validation cohort (n = 377), and the prospective validation cohort (n = 749)] to assess generalizability. We constructed an individual microbiome risk score (MRS) based on the identified gut microbiota and conducted animal faecal microbiome transplantation experiment using faecal samples from individuals with different levels of MRS to determine the relationship between MRS and NAFLD. Additionally, we conducted targeted metabolomic sequencing of faecal samples to analyse potential metabolites. RESULTS: Among the four machine learning models used, the lightGBM algorithm achieved the best performance. A total of 12 taxa-related features of the microbiota were selected by the lightGBM algorithm and further used to calculate the MRS. Increased MRS was positively associated with the presence of NAFLD, with odds ratio (OR) of 1.86 (1.72, 2.02) per 1-unit increase in MRS. An elevated abundance of the faecal microbiota (f__veillonellaceae) was associated with increased NAFLD risk, whereas f__rikenellaceae, f__barnesiellaceae, and s__adolescentis were associated with a decreased presence of NAFLD. Higher levels of specific gut microbiota-derived metabolites of bile acids (taurocholic acid) might be positively associated with both a higher MRS and NAFLD risk. FMT in mice further confirmed a causal association between a higher MRS and the development of NAFLD. CONCLUSIONS: We confirmed that an alteration in the composition of the core gut microbiota might be biologically relevant to NAFLD development. Our work demonstrated the role of the microbiota in the development of NAFLD. AU - Zeng, F.* AU - Su, X.* AU - Liang, X.* AU - Liao, M. AU - Zhong, H.* AU - Xu, J.* AU - Gou, W.* AU - Zhang, X.* AU - Shen, L.* AU - Zheng, J.S.* AU - Chen, Y.M.* C1 - 70173 C2 - 55439 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Gut microbiome features and metabolites in non-alcoholic fatty liver disease among community-dwelling middle-aged and older adults. JO - BMC Med. VL - 22 IS - 1 PB - Bmc PY - 2024 SN - 1741-7015 ER - TY - JOUR AB - BACKGROUND: Personalised medicine is a medical model that aims to provide tailor-made prevention and treatment strategies for defined groups of individuals. The concept brings new challenges to the translational step, both in clinical relevance and validity of models. We have developed a set of recommendations aimed at improving the robustness of preclinical methods in translational research for personalised medicine. METHODS: These recommendations have been developed following four main steps: (1) a scoping review of the literature with a gap analysis, (2) working sessions with a wide range of experts in the field, (3) a consensus workshop, and (4) preparation of the final set of recommendations. RESULTS: Despite the progress in developing innovative and complex preclinical model systems, to date there are fundamental deficits in translational methods that prevent the further development of personalised medicine. The literature review highlighted five main gaps, relating to the relevance of experimental models, quality assessment practices, reporting, regulation, and a gap between preclinical and clinical research. We identified five points of focus for the recommendations, based on the consensus reached during the consultation meetings: (1) clinically relevant translational research, (2) robust model development, (3) transparency and education, (4) revised regulation, and (5) interaction with clinical research and patient engagement. Here, we present a set of 15 recommendations aimed at improving the robustness of preclinical methods in translational research for personalised medicine. CONCLUSIONS: Appropriate preclinical models should be an integral contributor to interventional clinical trial success rates, and predictive translational models are a fundamental requirement to realise the dream of personalised medicine. The implementation of these guidelines is ambitious, and it is only through the active involvement of all relevant stakeholders in this field that we will be able to make an impact and effectuate a change which will facilitate improved translation of personalised medicine in the future. AU - Fosse, V.* AU - Oldoni, E.* AU - Bietrix, F.* AU - Budillon, A.* AU - Daskalopoulos, E.P.* AU - Fratelli, M.* AU - Gerlach, B.* AU - Groenen, P.M.A.* AU - Hölter, S.M. AU - Menon, J.M.L.* AU - Mobasheri, A.* AU - Osborne, N.* AU - Ritskes-Hoitinga, M.* AU - Ryll, B.* AU - Schmitt, E.* AU - Ussi, A.* AU - Andreu, A.L.* AU - McCormack, E.* AU - PERMIT group* C1 - 67170 C2 - 54229 TI - Recommendations for robust and reproducible preclinical research in personalised medicine. JO - BMC Med. VL - 21 IS - 1 PY - 2023 SN - 1741-7015 ER - TY - JOUR AB - BACKGROUND: Solute carrier family 13 member 5 (SLC13A5) is a Na+-coupled citrate co-transporter that mediates entry of extracellular citrate into the cytosol. SLC13A5 inhibition has been proposed as a target for reducing progression of kidney disease. The aim of this study was to leverage the Mendelian randomization paradigm to gain insight into the effects of SLC13A5 inhibition in humans, towards prioritizing and informing clinical development efforts. METHODS: The primary Mendelian randomization analyses investigated the effect of SLC13A5 inhibition on measures of kidney function, including creatinine and cystatin C-based measures of estimated glomerular filtration rate (creatinine-eGFR and cystatin C-eGFR), blood urea nitrogen (BUN), urine albumin-creatinine ratio (uACR), and risk of chronic kidney disease and microalbuminuria. Secondary analyses included a paired plasma and urine metabolome-wide association study, investigation of secondary traits related to SLC13A5 biology, a phenome-wide association study (PheWAS), and a proteome-wide association study. All analyses were compared to the effect of genetically predicted plasma citrate levels using variants selected from across the genome, and statistical sensitivity analyses robust to the inclusion of pleiotropic variants were also performed. Data were obtained from large-scale genetic consortia and biobanks, with sample sizes ranging from 5023 to 1,320,016 individuals. RESULTS: We found evidence of associations between genetically proxied SLC13A5 inhibition and higher creatinine-eGFR (p = 0.002), cystatin C-eGFR (p = 0.005), and lower BUN (p = 3 × 10-4). Statistical sensitivity analyses robust to the inclusion of pleiotropic variants suggested that these effects may be a consequence of higher plasma citrate levels. There was no strong evidence of associations of genetically proxied SLC13A5 inhibition with uACR or risk of CKD or microalbuminuria. Secondary analyses identified evidence of associations with higher plasma calcium levels (p = 6 × 10-13) and lower fasting glucose (p = 0.02). PheWAS did not identify any safety concerns. CONCLUSIONS: This Mendelian randomization analysis provides human-centric insight to guide clinical development of an SLC13A5 inhibitor. We identify plasma calcium and citrate as biologically plausible biomarkers of target engagement, and plasma citrate as a potential biomarker of mechanism of action. Our human genetic evidence corroborates evidence from various animal models to support effects of SLC13A5 inhibition on improving kidney function. AU - Gill, D.* AU - Zagkos, L.* AU - Gill, R.* AU - Benzing, T.* AU - Jordan, J.* AU - Birkenfeld, A.L. AU - Burgess, S.* AU - Zahn, G.* C1 - 69065 C2 - 53840 CY - Campus, 4 Crinan St, London N1 9xw, England TI - The citrate transporter SLC13A5 as a therapeutic target for kidney disease: Evidence from Mendelian randomization to inform drug development. JO - BMC Med. VL - 21 IS - 1 PB - Bmc PY - 2023 SN - 1741-7015 ER - TY - JOUR AB - Background: Due to the asymptomatic nature of the early stages, chronic kidney disease (CKD) is usually diagnosed at late stages and lacks targeted therapy, highlighting the need for new biomarkers to better understand its pathophysiology and to be used for early diagnosis and therapeutic targets. Given the close relationship between CKD and cardiovascular disease (CVD), we investigated the associations of 233 CVD- and inflammation-related plasma proteins with kidney function decline and aimed to assess whether the observed associations are causal. Methods: We included 1140 participants, aged 55–74 years at baseline, from the Cooperative Health Research in the Region of Augsburg (KORA) cohort study, with a median follow-up time of 13.4 years and 2 follow-up visits. We measured 233 plasma proteins using a proximity extension assay at baseline. In the discovery analysis, linear regression models were used to estimate the associations of 233 proteins with the annual rate of change in creatinine-based estimated glomerular filtration rate (eGFRcr). We further investigated the association of eGFRcr-associated proteins with the annual rate of change in cystatin C-based eGFR (eGFRcys) and eGFRcr-based incident CKD. Two-sample Mendelian randomization was used to infer causality. Results: In the fully adjusted model, 66 out of 233 proteins were inversely associated with the annual rate of change in eGFRcr, indicating that higher baseline protein levels were associated with faster eGFRcr decline. Among these 66 proteins, 21 proteins were associated with both the annual rate of change in eGFRcys and incident CKD. Mendelian randomization analyses on these 21 proteins suggest a potential causal association of higher tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) level with eGFR decline. Conclusions: We reported 21 proteins associated with kidney function decline and incident CKD and provided preliminary evidence suggesting a potential causal association between TNFRSF11A and kidney function decline. Further Mendelian randomization studies are needed to establish a conclusive causal association. AU - Lin, J. AU - Nano, J. AU - Petrera, A. AU - Hauck, S.M. AU - Zeller, T.* AU - Koenig, W.* AU - Müller, C.L. AU - Peters, A. AU - Thorand, B. C1 - 68431 C2 - 54625 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Proteomic profiling of longitudinal changes in kidney function among middle-aged and older men and women: The KORA S4/F4/FF4 study. JO - BMC Med. VL - 21 IS - 1 PB - Bmc PY - 2023 SN - 1741-7015 ER - TY - JOUR AB - BACKGROUND: Amino acid metabolism is dysregulated in colorectal cancer patients; however, it is not clear whether pre-diagnostic levels of amino acids are associated with subsequent risk of colorectal cancer. We investigated circulating levels of amino acids in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank cohorts. METHODS: Concentrations of 13-21 amino acids were determined in baseline fasting plasma or serum samples in 654 incident colorectal cancer cases and 654 matched controls in EPIC. Amino acids associated with colorectal cancer risk following adjustment for the false discovery rate (FDR) were then tested for associations in the UK Biobank, for which measurements of 9 amino acids were available in 111,323 participants, of which 1221 were incident colorectal cancer cases. RESULTS: Histidine levels were inversely associated with colorectal cancer risk in EPIC (odds ratio [OR] 0.80 per standard deviation [SD], 95% confidence interval [CI] 0.69-0.92, FDR P-value=0.03) and in UK Biobank (HR 0.93 per SD, 95% CI 0.87-0.99, P-value=0.03). Glutamine levels were borderline inversely associated with colorectal cancer risk in EPIC (OR 0.85 per SD, 95% CI 0.75-0.97, FDR P-value=0.08) and similarly in UK Biobank (HR 0.95, 95% CI 0.89-1.01, P=0.09) In both cohorts, associations changed only minimally when cases diagnosed within 2 or 5 years of follow-up were excluded. CONCLUSIONS: Higher circulating levels of histidine were associated with a lower risk of colorectal cancer in two large prospective cohorts. Further research to ascertain the role of histidine metabolism and potentially that of glutamine in colorectal cancer development is warranted. AU - Rothwell, J.A.* AU - Bešević, J.* AU - Dimou, N.* AU - Breeur, M.* AU - Murphy, N.* AU - Jenab, M.* AU - Wedekind, R.* AU - Viallon, V.* AU - Ferrari, P.* AU - Achaintre, D.* AU - Gicquiau, A.* AU - Rinaldi, S.* AU - Scalbert, A.* AU - Huybrechts, I.* AU - Prehn, C. AU - Adamski, J. AU - Cross, A.J.* AU - Keun, H.* AU - Chadeau-Hyam, M.* AU - Boutron-Ruault, M.C.* AU - Overvad, K.* AU - Dahm, C.C.* AU - Nøst, T.H.* AU - Sandanger, T.M.* AU - Skeie, G.* AU - Zamora-Ros, R.* AU - Tsilidis, K.K.* AU - Eichelmann, F.* AU - Schulze, M.B.* AU - van Guelpen, B.* AU - Vidman, L.* AU - Sánchez, M.J.* AU - Amiano, P.* AU - Ardanaz, E.* AU - Smith-Byrne, K.* AU - Travis, R.* AU - Katzke, V.* AU - Kaaks, R.* AU - Derksen, J.W.G.* AU - Colorado-Yohar, S.* AU - Tumino, R.* AU - Bueno-de-Mesquita, B.* AU - Vineis, P.* AU - Palli, D.* AU - Pasanisi, F.* AU - Eriksen, A.K.* AU - Tjønneland, A.* AU - Severi, G.* AU - Gunter, M.J.* C1 - 67574 C2 - 54076 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Circulating amino acid levels and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition and UK Biobank cohorts. JO - BMC Med. VL - 21 IS - 1 PB - Bmc PY - 2023 SN - 1741-7015 ER - TY - JOUR AB - BACKGROUND: Type 1 diabetes (T1D) is a CD4+ T cell-driven autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells by CD8+ T cells. Achieving glycemic targets in T1D remains challenging in clinical practice; new treatments aim to halt autoimmunity and prolong β-cell survival. IMCY-0098 is a peptide derived from human proinsulin that contains a thiol-disulfide oxidoreductase motif at the N-terminus and was developed to halt disease progression by promoting the specific elimination of pathogenic T cells. METHODS: This first-in-human, 24-week, double-blind phase 1b study evaluated the safety of three dosages of IMCY-0098 in adults diagnosed with T1D < 6 months before study start. Forty-one participants were randomized to receive four bi-weekly injections of placebo or increasing doses of IMCY-0098 (dose groups A/B/C received 50/150/450 μg for priming followed by three further administrations of 25/75/225 μg, respectively). Multiple T1D-related clinical parameters were also assessed to monitor disease progression and inform future development. Long-term follow-up to 48 weeks was also conducted in a subset of patients. RESULTS: Treatment with IMCY-0098 was well tolerated with no systemic reactions; a total of 315 adverse events (AEs) were reported in 40 patients (97.6%) and were related to study treatment in 29 patients (68.3%). AEs were generally mild; no AE led to discontinuation of the study or death. No significant decline in C-peptide was noted from baseline to Week 24 for dose A, B, C, or placebo (mean change - 0.108, - 0.041, - 0.040, and - 0.012, respectively), suggesting no disease progression. CONCLUSIONS: Promising safety profile and preliminary clinical response data support the design of a phase 2 study of IMCY-0098 in patients with recent-onset T1D. TRIAL REGISTRATION: IMCY-T1D-001: ClinicalTrials.gov NCT03272269; EudraCT: 2016-003514-27; and IMCY-T1D-002: ClinicalTrials.gov NCT04190693; EudraCT: 2018-003728-35. AU - Van Rampelbergh, J.* AU - Achenbach, P. AU - Leslie, R.D.* AU - Ali, M.A.* AU - Dayan, C.* AU - Keymeulen, B.* AU - Owen, K.R.* AU - Kindermans, M.* AU - Parmentier, F.* AU - Carlier, V.* AU - Ahangarani, R.R.* AU - Gebruers, E.* AU - Bovy, N.* AU - Vanderelst, L.* AU - Van Mechelen, M.* AU - Vandepapeliere, P.* AU - Boitard, C.* C1 - 67897 C2 - 54375 CY - Campus, 4 Crinan St, London N1 9xw, England TI - First-in-human, double-blind, randomized phase 1b study of peptide immunotherapy IMCY-0098 in new-onset type 1 diabetes. JO - BMC Med. VL - 21 IS - 1 PB - Bmc PY - 2023 SN - 1741-7015 ER - TY - JOUR AB - Background: Epigenetic age is an estimator of biological age based on DNA methylation; its discrepancy from chronologic age warrants further investigation. We recently reported that greater polyphenol intake benefitted ectopic fats, brain function, and gut microbiota profile, corresponding with elevated urine polyphenols. The effect of polyphenol-rich dietary interventions on biological aging is yet to be determined. Methods: We calculated different biological aging epigenetic clocks of different generations (Horvath2013, Hannum2013, Li2018, Horvath skin and blood2018, PhenoAge2018, PCGrimAge2022), their corresponding age and intrinsic age accelerations, and DunedinPACE, all based on DNA methylation (Illumina EPIC array; pre-specified secondary outcome) for 256 participants with abdominal obesity or dyslipidemia, before and after the 18-month DIRECT PLUS randomized controlled trial. Three interventions were assigned: healthy dietary guidelines, a Mediterranean (MED) diet, and a polyphenol-rich, low-red/processed meat Green-MED diet. Both MED groups consumed 28 g walnuts/day (+ 440 mg/day polyphenols). The Green-MED group consumed green tea (3–4 cups/day) and Mankai (Wolffia globosa strain) 500-ml green shake (+ 800 mg/day polyphenols). Adherence to the Green-MED diet was assessed by questionnaire and urine polyphenols metabolomics (high-performance liquid chromatography quadrupole time of flight). Results: Baseline chronological age (51.3 ± 10.6 years) was significantly correlated with all methylation age (mAge) clocks with correlations ranging from 0.83 to 0.95; p < 2.2e − 16 for all. While all interventions did not differ in terms of changes between mAge clocks, greater Green-Med diet adherence was associated with a lower 18-month relative change (i.e., greater mAge attenuation) in Li and Hannum mAge (beta = − 0.41, p = 0.004 and beta = − 0.38, p = 0.03, respectively; multivariate models). Greater Li mAge attenuation (multivariate models adjusted for age, sex, baseline mAge, and weight loss) was mostly affected by higher intake of Mankai (beta = − 1.8; p = 0.061) and green tea (beta = − 1.57; p = 0.0016) and corresponded with elevated urine polyphenols: hydroxytyrosol, tyrosol, and urolithin C (p < 0.05 for all) and urolithin A (p = 0.08), highly common in green plants. Overall, participants undergoing either MED-style diet had ~ 8.9 months favorable difference between the observed and expected Li mAge at the end of the intervention (p = 0.02). Conclusions: This study showed that MED and green-MED diets with increased polyphenols intake, such as green tea and Mankai, are inversely associated with biological aging. To the best of our knowledge, this is the first clinical trial to indicate a potential link between polyphenol intake, urine polyphenols, and biological aging. Trial registration: ClinicalTrials.gov, NCT03020186. AU - Yaskolka Meir, A.* AU - Keller, M. AU - Hoffmann, A. AU - Rinott, E.* AU - Tsaban, G.* AU - Kaplan, A.* AU - Zelicha, H.* AU - Hagemann, T. AU - Ceglarek, U.* AU - Isermann, B.* AU - Shelef, I.* AU - Blüher, M. AU - Stumvoll, M. AU - Li, J.* AU - Haange, S.B.* AU - Engelmann, B.* AU - Rolle-Kampczyk, U.* AU - von Bergen, M.* AU - Hu, F.B.* AU - Stampfer, M.J.* AU - Kovacs, P.* AU - Liang, L.* AU - Shai, I. C1 - 68220 C2 - 54788 CY - Campus, 4 Crinan St, London N1 9xw, England TI - The effect of polyphenols on DNA methylation-assessed biological age attenuation: The DIRECT PLUS randomized controlled trial. JO - BMC Med. VL - 21 IS - 1 PB - Bmc PY - 2023 SN - 1741-7015 ER - TY - JOUR AB - BACKGROUND: Epidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations. METHODS: We analysed targeted metabolomics data available for 5828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data-shared lasso penalty. RESULTS: Out of the 50 studied metabolites, (i) six were inversely associated with the risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2, and three clusters of phosphatidylcholines (PCs); (ii) three were positively associated with most cancer types: proline, decanoylcarnitine, and one cluster of PCs; and (iii) 10 were specifically associated with particular cancer types, including histidine that was inversely associated with colorectal cancer risk and one cluster of sphingomyelins that was inversely associated with risk of hepatocellular carcinoma and positively with endometrial cancer risk. CONCLUSIONS: These results could provide novel insights for the identification of pathways for cancer development, in particular those shared across different cancer types. AU - Breeur, M.* AU - Ferrari, P.* AU - Dossus, L.* AU - Jenab, M.* AU - Johansson, M.* AU - Rinaldi, S.* AU - Travis, R.C.* AU - His, M.* AU - Key, T.J.* AU - Schmidt, J.A.* AU - Overvad, K.* AU - Tjønneland, A.* AU - Kyrø, C.* AU - Rothwell, J.A.* AU - Laouali, N.* AU - Severi, G.* AU - Kaaks, R.* AU - Katzke, V.* AU - Schulze, M.B.* AU - Eichelmann, F.* AU - Palli, D.* AU - Grioni, S.* AU - Panico, S.* AU - Tumino, R.* AU - Sacerdote, C.* AU - Bueno-de-Mesquita, B.* AU - Olsen, K.S.* AU - Sandanger, T.M.* AU - Nøst, T.H.* AU - Quirós, J.R.* AU - Bonet, C.* AU - Barranco, M.R.* AU - Chirlaque, M.D.* AU - Ardanaz, E.* AU - Sandsveden, M.* AU - Manjer, J.* AU - Vidman, L.* AU - Rentoft, M.* AU - Muller, D.* AU - Tsilidis, K.K.* AU - Heath, A.K.* AU - Keun, H.C.* AU - Adamski, J. AU - Keski-Rahkonen, P.* AU - Scalbert, A.* AU - Gunter, M.J.* AU - Viallon, V.* C1 - 66479 C2 - 52836 TI - Pan-cancer analysis of pre-diagnostic blood metabolite concentrations in the European Prospective Investigation into Cancer and Nutrition. JO - BMC Med. VL - 20 IS - 1 PY - 2022 SN - 1741-7015 ER - TY - JOUR AB - BACKGROUND: The question of whether asthma is causally related to gastrointestinal disorders remained unanswered so far. Thus, this study investigated whether there is such a relation and whether the time of onset of asthma plays a role in the occurrence of the following gastrointestinal disorders: peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD), irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD) including the distinction between Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Using summary data of genome-wide association studies (GWASs), we ran Mendelian randomization analyses based on up to 456,327 European participants. Outlier assessment, a series of sensitivity analyses and validation of IBD results in a second GWAS were performed to confirm the results. RESULTS: Presented ORs represent the average change in the outcome per 2.72-fold increase in the prevalence of the exposure. Genetically predicted childhood-onset asthma was positively associated with PUD, GORD, and IBS with similar odds ratios near 1.003 and adjusted P-values from 0.007 (GORD) to 0.047 (PUD). Furthermore, it was inversely related to IBD (OR = 0.992, 95% CI: 0.986, 0.998, adjusted P = 0.023) and suggestively associated with its UC subtype (OR = 0.990, 95% CI: 0.982, 0.998, adjusted P = 0.059). There were no associations between genetically predicted adult-onset asthma and the mentioned gastrointestinal disorders. CONCLUSIONS: This study provides evidence that the presence of asthma onset in childhood increases the risk for GORD, PUD, and IBS but decreases the risk for IBD in adults. The lower risk for IBD may be attributed to a lower risk primarily for UC. AU - Freuer, D.* AU - Linseisen, J. AU - Meisinger, C.* C1 - 64640 C2 - 52352 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Asthma and the risk of gastrointestinal disorders: A Mendelian randomization study. JO - BMC Med. VL - 20 IS - 1 PB - Bmc PY - 2022 SN - 1741-7015 ER - TY - JOUR AB - BACKGROUND: Mediterranean (MED) diet is a rich source of polyphenols, which benefit adiposity by several mechanisms. We explored the effect of the green-MED diet, twice fortified in dietary polyphenols and lower in red/processed meat, on visceral adipose tissue (VAT). METHODS: In the 18-month Dietary Intervention Randomized Controlled Trial PoLyphenols UnproceSsed (DIRECT-PLUS) weight-loss trial, 294 participants were randomized to (A) healthy dietary guidelines (HDG), (B) MED, or (C) green-MED diets, all combined with physical activity. Both isocaloric MED groups consumed 28 g/day of walnuts (+ 440 mg/day polyphenols). The green-MED group further consumed green tea (3-4 cups/day) and Wolffia globosa (duckweed strain) plant green shake (100 g frozen cubes/day) (+ 800mg/day polyphenols) and reduced red meat intake. We used magnetic resonance imaging (MRI) to quantify the abdominal adipose tissues. RESULTS: Participants (age = 51 years; 88% men; body mass index = 31.2 kg/m2; 29% VAT) had an 89.8% retention rate and 79.3% completed eligible MRIs. While both MED diets reached similar moderate weight (MED: - 2.7%, green-MED: - 3.9%) and waist circumference (MED: - 4.7%, green-MED: - 5.7%) loss, the green-MED dieters doubled the VAT loss (HDG: - 4.2%, MED: - 6.0%, green-MED: - 14.1%; p < 0.05, independent of age, sex, waist circumference, or weight loss). Higher dietary consumption of green tea, walnuts, and Wolffia globosa; lower red meat intake; higher total plasma polyphenols (mainly hippuric acid), and elevated urine urolithin A polyphenol were significantly related to greater VAT loss (p < 0.05, multivariate models). CONCLUSIONS: A green-MED diet, enriched with plant-based polyphenols and lower in red/processed meat, may be a potent intervention to promote visceral adiposity regression. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03020186. AU - Zelicha, H.* AU - Klöting, N.* AU - Kaplan, A.* AU - Yaskolka Meir, A.* AU - Rinott, E.* AU - Tsaban, G.* AU - Chassidim, Y.* AU - Blüher, M. AU - Ceglarek, U.* AU - Isermann, B.* AU - Stumvoll, M.* AU - Quayson, R.N.* AU - von Bergen, M.* AU - Engelmann, B.* AU - Rolle-Kampczyk, U.E.* AU - Haange, S.B.* AU - Tuohy, K.M.* AU - Diotallevi, C.* AU - Shelef, I.* AU - Hu, F.B.* AU - Stampfer, M.J.* AU - Shai, I.* C1 - 66322 C2 - 52779 TI - The effect of high-polyphenol Mediterranean diet on visceral adiposity: The DIRECT PLUS randomized controlled trial. JO - BMC Med. VL - 20 IS - 1 PY - 2022 SN - 1741-7015 ER - TY - JOUR AB - BACKGROUND: Periodontitis is among the most common chronic diseases worldwide, and it is one of the main reasons for tooth loss. Comprehensive profiling of the metabolite content of the saliva can enable the identification of novel pathways associated with periodontitis and highlight non-invasive markers to facilitate time and cost-effective screening efforts for the presence of periodontitis and the prediction of tooth loss. METHODS: We first investigated cross-sectional associations of 13 oral health variables with saliva levels of 562 metabolites, measured by untargeted mass spectrometry among a sub-sample (n = 938) of the Study of Health in Pomerania (SHIP-2) using linear regression models adjusting for common confounders. We took forward any candidate metabolite associated with at least two oral variables, to test for an association with a 5-year tooth loss over and above baseline oral health status using negative binomial regression models. RESULTS: We identified 84 saliva metabolites that were associated with at least one oral variable cross-sectionally, for a subset of which we observed robust replication in an independent study. Out of 34 metabolites associated with more than two oral variables, baseline saliva levels of nine metabolites were positively associated with a 5-year tooth loss. Across all analyses, the metabolites 2-pyrrolidineacetic acid and butyrylputrescine were the most consistent candidate metabolites, likely reflecting oral dysbiosis. Other candidate metabolites likely reflected tissue destruction and cell proliferation. CONCLUSIONS: Untargeted metabolic profiling of saliva replicated metabolic signatures of periodontal status and revealed novel metabolites associated with periodontitis and future tooth loss. AU - Andörfer, L.* AU - Holtfreter, B.* AU - Weiss, S.* AU - Matthes, R.* AU - Pitchika, V.* AU - Schmidt, C.O.* AU - Samietz, S.* AU - Kastenmüller, G. AU - Nauck, M.* AU - Völker, U.* AU - Völzke, H.* AU - Csonka, L.N.* AU - Suhre, K. AU - Pietzner, M.* AU - Kocher, T.* C1 - 62581 C2 - 50957 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Salivary metabolites associated with a 5-year tooth loss identified in a population-based setting. JO - BMC Med. VL - 19 IS - 1 PB - Bmc PY - 2021 SN - 1741-7015 ER - TY - JOUR AB - Background: Neurofilament light chain (NfL) is a cytoskeletal protein component whose release into blood is indicative of neuronal damage. Tau is a microtubule-associated protein in neurons and strongly associated with overall brain degeneration. NfL and tau levels are associated with mortality in different neurological diseases, but studies in the general population are missing. We investigated whether NfL and tau serum levels could serve as prognostic markers for overall mortality in elderly individuals without pre-defined neurological conditions. Further, we investigated the cross-sectional associations between NfL, tau, neuropsychological functioning, and brain structures. Methods: In 1997, 385 inhabitants of Augsburg who were aged 65 years and older were included in the Memory and Morbidity in Augsburg Elderly (MEMO) study. They participated in a face-to-face medical interview including neuropsychological tests and magnetic resonance imaging (MRI) of the brain. NfL and tau were measured from non-fasting blood samples using highly sensitive single molecule array assays. To assess the prognostic accuracy of the biomarkers, concordance statistics based on the predicted 5-year survival probabilities were calculated for different Cox regression models. Associations between the biomarkers and the neuropsychological test scores or brain structures were investigated using linear or logistic regression. Results: NfL (HR 1.27, 95% CI [1.14–1.42]) and tau (1.20 [1.07–1.35]) serum levels were independently associated with all-cause mortality. NfL, but not tau, increased the prognostic accuracy when added to a model containing sociodemographic characteristics (concordance statistic 0.684 [0.612–0.755] vs. 0.663 [0.593–0.733]), but not when added to a model containing sociodemographic characteristics and brain atrophy or neuropsychological test scores. NfL serum levels were cross-sectionally associated with neuropsychological test scores and brain structures. Conclusions: The association between NfL serum levels and brain atrophy and neuropsychological performance in individuals without overt neurological disease is similar to that seen in patients with neurodegenerative diseases. These findings support the concept of a continuum of physiological aging and incipient, subclinical pathology, and manifest disease. NfL, but not tau, serum levels might serve as a prognostic marker for all-cause mortality if no other clinical information is available. AU - Rübsamen, N.* AU - Maceski, A.* AU - Leppert, D.* AU - Benkert, P.* AU - Kuhle, J.* AU - Wiendl, H.* AU - Peters, A. AU - Karch, A.* AU - Berger, K.* C1 - 61380 C2 - 49837 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Serum neurofilament light and tau as prognostic markers for all-cause mortality in the elderly general population—an analysis from the MEMO study. JO - BMC Med. VL - 19 IS - 1 PB - Bmc PY - 2021 SN - 1741-7015 ER - TY - JOUR AB - BackgroundMaternal weight variables are important predictors of postpartum depression (PPD). While preliminary evidence points to an association between pre-pregnancy obesity and PPD, the role of excessive gestational weight gain (GWG) on PPD is less studied. In this secondary cohort analysis of the German 'healthy living in pregnancy' (GeliS) trial, we aimed to investigate associations between weight-related variables and PPD and to assess the influence of GWG on the risk for PPD.MethodsWe included women with normal weight, overweight, and obesity (BMI 18.5-40.0kg/m(2)). Symptoms of PPD were assessed 6-8weeks postpartum using the Edinburgh Postnatal Depression Scale. Pre-pregnancy BMI was self-reported. During the course of pregnancy, weight was measured at gynaecological practices within regular check-ups. GWG was defined as the difference between the last measured weight before delivery and the first measured weight at the time of recruitment (<= 12(th) week of gestation). Excessive GWG was classified according to the Institute of Medicine. Multiple logistic regression analyses were used to estimate the odds of PPD in relation to pre-pregnancy BMI, GWG, and excessive GWG adjusting for important confounders.ResultsOf the total 1583 participants, 45.6% (n=722) showed excessive GWG and 7.9% (n=138) experienced PPD. Pre-pregnancy BMI (per 5-unit increase; OR=1.23, 95% CI 1.08-1.41, p=0.002) and pre-pregnancy overweight or obesity were significantly positively associated with the odds of developing PPD, particularly among women with an antenatal history of anxiety or depressive symptoms (overweight: OR=1.93, 95% CI=1.15-3.22, p=0.01; obesity: OR=2.11, 95% CI=1.13-3.96, p=0.02). Sociodemographic or lifestyle factors did not additively influence the odds of having PPD. In fully adjusted models, there was no significant evidence that GWG or the occurrence of excessive GWG increased the odds of experiencing PPD (excessive vs. non-excessive: OR=3.48, 95% CI 0.35-34.94; GWG per 1kg increase: OR=1.16, 95% CI 0.94-1.44).ConclusionPre-pregnancy overweight or obesity is associated with PPD independent of concurrent risk factors. History of anxiety or depressive symptoms suggests a stress-induced link between pre-pregnancy weight and PPD.Trial registrationNCT01958307, ClinicalTrials.gov, retrospectively registered on 9 October 2013. AU - Johar, H. AU - Hoffmann, J.* AU - Günther, J.* AU - Atasoy, S. AU - Stecher, L.* AU - Spies, M.* AU - Hauner, H.* AU - Ladwig, K.-H. C1 - 59768 C2 - 48952 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Evaluation of antenatal risk factors for postpartum depression: A secondary cohort analysis of the cluster-randomised GeliS trial. JO - BMC Med. VL - 18 IS - 1 PB - Bmc PY - 2020 SN - 1741-7015 ER - TY - JOUR AB - Background: Chronic kidney disease has emerged as a strong cardiovascular risk factor, and in many current guidelines, it is already considered as a coronary heart disease (CHD) equivalent. Routinely, creatinine has been used as the main marker of renal function, but recently, cystatin C emerged as a more promising marker. The aim of this study was to assess the comparative cardiovascular and mortality risk of chronic kidney disease (CKD) using cystatin C-based and creatinine-based equations of the estimated glomerular filtration rate (eGFR) in participants of population-based and disease cohorts. Methods: The present study has been conducted within the BiomarCaRE project, with harmonized data from 20 population-based cohorts (n = 76,954) from 6 European countries and 3 cardiovascular disease (CVD) cohorts (n = 4982) from Germany. Cox proportional hazards models were used to assess hazard ratios (HRs) for the various CKD definitions with adverse outcomes and mortality after adjustment for the Systematic COronary Risk Evaluation (SCORE) variables and study center. Main outcome measures were cardiovascular diseases, cardiovascular death, and all-cause mortality. Results: The overall prevalence of CKD stage 3–5 by creatinine- and cystatin C-based eGFR, respectively, was 3.3% and 7.4% in the population-based cohorts and 13.9% and 14.4% in the disease cohorts. CKD was an important independent risk factor for subsequent CVD events and mortality. For example, in the population-based cohorts, the HR for CVD mortality was 1.72 (95% CI 1.53 to 1.92) with creatinine-based CKD and it was 2.14 (95% CI 1.90 to 2.40) based on cystatin-based CKD compared to participants without CKD. In general, the HRs were higher for cystatin C-based CKD compared to creatinine-based CKD, for all three outcomes and risk increased clearly below the conventional threshold for CKD, also in older adults. Net reclassification indices were larger for a cystatin-C based CKD definition. Differences in HRs (between the two CKD measures) in the disease cohorts were less pronounced than in the population-based cohorts. Conclusion: CKD is an important risk factor for subsequent CVD events and total mortality. However, point estimates of creatinine- and cystatin C-based CKD differed considerably between low- and high-risk populations. Especially in low-risk settings, the use of cystatin C-based CKD may result in more accurate risk estimates and have better prognostic value. AU - Rothenbacher, D.* AU - Rehm, M.* AU - Iacoviello, L.* AU - Costanzo, S.* AU - Tunstall-Pedoe, H.* AU - Belch, J.J.F.* AU - Söderberg, S.* AU - Hultdin, J.* AU - Salomaa, V.* AU - Jousilahti, P.* AU - Linneberg, A.* AU - Sans, S.* AU - Padró, T.* AU - Thorand, B. AU - Meisinger, C. AU - Kee, F.* AU - McKnight, A.J.* AU - Palosaari, T.* AU - Kuulasmaa, K.* AU - Waldeyer, C.* AU - Zeller, T.* AU - Blankenberg, S.* AU - Koenig, W.* C1 - 60498 C2 - 49470 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Contribution of cystatin C- and creatinine-based definitions of chronic kidney disease to cardiovascular risk assessment in 20 population-based and 3 disease cohorts: The BiomarCaRE project. JO - BMC Med. VL - 18 IS - 1 PB - Bmc PY - 2020 SN - 1741-7015 ER - TY - JOUR AB - Background Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. Methods In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 x 10(-8)) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study. Results The associations between circulating UCB levels and CRC risk differed by sex (P-heterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the mainUGT1A1SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12);P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06);P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (P-heterogeneity >= 0.2). Conclusions Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development. AU - Seyed Khoei, N.* AU - Jenab, M.* AU - Murphy, N.* AU - Banbury, B.L.* AU - Carreras-Torres, R.* AU - Viallon, V.* AU - Kühn, T.* AU - Bueno-de-Mesquita, B.* AU - Aleksandrova, K.* AU - Cross, A.J.* AU - Weiderpass, E.* AU - Stepien, M.* AU - Bulmer, A.* AU - Tjønneland, A.* AU - Boutron-Ruault, M.C.* AU - Severi, G.* AU - Carbonnel, F.* AU - Katzke, V.* AU - Boeing, H.* AU - Bergmann, M.M.* AU - Trichopoulou, A.* AU - Karakatsani, A.* AU - Martimianaki, G.* AU - Palli, D.* AU - Tagliabue, G.* AU - Panico, S.* AU - Tumino, R.* AU - Sacerdote, C.* AU - Skeie, G.* AU - Merino, S.* AU - Bonet, C.* AU - Rodríguez-Barranco, M.* AU - Gil, L.* AU - Chirlaque, M.D.* AU - Ardanaz, E.* AU - Myte, R.* AU - Hultdin, J.* AU - Perez-Cornago, A.* AU - Aune, D.* AU - Tsilidis, K.K.* AU - Albanes, D.* AU - Baron, J.A.* AU - Berndt, S.I.* AU - Bézieau, S.* AU - Brenner, H.* AU - Campbell, P.T.* AU - Casey, G.* AU - Chang-Claude, J.* AU - Chanock, S.J.* AU - Cotterchio, M.* AU - Gallinger, S.* AU - Gruber, S.B.* AU - Haile, R.W.* AU - Hampe, J.* AU - Hoffmeister, M.* AU - Hopper, J.L.* AU - Hsu, L.* AU - Huyghe, J.R.* AU - Jenkins, M.A.* AU - Joshi, A.D.* AU - Kampman, E.* AU - Larsson, S.C.* AU - Le Marchand, L.* AU - Li, C.I.* AU - Li, L.* AU - Lindblom, A.* AU - Lindor, N.M.* AU - Martín, V.* AU - Moreno, V.* AU - Newcomb, P.A.* AU - Offit, K.* AU - Ogino, S.* AU - Parfrey, P.S.* AU - Pharoah, P.D.P.* AU - Rennert, G.* AU - Sakoda, L.C.* AU - Schafmayer, C.* AU - Schmit, S.L.* AU - Schoen, R.E.* AU - Slattery, M.L.* AU - Thibodeau, S.N.* AU - Ulrich, C.M.* AU - van Duijnhoven, F.J.B.* AU - Weigl, K.* AU - Weinstein, S.J.* AU - White, E.* AU - Wolk, A.* AU - Woods, M.O.* AU - Wu, A.H.* AU - Zhang, X.* AU - Ferrari, P.* AU - Anton, G. AU - Peters, A. AU - Peters, U.* AU - Gunter, M.J.* AU - Wagner, K.H.* AU - Freisling, H.* C1 - 60018 C2 - 49076 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses. JO - BMC Med. VL - 18 IS - 1 PB - Bmc PY - 2020 SN - 1741-7015 ER - TY - JOUR AB - BackgroundAutoimmune diseases are often preceded by an asymptomatic autoantibody-positive phase. In type 1 diabetes, the detection of autoantibodies to pancreatic islet antigens in genetically at-risk children is prognostic for future clinical diabetes. Testing for islet autoantibodies is, therefore, performed in a range of clinical studies. Accurate risk estimates that consider the a priori genetic risk and other risk modifiers are an important component of screening. The age of an individual is an under-appreciated risk modifier. The aim of this study was to provide age-adjusted risk estimates for the development of autoantibodies across childhood in genetically at-risk children.MethodsThe prospective BABYDIAB and BABYDIET studies included 2441 children from birth who had a first-degree relative with type 1 diabetes. Children were born between 1989 and 2006 and were regularly followed from birth for the development of islet autoantibodies and diabetes. A landmark analysis was performed to estimate the risk of islet autoantibodies at birth and at the age 3.5, 6.5 and 12.5years. Exponential decay curves were fitted for the risk by the age of 20years.ResultsThe risk of islet autoantibodies by the age of 20years was 8%, 4.6%, 2.6% and 0.9%, at the landmark ages of birth, 3.5, 6.5 and 12.5years, respectively. The short-term risks (within 6years of follow-up) at these landmark ages were 5.3%, 2.9%, 1.8% and 1%, respectively. The decline in autoantibody risk with age was modelled using a one-phase exponential decay curve (r=0.99) with a risk half-life of 3.7years. This risk decay model was remarkably consistent when the outcome was defined as islet autoantibody-positive or multiple islet autoantibody-positive and when the study cohort was stratified by HLA risk genotype. A similar decay model was observed for coeliac disease-associated transglutaminase antibodies in the same cohort. Unlike the risk of developing islet autoantibodies, the rate of developing clinical diabetes in children who were islet autoantibody-positive did not decline with age.ConclusionThe risk of developing autoantibodies drops exponentially with age in children with a first-degree relative with type 1 diabetes. AU - Hoffmann, V. AU - Weiß, A. AU - Winkler, C. AU - Knopff, A. AU - Jolink, M. AU - Bonifacio, E. AU - Ziegler, A.-G. C1 - 56529 C2 - 47080 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Landmark models to define the age-adjusted risk of developing stage 1 type 1 diabetes across childhood and adolescence. JO - BMC Med. VL - 17 IS - 1 PB - Bmc PY - 2019 SN - 1741-7015 ER - TY - JOUR AB - BackgroundGestational weight gain differs according to pre-pregnancy body mass index and is related to the risks of adverse maternal and child health outcomes. Gestational weight gain charts for women in different pre-pregnancy body mass index groups enable identification of women and offspring at risk for adverse health outcomes. We aimed to construct gestational weight gain reference charts for underweight, normal weight, overweight, and grades 1, 2 and 3 obese women and to compare these charts with those obtained in women with uncomplicated term pregnancies.MethodsWe used individual participant data from 218,216 pregnant women participating in 33 cohorts from Europe, North America, and Oceania. Of these women, 9065 (4.2%), 148,697 (68.1%), 42,678 (19.6%), 13,084 (6.0%), 3597 (1.6%), and 1095 (0.5%) were underweight, normal weight, overweight, and grades 1, 2, and 3 obese women, respectively. A total of 138, 517 women from 26 cohorts had pregnancies with no hypertensive or diabetic disorders and with term deliveries of appropriate for gestational age at birth infants. Gestational weight gain charts for underweight, normal weight, overweight, and grade 1, 2, and 3 obese women were derived by the Box-Cox t method using the generalized additive model for location, scale, and shape.ResultsWe observed that gestational weight gain strongly differed per maternal pre-pregnancy body mass index group. The median (interquartile range) gestational weight gain at 40weeks was 14.2kg (11.4-17.4) for underweight women, 14.5kg (11.5-17.7) for normal weight women, 13.9kg (10.1-17.9) for overweight women, and 11.2kg (7.0-15.7), 8.7kg (4.3-13.4) and 6.3kg (1.9-11.1) for grades 1, 2, and 3 obese women, respectively. The rate of weight gain was lower in the first half than in the second half of pregnancy. No differences in the patterns of weight gain were observed between cohorts or countries. Similar weight gain patterns were observed in mothers without pregnancy complications.ConclusionsGestational weight gain patterns are strongly related to pre-pregnancy body mass index. The derived charts can be used to assess gestational weight gain in etiological research and as a monitoring tool for weight gain during pregnancy in clinical practice. AU - Santos, S.* AU - Eekhout, I.* AU - Voerman, E.* AU - Gaillard, R.* AU - Barros, H.* AU - Charles, M.A.* AU - Chatzi, L.* AU - Chévrier, C.* AU - Chrousos, G.P.* AU - Corpeleijn, E.* AU - Costet, N.* AU - Crozier, S.* AU - Doyon, M.* AU - Eggesbø, M.* AU - Fantini, M.P.* AU - Farchi, S.* AU - Forastiere, F.* AU - Gagliardi, L.* AU - Georgiu, V.* AU - Godfrey, K.M.* AU - Gori, D.* AU - Grote, V.* AU - Hanke, W.* AU - Hertz-Picciotto, I.* AU - Heude, B.* AU - Hivert, M.F.* AU - Hryhorczuk, D.* AU - Huang, R.C.* AU - Inskip, H.M.* AU - Jusko, T.A.* AU - Karvonen, A.M.* AU - Koletzko, B.* AU - Küpers, L.K.* AU - Lagström, H.* AU - Lawlor, D.A.* AU - Lehmann, I.* AU - Lopez-Espinosa, M.J.* AU - Magnus, P.* AU - Majewska, R.* AU - Mäkelä, J.* AU - Manios, Y.* AU - McDonald, S.W.* AU - Mommers, M.* AU - Morgen, C.S.* AU - Moschonis, G.* AU - Murínová,* AU - Newnham, J.* AU - Nohr, E.A.* AU - Andersen, A.N.* AU - Oken, E.* AU - Oostvogels, A.J.J.M.* AU - Pac, A.* AU - Papadopoulou, E.* AU - Pekkanen, J.* AU - Pizzi, C.* AU - Polanska, K.* AU - Porta, D.* AU - Richiardi, L.* AU - Rifas-Shiman, S.L.* AU - Roeleveld, N.* AU - Santa-Marina, L.* AU - Santos, A.C.* AU - Smit, H.A.* AU - Sørensen, T.I.A.* AU - Standl, M. AU - Stanislawski, M.* AU - Stoltenberg, C.* AU - Thiering, E. AU - Thijs, C.* AU - Torrent, M.* AU - Tough, S.C.* AU - Trnovec, T.* AU - van Gelder, M.M.H.J.* AU - van Rossem, L.* AU - von Berg, A.* AU - Vrijheid, M.* AU - Vrijkotte, T.G.M.* AU - Zvinchuk, O.* AU - van Buuren, S.* AU - Jaddoe, V.W.V.* C1 - 54684 C2 - 45757 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Gestational weight gain charts for different body mass index groups for women in Europe, North America, and Oceania. JO - BMC Med. VL - 16 IS - 1 PB - Bmc PY - 2018 SN - 1741-7015 ER - TY - JOUR AB - BACKGROUND: Inflammation occurs as an immediate protective response of the immune system to a harmful stimulus, whether locally confined or systemic. In contrast, a persisting, i.e., chronic, inflammatory state, even at a low-grade, is a well-known risk factor in the development of common diseases like diabetes or atherosclerosis. In clinical practice, laboratory markers like high-sensitivity C-reactive protein (hsCRP), white blood cell count (WBC), and fibrinogen, are used to reveal inflammatory processes. In order to gain a deeper insight regarding inflammation-related changes in metabolism, the present study assessed the metabolic patterns associated with alterations in inflammatory markers. METHODS: Based on mass spectrometry and nuclear magnetic resonance spectroscopy we determined a comprehensive panel of 613 plasma and 587 urine metabolites among 925 apparently healthy individuals. Associations between inflammatory markers, namely hsCRP, WBC, and fibrinogen, and metabolite levels were tested by linear regression analyses controlling for common confounders. Additionally, we tested for a discriminative signature of an advanced inflammatory state using random forest analysis. RESULTS: HsCRP, WBC, and fibrinogen were significantly associated with 71, 20, and 19 plasma and 22, 3, and 16 urine metabolites, respectively. Identified metabolites were related to the bradykinin system, involved in oxidative stress (e.g., glutamine or pipecolate) or linked to the urea cycle (e.g., ornithine or citrulline). In particular, urine 3'-sialyllactose was found as a novel metabolite related to inflammation. Prediction of an advanced inflammatory state based solely on 10 metabolites was well feasible (median AUC: 0.83). CONCLUSIONS: Comprehensive metabolic profiling confirmed the far-reaching impact of inflammatory processes on human metabolism. The identified metabolites included not only those already described as immune-modulatory but also completely novel patterns. Moreover, the observed alterations provide molecular links to inflammation-associated diseases like diabetes or cardiovascular disorders.   AU - Pietzner, M.* AU - Kaul, A.K.* AU - Henning, A.-K.* AU - Kastenmüller, G. AU - Artati, A. AU - Lerch, M.M.* AU - Adamski, J. AU - Nauck, M.* AU - Friedrich, N.* C1 - 52440 C2 - 43976 CY - London TI - Comprehensive metabolic profiling of chronic low-grade inflammation among generally healthy individuals. JO - BMC Med. VL - 15 IS - 1 PB - Biomed Central Ltd PY - 2017 SN - 1741-7015 ER - TY - JOUR AB - BACKGROUND: To determine the shape of the associations of HbA1c with mortality and cardiovascular outcomes in non-diabetic individuals and explore potential explanations. METHODS: The associations of HbA1c with all-cause mortality, cardiovascular mortality and primary cardiovascular events (myocardial infarction or stroke) were assessed in non-diabetic subjects ≥50 years from six population-based cohort studies from Europe and the USA and meta-analyzed. Very low, low, intermediate and increased HbA1c were defined as <5.0, 5.0 to <5.5, 5.5 to <6.0 and 6.0 to <6.5 % (equals <31, 31 to <37, 37 to <42 and 42 to <48 mmol/mol), respectively, and low HbA1c was used as reference in Cox proportional hazards models. RESULTS: Overall, 6,769 of 28,681 study participants died during a mean follow-up of 10.7 years, of whom 2,648 died of cardiovascular disease. Furthermore, 2,493 experienced a primary cardiovascular event. A linear association with primary cardiovascular events was observed. Adjustment for cardiovascular risk factors explained about 50 % of the excess risk and attenuated hazard ratios (95 % confidence interval) for increased HbA1c to 1.14 (1.03-1.27), 1.17 (1.00-1.37) and 1.19 (1.04-1.37) for all-cause mortality, cardiovascular mortality and cardiovascular events, respectively. The six cohorts yielded inconsistent results for the association of very low HbA1c levels with the mortality outcomes and the pooled effect estimates were not statistically significant. In one cohort with a pronounced J-shaped association of HbA1c levels with all-cause and cardiovascular mortality (NHANES), the following confounders of the association of very low HbA1c levels with mortality outcomes were identified: race/ethnicity; alcohol consumption; BMI; as well as biomarkers of iron deficiency anemia and liver function. Associations for very low HbA1c levels lost statistical significance in this cohort after adjusting for these confounders. CONCLUSIONS: A linear association of HbA1c levels with primary cardiovascular events was observed. For cardiovascular and all-cause mortality, the observed small effect sizes at both the lower and upper end of HbA1c distribution do not support the notion of a J-shaped association of HbA1c levels because a certain degree of residual confounding needs to be considered in the interpretation of the results. AU - Schöttker, B.* AU - Rathmann, W.* AU - Herder, C.* AU - Thorand, B. AU - Wilsgaard, T.* AU - Njølstad, I.* AU - Siganos, G.* AU - Mathiesen, E.B.* AU - Saum, K.U.* AU - Peasey, A.* AU - Feskens, E.* AU - Boffetta, P.* AU - Trichopoulou, A.* AU - Kuulasmaa, K.* AU - Kee, F.* AU - Brenner, H.* AU - CHANCES Consortium (Peters, A. AU - Meisinger, C. AU - Schneider, A.E.) C1 - 47889 C2 - 39692 CY - London TI - HbA1c levels in non-diabetic older adults - no J-shaped associations with primary cardiovascular events, cardiovascular and all-cause mortality after adjustment for confounders in a meta-analysis of individual participant data from six cohort studies. JO - BMC Med. VL - 14 IS - 1 PB - Biomed Central Ltd PY - 2016 SN - 1741-7015 ER - TY - JOUR AB - Background Excess body weight is a major risk factor for cardiometabolic diseases. The complex molecular mechanisms of body weight change-induced metabolic perturbations are not fully understood. Specifically, in-depth molecular characterization of long-term body weight change in the general population is lacking. Here, we pursued a multi-omic approach to comprehensively study metabolic consequences of body weight change during a seven-year follow-up in a large prospective study. Methods We used data from the population-based Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 cohort. At follow-up (F4), two-platform serum metabolomics and whole blood gene expression measurements were obtained for 1,631 and 689 participants, respectively. Using weighted correlation network analysis, omics data were clustered into modules of closely connected molecules, followed by the formation of a partial correlation network from the modules. Association of the omics modules with previous annual percentage weight change was then determined using linear models. In addition, we performed pathway enrichment analyses, stability analyses, and assessed the relation of the omics modules with clinical traits. Results Four metabolite and two gene expression modules were significantly and stably associated with body weight change (P-values ranging from 1.9 × 10−4 to 1.2 × 10−24). The four metabolite modules covered major branches of metabolism, with VLDL, LDL and large HDL subclasses, triglycerides, branched-chain amino acids and markers of energy metabolism among the main representative molecules. One gene expression module suggests a role of weight change in red blood cell development. The other gene expression module largely overlaps with the lipid-leukocyte (LL) module previously reported to interact with serum metabolites, for which we identify additional co-expressed genes. The omics modules were interrelated and showed cross-sectional associations with clinical traits. Moreover, weight gain and weight loss showed largely opposing associations with the omics modules. Conclusions Long-term weight change in the general population globally associates with serum metabolite concentrations. An integrated metabolomics and transcriptomics approach improved the understanding of molecular mechanisms underlying the association of weight gain with changes in lipid and amino acid metabolism, insulin sensitivity, mitochondrial function as well as blood cell development and function. AU - Wahl, S. AU - Vogt, S.* AU - Stückler, F. AU - Krumsiek, J. AU - Bartel, J. AU - Kacprowski, T.* AU - Schramm, K. AU - Carstensen, M.* AU - Rathmann, W.* AU - Roden, M.* AU - Jourdan, C. AU - Kangas, A.J.* AU - Soininen, P.* AU - Ala-Korpela, M.* AU - Nöthlings, U.* AU - Boeing, H.* AU - Theis, F.J. AU - Meisinger, C. AU - Waldenberger, M. AU - Suhre, K. AU - Homuth, G.* AU - Gieger, C. AU - Kastenmüller, G. AU - Illig, T. AU - Linseisen, J. AU - Peters, A. AU - Prokisch, H. AU - Herder, C. AU - Thorand, B. AU - Grallert, H. C1 - 43813 C2 - 36543 CY - London TI - Multi-omic signature of body weight change: Results from a population-based cohort study. JO - BMC Med. VL - 13 PB - Biomed Central Ltd PY - 2015 SN - 1741-7015 ER - TY - JOUR AB - BACKGROUND: Recently, some US cohorts have shown a moderate association between red and processed meat consumption and mortality supporting the results of previous studies among vegetarians. The aim of this study was to examine the association of red meat, processed meat, and poultry consumption with the risk of early death in the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: Included in the analysis were 448,568 men and women without prevalent cancer, stroke, or myocardial infarction, and with complete information on diet, smoking, physical activity and body mass index, who were between 35 and 69 years old at baseline. Cox proportional hazards regression was used to examine the association of meat consumption with all-cause and cause-specific mortality. RESULTS: As of June 2009, 26,344 deaths were observed. After multivariate adjustment, a high consumption of red meat was related to higher all-cause mortality (hazard ratio (HR) = 1.14, 95% confidence interval (CI) 1.01 to 1.28, 160+ versus 10 to 19.9 g/day), and the association was stronger for processed meat (HR = 1.44, 95% CI 1.24 to 1.66, 160+ versus 10 to 19.9 g/day). After correction for measurement error, higher all-cause mortality remained significant only for processed meat (HR = 1.18, 95% CI 1.11 to 1.25, per 50 g/d). We estimated that 3.3% (95% CI 1.5% to 5.0%) of deaths could be prevented if all participants had a processed meat consumption of less than 20 g/day. Significant associations with processed meat intake were observed for cardiovascular diseases, cancer, and 'other causes of death'. The consumption of poultry was not related to all-cause mortality. CONCLUSIONS: The results of our analysis support a moderate positive association between processed meat consumption and mortality, in particular due to cardiovascular diseases, but also to cancer. AU - Rohrmann, S.* AU - Overvad, K.* AU - Bueno-de-Mesquita, H.B.* AU - Jakobsen, M.U.* AU - Egeberg, R.* AU - Tjønneland, A.* AU - Nailler, L.* AU - Boutron-Ruault, M.C.* AU - Clavel-Chapelon, F.* AU - Krogh, V.* AU - Palli, D.* AU - Panico, S.* AU - Tumino, R.* AU - Ricceri, F.* AU - Bergmann, M.M.* AU - Boeing, H.* AU - Li, K.* AU - Kaaks, R.* AU - Khaw, K.T.* AU - Wareham, N.J.* AU - Crowe, F.L.* AU - Key, T.J.* AU - Naska, A.* AU - Trichopoulou, A.* AU - Trichopoulos, D.* AU - Leenders, M.* AU - Peeters, P.H.* AU - Engeset, D.* AU - Parr, C.L.* AU - Skeie, G.* AU - Jakszyn, P.* AU - Sánchez, M.J.* AU - Huerta, J.M.* AU - Redondo, M.L.* AU - Barricarte, A.* AU - Amiano, P.* AU - Drake, I.* AU - Sonestedt, E.* AU - Hallmans, G.* AU - Johansson, I.* AU - Fedirko, V.* AU - Romieux, I.* AU - Ferrari, P.* AU - Norat, T.* AU - Vergnaud, A.C.* AU - Riboli, E.* AU - Linseisen, J. C1 - 24376 C2 - 31529 TI - Meat consumption and mortality - results from the European Prospective Investigation into Cancer and Nutrition. JO - BMC Med. VL - 11 IS - 1 PB - BioMed Central PY - 2013 SN - 1741-7015 ER - TY - JOUR AB - Background: Almost nothing is known about the medical aspects of runners doing a transcontinental ultramarathon over several weeks. The results of differentiated measurements of changes in body composition during the Transeurope Footrace 2009 using a mobile whole body magnetic resonance (MR) imager are presented and the proposed influence of visceral and somatic adipose and lean tissue distribution on performance tested. Methods: 22 participants were randomly selected for the repeated MR measurements (intervals: 800 km) with a 1.5 Tesla MR scanner mounted on a mobile unit during the 64-stage 4,486 km ultramarathon. A standardized and validated MRI protocol was used: T1 weighted turbo spin echo sequence, echo time 12 ms, repetition time 490 ms, slice thickness 10 mm, slice distance 10mm (breath holding examinations). For topographic tissue segmentation and mapping a modified fuzzy c-means algorithm was used. A semi-automatic post-processing of whole body MRI data sets allows reliable analysis of the following body tissue compartments: Total body volume (TV), total somatic (TSV) and total visceral volume (TVV), total adipose (TAT) and total lean tissue (TLT), somatic (SLT) and visceral lean tissue (VLT), somatic (SAT) and visceral adipose tissue (VAT) and somatic adipose soft tissue (SAST). Specific volume changes were tested on significance. Tests on difference and relationship regarding prerace and race performance and non-finishing were done using statistical software SPSS. Results: Total, somatic and visceral volumes showed a significant decrease throughout the race. Adipose tissue showed a significant decrease compared to the start at all measurement times for TAT, SAST and VAT. Lean adipose tissues decreased until the end of the race, but not significantly. The mean relative volume changes of the different tissue compartments at the last measurement compared to the start were: TV -9.5% (SE 1.5%), TSV -9.4% (SE 1.5%), TVV -10.0% (SE 1.4%), TAT -41.3% (SE 2.3%), SAST -48.7% (SE 2.8%), VAT -64.5% (SE 4.6%), intraabdominal adipose tissue (IAAT) -67.3% (SE 4.3%), mediastinal adopose tissue (MAT) -41.5% (SE 7.1%), TLT -1.2% (SE 1.0%), SLT -1.4% (SE 1.1%). Before the start and during the early phase of the Transeurope Footrace 2009, the non-finisher group had a significantly higher percentage volume of TVV, TAT, SAST and VAT compared to the finisher group. VAT correlates significantly with prerace training volume and intensity one year before the race and with 50 km-and 24 hour-race records. Neither prerace body composition nor specific tissue compartment volume changes showed a significant relationship to performance in the last two thirds of the Transeurope Footrace 2009. Conclusions: With this mobile MRI field study the complex changes in body composition during a multistage ultramarathon could be demonstrated in detail in a new and differentiated way. Participants lost more than half of their adipose tissue. Even lean tissue volume (mainly skeletal muscle tissue) decreased due to the unpreventable chronic negative energy balance during the race. VAT has the fastest and highest decrease compared to SAST and lean tissue compartments during the race. It seems to be the most sensitive morphometric parameter regarding the risk of non-finishing a transcontinental footrace and shows a direct relationship to prerace-performance. However, body volume or body mass and, therefore, fat volume has no correlation with total race performances of ultra-athletes finishing a 4,500 km multistage race. AU - Schütz, U.H.W.* AU - Billich, C.* AU - König, K.* AU - Würslin, C.* AU - Wiedelbach, H.* AU - Brambs, H.J.* AU - Machann, J. C1 - 25519 C2 - 31869 TI - Characteristics, changes and influence of body composition during a 4486 km transcontinental ultramarathon: Results from the Transeurope Footrace mobile whole body MRI-project. JO - BMC Med. VL - 11 PB - Biomed Central PY - 2013 SN - 1741-7015 ER - TY - JOUR AB - BACKGROUND: Metabolomics helps to identify links between environmental exposures and intermediate biomarkers of disturbed pathways. We previously reported variations in phosphatidylcholines in male smokers compared with non-smokers in a cross-sectional pilot study with a small sample size, but knowledge of the reversibility of smoking effects on metabolite profiles is limited. Here, we extend our metabolomics study with a large prospective study including female smokers and quitters. METHODS: Using targeted metabolomics approach, we quantified 140 metabolite concentrations for 1,241 fasting serum samples in the population-based Cooperative Health Research in the Region of Augsburg (KORA) human cohort at two time points: baseline survey conducted between 1999 and 2001 and follow-up after seven years. Metabolite profiles were compared among groups of current smokers, former smokers and never smokers, and were further assessed for their reversibility after smoking cessation. Changes in metabolite concentrations from baseline to the follow-up were investigated in a longitudinal analysis comparing current smokers, never smokers and smoking quitters, who were current smokers at baseline but former smokers by the time of follow-up. In addition, we constructed protein-metabolite networks with smoking-related genes and metabolites. RESULTS: We identified 21 smoking-related metabolites in the baseline investigation (18 in men and six in women, with three overlaps) enriched in amino acid and lipid pathways, which were significantly different between current smokers and never smokers. Moreover, 19 out of the 21 metabolites were found to be reversible in former smokers. In the follow-up study, 13 reversible metabolites in men were measured, of which 10 were confirmed to be reversible in male quitters. Protein-metabolite networks are proposed to explain the consistent reversibility of smoking effects on metabolites. CONCLUSIONS: We showed that smoking-related changes in human serum metabolites are reversible after smoking cessation, consistent with the known cardiovascular risk reduction. The metabolites identified may serve as potential biomarkers to evaluate the status of smoking cessation and characterize smoking-related diseases.   AU - Xu, T. AU - Holzapfel, C. AU - Dong, X.* AU - Bader, E. AU - Yu, Z. AU - Prehn, C. AU - Perstorfer, K. AU - Jaremek, M. AU - Römisch-Margl, W. AU - Rathmann, W.* AU - Li, Y.* AU - Wichmann, H.-E. AU - Wallaschofski, H.* AU - Ladwig, K.-H. AU - Theis, F.J. AU - Suhre, K. AU - Adamski, J. AU - Illig, T. AU - Peters, A. AU - Wang-Sattler, R. C1 - 23629 C2 - 31222 TI - Effects of smoking and smoking cessation on human serum metabolite profile: Results from the KORA cohort study. JO - BMC Med. VL - 11 IS - 1 PB - Biomed Central PY - 2013 SN - 1741-7015 ER -