Rui Wang-sattler - Academia.edu (original) (raw)

Papers by Rui Wang-sattler

Metabolites, 2021

Biological exploration of early biomarkers for chronic kidney disease (CKD) in (pre)diabetic indi... more Biological exploration of early biomarkers for chronic kidney disease (CKD) in (pre)diabetic individuals is crucial for personalized management of diabetes. Here, we evaluated two candidate biomarkers of incident CKD (sphingomyelin (SM) C18:1 and phosphatidylcholine diacyl (PC aa) C38:0) concerning kidney function in hyperglycemic participants of the Cooperative Health Research in the Region of Augsburg (KORA) cohort, and in two biofluids and six organs of leptin receptor-deficient (db/db) mice and wild type controls. Higher serum concentrations of SM C18:1 and PC aa C38:0 in hyperglycemic individuals were found to be associated with lower estimated glomerular filtration rate (eGFR) and higher odds of CKD. In db/db mice, both metabolites had a significantly lower concentration in urine and adipose tissue, but higher in the lungs. Additionally, db/db mice had significantly higher SM C18:1 levels in plasma and liver, and PC aa C38:0 in adrenal glands. This cross-sectional human study ...

Theory underlying pulver. This file describes the derivation of the t-value computed from the bet... more Theory underlying pulver. This file describes the derivation of the t-value computed from the beta value divided by the standard error and the correlation value. (PDF 426 kb)

Briefings in Bioinformatics, 2021

Large metabolomics datasets inevitably contain unwanted technical variations which can obscure me... more Large metabolomics datasets inevitably contain unwanted technical variations which can obscure meaningful biological signals and affect how this information is applied to personalized healthcare. Many methods have been developed to handle unwanted variations. However, the underlying assumptions of many existing methods only hold for a few specific scenarios. Some tools remove technical variations with models trained on quality control (QC) samples which may not generalize well on subject samples. Additionally, almost none of the existing methods supports datasets with multiple types of QC samples, which greatly limits their performance and flexibility. To address these issues, a non-parametric method TIGER (Technical variation elImination with ensemble learninG architEctuRe) is developed in this study and released as an R package (https://CRAN.R-project.org/package=TIGERr). TIGER integrates the random forest algorithm into an adaptable ensemble learning architecture. Evaluation resu...

Human Molecular Genetics, 2021

In the era of personalized medicine with more and more patient-specific targeted therapies being ... more In the era of personalized medicine with more and more patient-specific targeted therapies being used, we need reliable, dynamic, faster and sensitive biomarkers both to track the causes of disease and to develop and evolve therapies during the course of treatment. Metabolomics recently has shown substantial evidence to support its emerging role in disease diagnosis and prognosis. Aside from biomarkers and development of therapies, it is also an important goal to understand the involvement of mitochondrial DNA (mtDNA) in metabolic regulation, aging and disease development. Somatic mutations of the mitochondrial genome are also heavily implicated in age-related disease and aging. The general hypothesis is that an alteration in the concentration of metabolite profiles (possibly conveyed by lifestyle and environmental factors) influences the increase of mutation rate in the mtDNA and thereby contributes to a range of pathophysiological alterations observed in complex diseases. We perfo...

Annals of Neurology, 2020

ObjectiveEarly discrimination of patients with ischemic stroke (IS) from stroke mimics (SMs) pose... more ObjectiveEarly discrimination of patients with ischemic stroke (IS) from stroke mimics (SMs) poses a diagnostic challenge. The circulating metabolome might reflect pathophysiological events related to acute IS. Here, we investigated the utility of early metabolic changes for differentiating IS from SM.MethodsWe performed untargeted metabolomics on serum samples obtained from patients with IS (N = 508) and SM (N = 349; defined by absence of a diffusion weighted imaging [DWI] positive lesion on magnetic resonance imaging [MRI]) who presented to the hospital within 24 hours after symptom onset (median time from symptom onset to blood sampling = 3.3 hours; interquartile range [IQR] = 1.6–6.7 hours) and from neurologically normal controls (NCs; N = 112). We compared diagnostic groups in a discovery‐validation approach by applying multivariable linear regression models, machine learning techniques, and propensity score matching. We further performed a targeted look‐up of published metabol...

BMC Bioinformatics, 2017

Background: Genome-wide association studies allow us to understand the genetics of complex diseas... more Background: Genome-wide association studies allow us to understand the genetics of complex diseases. Human metabolism provides information about the disease-causing mechanisms, so it is usual to investigate the associations between genetic variants and metabolite levels. However, only considering genetic variants and their effects on one trait ignores the possible interplay between different "omics" layers. Existing tools only consider single-nucleotide polymorphism (SNP)-SNP interactions, and no practical tool is available for large-scale investigations of the interactions between pairs of arbitrary quantitative variables. Results: We developed an R package called pulver to compute p-values for the interaction term in a very large number of linear regression models. Comparisons based on simulated data showed that pulver is much faster than the existing tools. This is achieved by using the correlation coefficient to test the null-hypothesis, which avoids the costly computation of inversions. Additional tricks are a rearrangement of the order, when iterating through the different "omics" layers, and implementing this algorithm in the fast programming language C++. Furthermore, we applied our algorithm to data from the German KORA study to investigate a real-world problem involving the interplay among DNA methylation, genetic variants, and metabolite levels. Conclusions: The pulver package is a convenient and rapid tool for screening huge numbers of linear regression models for significant interaction terms in arbitrary pairs of quantitative variables.

Scientific Reports, 2019

Telomere shortening has been associated with multiple age-related diseases such as cardiovascular... more Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10−6), methionine (p-value = 9.2 × 10−5), tyrosine (p-value = 2.1 × 10−4), phosphatidylcholine diacyl C32...

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Atherosclerosis, 2018

Preclinical experiments on animal models are essential to understand the mechanisms of cardiovasc... more Preclinical experiments on animal models are essential to understand the mechanisms of cardiovascular disease (CVD). Metabolomics allows access to the metabolic perturbations associated with CVD in heart and vessels. Here we assessed which potential animal CVD model most closely mimics the serum metabolite signature of increased carotid intima-media thickness (cIMT) in humans, a clinical parameter widely accepted as a surrogate of CVD. A targeted mass spectrometry assay was used to quantify and compare a series of blood metabolites between 1362 individuals (KORA F4 cohort) and 5 animal CVD models: ApoE, Ldlr, and klotho-hypomorphic mice (kl/kl) and SHRSP rats with or without salt feeding. The metabolite signatures were obtained using linear regressions adjusted for various co-variates. In human, increased cIMT [quartile Q4 vs. Q1] was associated with 26 metabolites (9 acylcarnitines, 2 lysophosphatidylcholines, 9 phosphatidylcholines and 6 sphingomyelins). Acylcarnitines correlated ...

Metabolites, Jan 21, 2018

Night shift work can have a serious impact on health. Here, we assess whether and how night shift... more Night shift work can have a serious impact on health. Here, we assess whether and how night shift work influences the metabolite profiles, specifically with respect to different chronotype classes. We have recruited 100 women including 68 nurses working both, day shift and night shifts for up to 5 consecutive days and collected 3640 spontaneous urine samples. About 424 waking-up urine samples were measured using a targeted metabolomics approach. To account for urine dilution, we applied three methods to normalize the metabolite values: creatinine-, osmolality- and regression-based normalization. Based on linear mixed effect models, we found 31 metabolites significantly (false discovery rate <0.05) affected in nurses working in night shifts. One metabolite, acylcarnitine C10:2, was consistently identified with all three normalization methods. We further observed 11 and 4 metabolites significantly associated with night shift in early and late chronotype classes, respectively. Incre...

Journal of proteome research, Jan 26, 2017

Blood is one of the most used biofluids in metabolomics studies, and the serum and plasma fractio... more Blood is one of the most used biofluids in metabolomics studies, and the serum and plasma fractions are routinely used as a proxy for blood itself. Here we investigated the association networks of an array of 29 metabolites identified and quantified via NMR in the plasma and serum samples of two cohorts of ∼1000 healthy blood donors each. A second study of 377 individuals was used to extract plasma and serum samples from the same individual on which a set of 122 metabolites were detected and quantified using FIA-MS/MS. Four different inference algorithms (ARANCE, CLR, CORR, and PCLRC) were used to obtain consensus networks. The plasma and serum networks obtained from different studies showed different topological properties with the serum network being more connected than the plasma network. On a global level, metabolite association networks from plasma and serum fractions obtained from the same blood sample of healthy people show similar topologies, and at a local level, some diffe...

The Journal of investigative dermatology, Jan 20, 2016

Epidemiological studies suggested an association between atopic dermatitis (AD) and cardiovascula... more Epidemiological studies suggested an association between atopic dermatitis (AD) and cardiovascular disease (CVD). Therefore, we investigate associations and potential underlying pathways of AD and CVD in large cohort studies: the AOK PLUS cohort (n=1.2Mio), the GINIplus/LISAplus birth cohorts (n=2286), and the KORA F4 cohort (n=2990). Additionally, metabolomics in KORA F4 and established cardiovascular risk loci in genome-wide data on 10,788 AD cases and 30,047 controls were analyzed. Longitudinal analysis of AD patients in AOK PLUS showed slightly increased risk for incident angina pectoris (AP) (adjusted risk ratio 1.17; 95%-confidence interval 1.12-1.23), hypertension (1.04 (1.02-1.06)) and peripheral arterial disease (PAD) (1.15 (1.11-1.19)) but not for myocardial infarction (MI) (1.05 (0.99-1.12) and stroke (1.02 (0.98-1.07)). In KORA F4 and GINIplus/LISAplus, AD was not associated with cardiovascular risk factors (CVRFs) and no differences in metabolite levels were detected. T...

PLOS ONE, 2016

Our study aims to identify metabolic markers associated with either a gain in abdominal (measured... more Our study aims to identify metabolic markers associated with either a gain in abdominal (measured by waist circumference) or peripheral (measured by hip circumference) body fat mass. Methods Data of 4 126 weight-gaining adults (18-75 years) from three population-based, prospective German cohort studies (EPIC, KORA, DEGS) were analysed regarding a waist-gaining (WG) or hip-gaining phenotype (HG). The phenotypes were obtained by calculating the differences of annual changes in waist minus hip circumference. The difference was displayed for all cohorts. The highest 10% of this difference were defined as WG whereas the lowest 10% were defined as HG. A total of 121 concordant metabolite measurements were conducted using Biocrates AbsoluteIDQ 1 kits in EPIC and KORA. Sex-specific associations with metabolite concentration as independent and phenotype as the dependent variable adjusted for confounders were calculated. The Benjamini-Hochberg method was used to correct for multiple testing.

Diabetes care, 2015

We thank Sonne and Knop for their comments (1) on our article (2). They recalled that the induced... more We thank Sonne and Knop for their comments (1) on our article (2). They recalled that the induced AMPK pathway we investigated is not the only potential root of the observed decrease in LDL cholesterol (LDL-C) levels after metformin treatment. Sonne and Knop indicated the highly probable influence of the bile acid synthesis and the underlying mode of action (1). We fully agree with this comment. However, we would like to clarify more precisely two points referred to by the authors. First, the statement referring to "decreased concentrations of three metabolites" when case subjects were compared with control subjects in our cross-sectional study (1) would be better described with the expression "lower concentration." The term "decreased" is appropriate when referring to our longitudinal results following the same person for 7 years (2), but it can be misleading when comparing groups of different individuals. Second, Sonne and Knop stated that "the cholesterollowering effects of metformin [had] long been recognized," citing a study by Giugliano et al.

Pneumologie, 2013

Background: Respiratory function shows a large interindividual variability which is related to ge... more Background: Respiratory function shows a large interindividual variability which is related to genetic, developmental and environmental factors. These determinants influence an individual's metabolism, but little is known about metabolic processes and lung function. Objective: To investigate the association between lung function and metabolite concentrations in adults from a population-based study. Methods: Spirometry was performed in a subpopulation of the KORA-F4 cohort (1321 subjects aged 41-62 years). In fasting blood samples, over 650 metabolites were determined on two different mass spectrometry based metabolomic platforms. Linear regression models were calculated for each metabolite after adjustment for age, sex, smoking, BMI and batch effects, and the residuals of these models were used to assess associations between metabolites and percent predicted (pp) values of FEV1 and FVC. Results: We identified 30 metabolites that were significantly associated with lung function indices after correction for multiple testing (q-values ranged from 4.9•10-2 to 3.3•10-4). Of these metabolites, 29 were associated with FVCpp and 23 were associated with FEV1pp. These indices are linked to different metabolites involved in lipid metabolism, tocopherol metabolism and tyrosine metabolism. An association with the xenobiotic pathway was also observed. Conclusion: The lipid metabolites identified suggest pulmonary surfactant is involved in lung function, as surfactant is mainly composed of different phospholipids and is vital for the facilitation of peripheral air spaces. The observed association with tocopherol metabolism may suggest an importance of antioxidant or anti-inflammatory defence for respiratory function.

Hypertension, 2015

High blood pressure is a major contributor to the global burden of disease and discovering novel ... more High blood pressure is a major contributor to the global burden of disease and discovering novel causal pathways of blood pressure regulation has been challenging. We tested blood pressure associations with 280 fasting blood metabolites in 3980 TwinsUK females. Survival analysis for all-cause mortality was performed on significant independent metabolites (P<8.9 10(-5)). Replication was conducted in 2 independent cohorts KORA (n=1494) and Hertfordshire (n=1515). Three independent animal experiments were performed to establish causality: (1) blood pressure change after increasing circulating metabolite levels in Wistar-Kyoto rats; (2) circulating metabolite change after salt-induced blood pressure elevation in spontaneously hypertensive stroke-prone rats; and (3) mesenteric artery response to noradrenaline and carbachol in metabolite treated and control rats. Of the15 metabolites that showed an independent significant association with blood pressure, only hexadecanedioate, a dicarb...

Translational Psychiatry, 2012

Schizophrenia is a severe complex mental disorder affecting 0.5-1% of the world population. To da... more Schizophrenia is a severe complex mental disorder affecting 0.5-1% of the world population. To date, diagnosis of the disease is mainly based on personal and thus subjective interviews. The underlying molecular mechanism of schizophrenia is poorly understood. Using targeted metabolomics we quantified and compared 103 metabolites in plasma samples from 216 healthy controls and 265 schizophrenic patients, including 52 cases that do not take antipsychotic medication. Compared with healthy controls, levels of five metabolites were found significantly altered in schizophrenic patients (P-values ranged from 2.9 Â 10 À 8 to 2.5 Â 10 À 4) and in neuroleptics-free probands (P-values ranging between 0.006 and 0.03), respectively. These metabolites include four amino acids (arginine, glutamine, histidine and ornithine) and one lipid (PC ae C38:6) and are suggested as candidate biomarkers for schizophrenia. To explore the genetic susceptibility on the associated metabolic pathways, we constructed a molecular network connecting these five aberrant metabolites with 13 schizophrenia risk genes. Our result implicated aberrations in biosynthetic pathways linked to glutamine and arginine metabolism and associated signaling pathways as genetic risk factors, which may contribute to patho-mechanisms and memory deficits associated with schizophrenia. This study illustrated that the metabolic deviations detected in plasma may serve as potential biomarkers to aid diagnosis of schizophrenia.

PLoS ONE, 2012

Objective: To characterise the influence of the fat free mass on the metabolite profile in serum ... more Objective: To characterise the influence of the fat free mass on the metabolite profile in serum samples from participants of the population-based KORA (Cooperative Health Research in the Region of Augsburg) S4 study. Subjects and Methods: Analyses were based on metabolite profile from 965 participants of the S4 and 890 weight-stable subjects of its seven-year follow-up study (KORA F4). 190 different serum metabolites were quantified in a targeted approach including amino acids, acylcarnitines, phosphatidylcholines (PCs), sphingomyelins and hexose. Associations between metabolite concentrations and the fat free mass index (FFMI) were analysed using adjusted linear regression models. To draw conclusions on enzymatic reactions, intra-metabolite class ratios were explored. Pairwise relationships among metabolites were investigated and illustrated by means of Gaussian graphical models (GGMs). Results: We found 339 significant associations between FFMI and various metabolites in KORA S4. Among the most prominent associations (p-values 4.75610 216-8.95610 206) with higher FFMI were increasing concentrations of the branched chained amino acids (BCAAs), ratios of BCAAs to glucogenic amino acids, and carnitine concentrations. For various PCs, a decrease in chain length or in saturation of the fatty acid moieties could be observed with increasing FFMI, as well as an overall shift from acyl-alkyl PCs to diacyl PCs. These findings were reproduced in KORA F4. The established GGMs supported the regression results and provided a comprehensive picture of the relationships between metabolites. In a subanalysis, most of the discovered associations did not exist in obese subjects in contrast to non-obese subjects, possibly indicating derangements in skeletal muscle metabolism. Conclusion: A set of serum metabolites strongly associated with FFMI was identified and a network explaining the relationships among metabolites was established. These results offer a novel and more complete picture of the FFMI effects on serum metabolites in a data-driven network.

PLoS Genetics, 2011

Metabolomic profiling and the integration of whole-genome genetic association data has proven to ... more Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values,3.8610 24 ; Bonferronicorrected threshold). Sex-specific genome-wide association studies (GWAS) showed genome-wide significant differences in beta-estimates for SNPs in the CPS1 locus (carbamoyl-phosphate synthase 1, significance level: p,3.8610 210 ; Bonferronicorrected threshold) for glycine. We showed that the metabolite profiles of males and females are significantly different and, furthermore, that specific genetic variants in metabolism-related genes depict sexual dimorphism. Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider sex-specific effects in design and interpretation.

PLoS ONE, 2014

Background: We aimed to assess whether whole blood expression quantitative trait loci (eQTLs) wit... more Background: We aimed to assess whether whole blood expression quantitative trait loci (eQTLs) with effects in cis and trans are robust and can be used to identify regulatory pathways affecting disease susceptibility. Materials and Methods: We performed whole-genome eQTL analyses in 890 participants of the KORA F4 study and in two independent replication samples (SHIP-TREND, N = 976 and EGCUT, N = 842) using linear regression models and Bonferroni correction. Results: In the KORA F4 study, 4,116 cis-eQTLs (defined as SNP-probe pairs where the SNP is located within a 500 kb window around the transcription unit) and 94 trans-eQTLs reached genome-wide significance and overall 91% (92% of cis-, 84% of trans-eQTLs) were confirmed in at least one of the two replication studies. Different study designs including distinct laboratory reagents (PAXgene TM vs. Tempus TM tubes) did not affect reproducibility (separate overall replication overlap: 78% and 82%). Immune response pathways were enriched in cis-and trans-eQTLs and significant cis-eQTLs were partly coexistent in other tissues (cross-tissue similarity 40-70%). Furthermore, four chromosomal regions displayed simultaneous impact on multiple gene expression levels in trans, and 746 eQTL-SNPs have been previously reported to have clinical relevance. We demonstrated cross-associations between eQTL-SNPs, gene expression levels in trans, and clinical phenotypes as well as a link between eQTLs and human metabolic traits via modification of gene regulation in cis. Conclusions: Our data suggest that whole blood is a robust tissue for eQTL analysis and may be used both for biomarker studies and to enhance our understanding of molecular mechanisms underlying gene-disease associations.