Publications by authors named "Matthias Nauck"

423 Publications

A Method to Combine Neurofilament Light Measurements From Blood Serum and Plasma in Clinical and Population-Based Studies.

Front Neurol 2022 14;13:894119. Epub 2022 Jun 14.

Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.

Introduction: Neurofilament light (NfL) can be detected in blood of healthy individuals and at elevated levels in those with different neurological diseases. We investigated if the choice of biological matrix can affect results when using NfL as biomarker in epidemiological studies.

Method: We obtained paired serum and EDTA-plasma samples of 299 individuals aged 37-67 years (BiDirect study) and serum samples of 373 individuals aged 65-83 years (MEMO study). In BiDirect, Passing-Bablok analyses were performed to assess proportional and systematic differences between biological matrices. Associations between serum or EDTA-plasma NfL and renal function (serum creatinine, serum cystatin C, glomerular filtration rate, and kidney disease) were investigated using linear or logistic regression, respectively. All regression coefficients were estimated (1) per one ng/L increase and (2) per one standard deviation increase (standardization using z-scores). In MEMO, regression coefficients were estimated (1) per one ng/L increase of serum or calculated EDTA-plasma NfL and (2) per one standard deviation increase providing a comparison to the results from BiDirect.

Results: We found proportional and systematic differences between paired NfL measurements in BiDirect, i.e., serum NfL [ng/L] = -0.33 [ng/L] + 1.11 × EDTA-plasma NfL [ng/L]. Linear regression coefficients for the associations between NfL and renal function did not vary between the different NfL measurements. In MEMO, one standard deviation increase in serum NfL was associated with greater changes in the outcomes than in BiDirect.

Conclusion: Although there are differences between serum and EDTA-plasma NfL, results can be used interchangeably if standardized values are used.
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http://dx.doi.org/10.3389/fneur.2022.894119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9237479PMC
June 2022

[Analytical Quality of Glucose Measurements in Germany].

Dtsch Med Wochenschr 2022 Jun 20. Epub 2022 Jun 20.

Institut für Klinische Chemie und Laboratoriumsmedizin, Universitätsmedizin Greifswald, Greifswald.

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http://dx.doi.org/10.1055/a-1866-7994DOI Listing
June 2022

Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies.

Kidney Int 2022 Jun 15. Epub 2022 Jun 15.

The George Institute for Global Health, University of New South Wales, Sydney, Australia.

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
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http://dx.doi.org/10.1016/j.kint.2022.05.021DOI Listing
June 2022

Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.

Commun Biol 2022 Jun 13;5(1):580. Epub 2022 Jun 13.

Division of Kidney, Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
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http://dx.doi.org/10.1038/s42003-022-03448-zDOI Listing
June 2022

Evaluation of a pneumatic tube system carrier prototype with fixing mechanism allowing for automated unloading.

Clin Chem Lab Med 2022 Jul 31;60(8):1202-1210. Epub 2022 May 31.

Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.

Objectives: A carrier prototype by Aerocom (Schwäbisch Gmünd, Germany) for pneumatic tube systems (PTS) is able to transport 9 blood tubes which are automatically fixed by closing the lid. In this study, we examined the influence of the transport on blood sample quality using the carrier prototype comparing to courier transport and a conventional carrier (AD160, Aerocom).

Methods: Triplicate blood samples sets (1 lithium heparin, 1 EDTA, 1 sodium citrate) of 35 probands were split among the transportation methods: 1. courier, 2. conventional carrier, and 3. carrier prototype. After transport 51 measurands from clinical chemistry, hematology and coagulation were measured and compared.

Results: Overall, 49 of the investigated 51 measurands showed a good concordance among the three transport types, especially between the conventional carrier and the carrier prototype. Focusing on well-known hemolysis sensitive measurands, potassium showed no statistically significant differences. However, between courier and both carrier types lactate dehydrogenase (LDH) and free hemoglobin (fHb) showed statistically significant shifts, whereas the clinical impact of the identified differences was neglectable. The median concentration of fHb, for example, was 0.29 g/L (18 µmol/L), 0.31 g/L (19 µmol/L) and 0.32 g/L (20 µmol/L) for courier transport, conventional carrier and carrier prototype, respectively. These differences cannot be resolved analytically since the minimal difference (MD) for fHb is 0.052 g/L (3.23 µmol/L), at this concentration.

Conclusions: The carrier prototype by Aerocom is suitable for transportation of diagnostic blood samples. The overall workflow is improved by decreasing hands-on-time on the ward and laboratory while minimizing the risk of incorrectly packed carriers.
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http://dx.doi.org/10.1515/cclm-2022-0193DOI Listing
July 2022

Insulin-Like Growth Factor, Inflammation, and MRI Markers of Alzheimer's Disease in Predominantly Middle-Aged Adults.

J Alzheimers Dis 2022 May 16. Epub 2022 May 16.

Department of Neurology, Boston University School of Medicine, Boston, MA, USA.

Background: Insulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer's disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults.

Objective: To investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer's disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation.

Methods: We included participants from the Framingham Heart Study (n = 1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n = 674, mean age 50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons.

Results: Meta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [β] [95% CI], -0.05 [-0.09, -0.02], p = 0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p = 0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations < 75th percentile. We did not observe associations between IGFBP-3 and MRI outcomes.

Conclusion: Our findings suggest that IGF-1-related signaling may be implicated in brain health as early as midlife.
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http://dx.doi.org/10.3233/JAD-220356DOI Listing
May 2022

The interplay between genetic variation and gene expression of the glucocorticoid receptor gene NR3C1 and blood cortisol levels on verbal memory and hippocampal volumes.

Eur Arch Psychiatry Clin Neurosci 2022 May 17. Epub 2022 May 17.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Ellernholzstraße 1-2, 17489, Greifswald, Germany.

The hypothalamus-pituitary-adrenal axis is the main physiological stress response system and regulating the release of cortisol. The two corticoid receptors encoded by the genes NR3C1 and NR3C2 are the main players in regulating the physiological response to cortisol. This biological system has been linked to neurocognitive processes and memory, yet the mechanisms remain largely unclear. In two independent general population studies (SHIP, total sample size > 5500), we aim to diseantangle the effects of genetic variation, gene expression and cortisol on verbal memory and memory associated brain volume. Especially for NR3C1 results exhibited a consistent pattern of direct an interactive effects. All three biological layers, genetic variation (rs56149945), gene expression for NR3C1 and cortisol levels, were directly associated with verbal memory. Interactions between these components showed significant effects on verbal memory as well as hippocampal volume. For NR3C2 such a complex association pattern could not be observed. Our analyses revealed that different components of the stress response system are acting together on different aspects of cognition. Complex phenotypes, such as cognition and memory function are regulated by a complex interplay between different genetic and epigenetic features. We promote the glucocorticoid receptor NR3C1 as a main target to focus in the context of verbal memory and provided a mechanistic concept of the interaction between various biological layers spanning NR3C1 function and its effects on memory. Especially the NR3C1 transcript seemed to be a key element in this complex system.
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http://dx.doi.org/10.1007/s00406-022-01420-wDOI Listing
May 2022

Association between bone turnover markers and periodontitis: A population-based cross-sectional study.

J Clin Periodontol 2022 Jul 23;49(7):633-641. Epub 2022 May 23.

Department of Restorative Dentistry, Periodontology, Endodontology, and Preventive and Pediatric Dentistry, University Medicine Greifswald, Greifswald, Germany.

Aim: To examine the associations between bone turnover markers and periodontitis in two cross-sectional population-based studies.

Materials And Methods: We used data from two independent adult samples (N = 4993), collected within the Study of Health in Pomerania project, to analyse cross-sectional associations of N-procollagen type 1 amino-terminal propeptide (P1NP), C-terminal cross-linking telopeptide, osteocalcin, bone-specific alkaline phosphatase (BAP), fibroblast growth factor 23, wingless-type mouse mammary tumour virus integration site family member 5a (WNT5A), and sclerostin values with periodontitis. Confounder-adjusted gamma and fractional response regression models were applied.

Results: Positive associations were found for P1NP with mean pocket probing depth (PPD; ; 95% confidence interval [CI]: 1.001-1.015), mean clinical attachment loss (mean CAL; ; 95% CI: 1.011-1.044), and proportion of sites with bleeding on probing (%BOP; ; 95% CI: 1.005-1.109). Similar associations were seen for BAP with %BOP ( ; 95% CI: 1.042-1.205), proportion of sites with PPD ≥4 mm (%PPD4) ( ; 95% CI: 1.005-1.161), and sclerostin with %BOP ( ; 95% CI: 1.005-1.704). WNT5A was inversely associated with mean PPD ( ; 95% CI: 0.920-0.993) and %PPD4 ( ; 95% CI: 0.642-0.982).

Conclusions: This study revealed scattered associations of P1NP, BAP, WNT5A, and sclerostin with periodontitis, but the results are contradictory in the overall context. Associations reported in previous studies could not be confirmed.
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http://dx.doi.org/10.1111/jcpe.13649DOI Listing
July 2022

Molybdenum Cofactor Catabolism Unravels the Physiological Role of the Drug Metabolizing Enzyme Thiopurine S-Methyltransferase.

Clin Pharmacol Ther 2022 May 10. Epub 2022 May 10.

Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.

Therapy of molybdenum cofactor (Moco) deficiency has received US Food and Drug Administration (FDA) approval in 2021. Whereas urothione, the urinary excreted catabolite of Moco, is used as diagnostic biomarker for Moco-deficiency, its catabolic pathway remains unknown. Here, we identified the urothione-synthesizing methyltransferase using mouse liver tissue by anion exchange/size exclusion chromatography and peptide mass fingerprinting. We show that the catabolic Moco S-methylating enzyme corresponds to thiopurine S-methyltransferase (TPMT), a highly polymorphic drug-metabolizing enzyme associated with drug-related hematotoxicity but unknown physiological role. Urothione synthesis was investigated in vitro using recombinantly expressed human TPMT protein, liver lysates from Tpmt wild-type and knock-out (Tpmt ) mice as well as human liver cytosol. Urothione levels were quantified by liquid-chromatography tandem mass spectrometry in the kidneys and urine of mice. TPMT-genotype/phenotype and excretion levels of urothione were investigated in human samples and validated in an independent population-based study. As Moco provides a physiological substrate (thiopterin) of TPMT, thiopterin-methylating activity was associated with TPMT activity determined with its drug substrate (6-thioguanin) in mice and humans. Urothione concentration was extremely low in the kidneys and urine of Tpmt mice. Urinary urothione concentration in TPMT-deficient patients depends on common TPMT polymorphisms, with extremely low levels in homozygous variant carriers (TPMT*3A/*3A) but normal levels in compound heterozygous carriers (TPMT*3A/*3C) as validated in the population-based study. Our work newly identified an endogenous substrate for TPMT and shows an unprecedented link between Moco catabolism and drug metabolism. Moreover, the TPMT example indicates that phenotypic consequences of genetic polymorphisms may differ between drug- and endogenous substrates.
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http://dx.doi.org/10.1002/cpt.2637DOI Listing
May 2022

Association of osteopontin with kidney function and kidney failure in chronic kidney disease patients: the GCKD study.

Nephrol Dial Transplant 2022 May 7. Epub 2022 May 7.

Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.

Background: Osteopontin (OPN), synthesized in the thick ascending limb of Henle's loop and in the distal tubule, is involved in the pathogenesis of kidney fibrosis, a hallmark of kidney failure (KF). In a cohort of chronic kidney disease (CKD) patients, we evaluated OPN's association with kidney markers and KF.

Methods: OPN was measured from baseline serum samples of German Chronic Kidney Disease study participants. Cross-sectional regression models for estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) as well as Cox regression models for all-cause mortality and KF were evaluated to estimate the OPN effect. Additionally, predictive ability, of OPN and time-dependent population-attributable fraction were evaluated.

Results: Over a median follow-up of 6.5 years, 471 KF events and 629 deaths occurred among 4,950 CKD patients. One-unit higher log(OPN) was associated with 5.5 mL/min/1.73m2 lower eGFR (95%CI: [-6.4,-4.6]) and 1% change in OPN with 0.7% higher UACR (estimated effect 0.7, 95%CI: [0.6,0.8]). Moreover, higher OPN levels were associated with a higher risk of KF (hazard ratio [HR] 1.4, 95%CI: [1.2,1.7]) and all-cause mortality (HR 1.5, 95%CI: [1.3,1.8]). After 6 years, 31% of the KF events could be attributed to higher OPN levels (95%CI: [3%,56%]).

Conclusions: In this study, higher OPN levels were associated with kidney function markers worsening, and a higher risk for adverse outcomes. A larger proportion of KF could be attributed to higher OPN levels warranting further research on OPN with regards to its role in CKD progression and possible treatment options.
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http://dx.doi.org/10.1093/ndt/gfac173DOI Listing
May 2022

Course of disease and risk factors for hospitalization in outpatients with a SARS-CoV-2 infection.

Sci Rep 2022 05 4;12(1):7249. Epub 2022 May 4.

Department of General Pharmacology, Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, 17489, Greifswald, Germany.

We analyzed symptoms and comorbidities as predictors of hospitalization in 710 outpatients in North-East Germany with PCR-confirmed SARS-CoV-2 infection. During the first 3 days of infection, commonly reported symptoms were fatigue (71.8%), arthralgia/myalgia (56.8%), headache (55.1%), and dry cough (51.8%). Loss of smell (anosmia), loss of taste (ageusia), dyspnea, and productive cough were reported with an onset of 4 days. Anosmia or ageusia were reported by only 18% of the participants at day one, but up to 49% between days 7 and 9. Not all participants who reported ageusia also reported anosmia. Individuals suffering from ageusia without anosmia were at highest risk of hospitalization (OR 6.8, 95% CI 2.5-18.1). They also experienced more commonly dyspnea and nausea (OR of 3.0, 2.9, respectively) suggesting pathophysiological connections between these symptoms. Other symptoms significantly associated with increased risk of hospitalization were dyspnea, vomiting, and fever. Among basic parameters and comorbidities, age > 60 years, COPD, prior stroke, diabetes, kidney and cardiac diseases were also associated with increased risk of hospitalization. In conclusion, due to the delayed onset, ageusia and anosmia may be of limited use in differential diagnosis of SARS-CoV-2. However, differentiation between ageusia and anosmia may be useful for evaluating risk for hospitalization.
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http://dx.doi.org/10.1038/s41598-022-11103-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065670PMC
May 2022

DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases.

Nat Commun 2022 05 3;13(1):2408. Epub 2022 May 3.

Departments of Gynecology and Obstetrics & Psychiatry and Behavioral Science, Emory University School of Medicine, Atlanta, GA, USA.

We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.
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http://dx.doi.org/10.1038/s41467-022-29792-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065016PMC
May 2022

Variability of biomarkers used for the classification of metabolic syndrome: A repeated measurements study.

Nutr Metab Cardiovasc Dis 2022 Jul 2;32(7):1693-1702. Epub 2022 Apr 2.

Institute for Community Medicine, University Medicine Greifswald, Germany.

Background And Aims: The definition of the metabolic syndrome consists of five components. The underlying measurements are subject to intra-individual variability. This repeated measurements study investigated the impact of intra-individual measurement variability on the stability of the diagnosis of metabolic syndrome over 12 months.

Methods And Results: Twenty-five employees of the University Medicine Greifswald aged 22-70 years were examined once a month over one year. Examinations included blood sampling and anthropometric and blood pressure measurements. Laboratory measurements included glucose, cholesterol (high-density lipoprotein [HDL], and low-density lipoprotein [LDL]), and triglycerides. The metabolic syndrome was defined according to the International Diabetes Federation modified for non-fasting blood samples. Variations in continuous metabolic markers were assessed using coefficients of variation (CV) and intra-class correlation coefficients (ICC). Overall eight participants (32%) were categorized at least once within 12 months as having a metabolic syndrome; in none of those metabolic syndrome was found consistently over the study follow-ups. The Cohen's Kappa for metabolic syndrome was 0.57. CV was highest for triglycerides (27.5%) followed by glucose (10.1%), LDL- (9.5%), and HDL-cholesterol (8.6%). ICC's were lowest for glucose (0.51), triglycerides (0.65), systolic (0.68), and diastolic blood pressure (0.69).

Conclusion: We showed that the measurement of biomarkers defining the metabolic syndrome is a time-varying condition with implications for the concept of the metabolic syndrome. To account for this uncertainty in prevalence studies we propose to identify uncertain cases according to the current definition of the metabolic syndrome. For analysing associations we recommend to apply probabilistic sensitivity analyses.
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http://dx.doi.org/10.1016/j.numecd.2022.03.022DOI Listing
July 2022

Definition, Classification and Diagnosis of Diabetes Mellitus.

Exp Clin Endocrinol Diabetes 2022 Apr 21. Epub 2022 Apr 21.

German Diabetes Foundation (DDS) Düsseldorf, Germany.

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http://dx.doi.org/10.1055/a-1624-2897DOI Listing
April 2022

NMR Metabolomics Reveal Urine Markers of Microbiome Diversity and Identify Benzoate Metabolism as a Mediator between High Microbial Alpha Diversity and Metabolic Health.

Metabolites 2022 Mar 31;12(4). Epub 2022 Mar 31.

Department of Internal Medicine A, University Medicine Greifswald, D-17475 Greifswald, Germany.

Microbial metabolites measured using NMR may serve as markers for physiological or pathological host-microbe interactions and possibly mediate the beneficial effects of microbiome diversity. Yet, comprehensive analyses of gut microbiome data and the urine NMR metabolome from large general population cohorts are missing. Here, we report the associations between gut microbiota abundances or metrics of alpha diversity, quantified from stool samples using 16S rRNA gene sequencing, with targeted urine NMR metabolites measures from 951 participants of the Study of Health in Pomerania (SHIP). We detected significant genus-metabolite associations for hippurate, succinate, indoxyl sulfate, and formate. Moreover, while replicating the previously reported association between hippurate and measures of alpha diversity, we identified formate and 4-hydroxyphenylacetate as novel markers of gut microbiome alpha diversity. Next, we predicted the urinary concentrations of each metabolite using genus abundances via an elastic net regression methodology. We found profound associations of the microbiome-based hippurate prediction score with markers of liver injury, inflammation, and metabolic health. Moreover, the microbiome-based prediction score for hippurate completely mediated the clinical association pattern of microbial diversity, hinting at a role of benzoate metabolism underlying the positive associations between high alpha diversity and healthy states. In conclusion, large-scale NMR urine metabolomics delivered novel insights into metabolic host-microbiome interactions, identifying pathways of benzoate metabolism as relevant candidates mediating the beneficial health effects of high microbial alpha diversity.
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http://dx.doi.org/10.3390/metabo12040308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9025190PMC
March 2022

Genetics of osteopontin in patients with chronic kidney disease: The German Chronic Kidney Disease study.

PLoS Genet 2022 04 6;18(4):e1010139. Epub 2022 Apr 6.

Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany.

Osteopontin (OPN), encoded by SPP1, is a phosphorylated glycoprotein predominantly synthesized in kidney tissue. Increased OPN mRNA and protein expression correlates with proteinuria, reduced creatinine clearance, and kidney fibrosis in animal models of kidney disease. But its genetic underpinnings are incompletely understood. We therefore conducted a genome-wide association study (GWAS) of OPN in a European chronic kidney disease (CKD) population. Using data from participants of the German Chronic Kidney Disease (GCKD) study (N = 4,897), a GWAS (minor allele frequency [MAF]≥1%) and aggregated variant testing (AVT, MAF<1%) of ELISA-quantified serum OPN, adjusted for age, sex, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR) was conducted. In the project, GCKD participants had a mean age of 60 years (SD 12), median eGFR of 46 mL/min/1.73m2 (p25: 37, p75: 57) and median UACR of 50 mg/g (p25: 9, p75: 383). GWAS revealed 3 loci (p<5.0E-08), two of which replicated in the population-based Young Finns Study (YFS) cohort (p<1.67E-03): rs10011284, upstream of SPP1 encoding the OPN protein and related to OPN production, and rs4253311, mapping into KLKB1 encoding prekallikrein (PK), which is processed to kallikrein (KAL) implicated through the kinin-kallikrein system (KKS) in blood pressure control, inflammation, blood coagulation, cancer, and cardiovascular disease. The SPP1 gene was also identified by AVT (p = 2.5E-8), comprising 7 splice-site and missense variants. Among others, downstream analyses revealed colocalization of the OPN association signal at SPP1 with expression in pancreas tissue, and at KLKB1 with various plasma proteins in trans, and with phenotypes (bone disorder, deep venous thrombosis) in human tissue. In summary, this GWAS of OPN levels revealed two replicated associations. The KLKB1 locus connects the function of OPN with PK, suggestive of possible further post-translation processing of OPN. Further studies are needed to elucidate the complex role of OPN within human (patho)physiology.
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http://dx.doi.org/10.1371/journal.pgen.1010139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9015153PMC
April 2022

[Analytical Quality of Glucose Measurements in Germany].

Dtsch Med Wochenschr 2022 Apr 28;147(7):407-413. Epub 2022 Mar 28.

Institut für Klinische Chemie und Laboratoriumsmedizin, Universitätsmedizin Greifswald, Greifswald.

The measurement quality of systems used for determination of glucose concentrations has to be sufficiently high to obtain measurement results that are reliable in a clinical context regarding the intended use (e. g., diabetes diagnosis and monitoring). The "Richtlinie der Bundesärztekammer zur Qualitätssicherung laboratoriumsmedizinischer Untersuchungen" (guideline of the German Medical Association on quality assurance in medical laboratory examinations) includes specifications on the internal and external quality assurance that are legally binding for glucose measurements in healthcare. In the opinion of the authors, however, there is room for improvement, and examples are provided. Systems for self-monitoring of blood glucose by patients do not fall under any legally binding requirements for quality assurance. With systems for continuous glucose monitoring, there are currently no technological means to regularly check measurement quality. Additionally, repeated manufacturer-independent evaluations, which could lead to improved measurement quality, are not available.
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http://dx.doi.org/10.1055/a-1741-2594DOI Listing
April 2022

Effects of Apolipoprotein E polymorphism on carotid intima-media thickness, incident myocardial infarction and incident stroke.

Sci Rep 2022 03 24;12(1):5142. Epub 2022 Mar 24.

Institute for Community Medicine, University Medicine Greifswald, SHIP/Clinical-Epidemiological Research, Walther Rathenau Str. 48, 17475, Greifswald, Germany.

The Apolipoprotein E (APOE) gene polymorphism (rs429358 and rs7412) shows a well-established association with lipid profiles, but its effect on cardiovascular disease is still conflicting. Therefore, we examined the association of different APOE alleles with common carotid artery intima-media thickness (CCA-IMT), carotid plaques, incident myocardial infarction (MI) and stroke. We analyzed data from 3327 participants aged 20-79 years of the population-based Study of Health in Pomerania (SHIP) from Northeast Germany with a median follow-up time of 14.5 years. Linear, logistic, and Cox-regression models were used to assess the associations of the APOE polymorphism with CCA-IMT, carotid plaques, incident MI and stroke, respectively. In our study, the APOE E2 allele was associated with lower CCA-IMT at baseline compared to E3 homozygotes (β: - 0.02 [95% CI - 0.04, - 0.004]). Over the follow-up, 244 MI events and 218 stroke events were observed. APOE E2 and E4 allele were not associated with incident MI (E2 HR: 1.06 [95% CI 0.68, 1.66]; E4 HR: 1.03 [95% CI 0.73, 1.45]) and incident stroke (E2 HR: 0.79 [95% CI 0.48, 1.30]; E4 HR: 0.96 [95% CI 0.66, 1.38]) in any of the models adjusting for potential confounders. However, the positive association between CCA-IMT and incident MI was more pronounced in E2 carriers than E3 homozygotes. Thus, our study suggests that while APOE E2 allele may predispose individuals to lower CCA-IMT, E2 carriers may be more prone to MI than E3 homozygotes as the CCA-IMT increases. APOE E4 allele had no effect on CCA-IMT, plaques, MI or stroke.
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http://dx.doi.org/10.1038/s41598-022-09129-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8948289PMC
March 2022

Decreased Intrathecal Concentrations of Free Light Chains Kappa in Multiple Sclerosis Patients Taking Very High Effective Disease-Modifying Treatment.

Diagnostics (Basel) 2022 Mar 16;12(3). Epub 2022 Mar 16.

Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.

Free light chains kappa (FLCκ) in cerebrospinal fluid (CSF) are a part of the intrathecal immune response. This observational study was conducted to investigate the effects of different disease-modifying therapies (DMT) on the humoral intrathecal immune response in the CSF of patients with multiple sclerosis (MS). FLCκ were analyzed in CSF and serum samples from MS patients taking DMT ( = 60) and those in a control cohort of treatment-naïve MS patients ( = 90). DMT was classified as moderately effective (including INFß-1a, INFß-1b, glatiramer acetate, dimethyl fumarate, teriflunomide, triamcinolone); highly effective (including fingolimod, daclizumab) and very highly effective (alemtuzumab, natalizumab, rituximab/ocrelizumab, mitoxantrone). FLCκ were measured using a nephelometric FLCκ kit. Intrathecal FLCκ and IgG concentrations were assessed in relation to the hyperbolic reference range in quotient diagrams. Intrathecal FLCκ concentrations and IgG concentrations were significantly lower in samples from the cohort of MS patients taking very highly effective DMT than in samples from the cohort of MS patients taking highly effective DMT and in the treatment-naïve cohort (FLCκ: = 0.004, < 0.0001 respectively/IgG: = 0.013; = 0.021). The reduction in FLCκ could contribute to an anti-inflammatory effect in the CNS through this mechanism. There was no difference in the appearance of CSF-specific oligoclonal bands ( = 0.830). Longitudinal analyses are required to confirm these results.
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http://dx.doi.org/10.3390/diagnostics12030720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8947149PMC
March 2022

Heart-Type Fatty Acid Binding Protein, Cardiovascular Outcomes, and Death: Findings From the German CKD Cohort Study.

Am J Kidney Dis 2022 Mar 11. Epub 2022 Mar 11.

Department of Nephrology and Hypertension, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany; Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Rationale & Objective: Heart-type fatty acid binding protein (H-FABP) is a biomarker that has been shown to provide long-term prognostic information in patients with coronary artery disease independently of high-sensitivity troponin T (hs-TNT). We examined the independent associations of H-FABP with cardiovascular outcomes in patients with chronic kidney disease (CKD).

Study Design: Prospective cohort study.

Setting & Participants: 4,951 patients enrolled in the German Chronic Kidney Disease (GCKD) study with an estimated glomerular filtration rate of 30-60 mL/min/1.73 m or overt proteinuria (urinary albumin-creatinine ratio > 300 mg/g or equivalent).

Exposure: Serum levels of H-FABP and hs-TNT were measured at study entry.

Outcome: Noncardiovascular (non-CV) death, CV death, combined major adverse CV events (MACE), and hospitalization for congestive heart failure (CHF).

Analytical Approach: Hazard ratios (HRs) for associations of H-FABP and hs-TNT with outcomes were estimated using Cox regression analyses adjusted for established risk factors.

Results: During a maximum follow-up of 6.5 years, 579 non-CV deaths, 190 CV deaths, 522 MACE, and 381 CHF hospitalizations were observed. In Cox regression analyses adjusted for established risk factors, H-FABP was associated with all 4 outcomes, albeit with lower HRs than those found for hs-TNT. After further adjustment for hs-TNT levels, H-FABP was found to be associated with non-CV death (HR, 1.57 [95% CI, 1.14-2.18]) and MACE (HR, 1.40 [95% CI, 1.02-1.92]) but with neither CV death (HR, 1.64 [95% CI, 0.90-2.99]) nor CHF hospitalizations (HR, 1.02 [95% CI, 0.70-1.49]).

Limitations: Single-point measurements of H-FABP and hs-TNT. Uncertain generalizability to non-European populations.

Conclusions: In this large cohort of patients with CKD, H-FABP was associated with non-CV death and MACE, even after adjustment for hs-TNT. Whether measurement of H-FABP improves cardiovascular disease risk prediction in these patients warrants further studies.
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http://dx.doi.org/10.1053/j.ajkd.2022.01.424DOI Listing
March 2022

Plasma circulating micro-RNAs associated with alexithymia reflect a high overlap on neuropsychiatric outcomes.

J Affect Disord 2022 05 10;305:206-212. Epub 2022 Mar 10.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany; German Centre for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.

Background: Alexithymia ("no word for feelings") is a personality feature that is common in patients with psychiatric disorders. However, little is known about biological causes and mechanism behind. Research so far focusses on genetic risk variants primary associated with depression, but analyses on epigenetic mechanisms are still missing.

Methods: In a sample of n = 813 subjects from the "Study of Health in Pomerania" we analyzed the association between alexithymia and plasma circulating micro RNAs (miRNA). Significant miRNAs were compared to associations regarding depression and pathway analyses were performed.

Results: Two miRNAs were significantly associated with at least one of the alexithymia scores (hsa-miR-324-3p, hsa-miR-33a-5p) and three miRNAs additionally revealed a strong association pattern to alexithymia (hsa-miR-106b-5p, hsa-miR-484, hsa-miR-25-3p). None of these miRNAs was significantly associated with depressive symptoms in our sample. Literature research showed that all of the miRNAs have been found in association with several neuropsychiatric phenotypes.

Limitations: Main limitations are the lack of a replication sample as well as the limited number of miRNAs analyzed.

Conclusions: This is the first analysis investigating the association between miRNAs and alexithymia. Results indicate that miRNAs are not specific for one psychiatric disorder but may influence biological mechanisms that are involved in various psychiatric conditions which might be relevant for future treatment options and improve the biological understanding of psychiatric conditions.
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http://dx.doi.org/10.1016/j.jad.2022.03.012DOI Listing
May 2022

Association between hepatic iron overload assessed by magnetic resonance imaging and glucose intolerance states in the general population.

Nutr Metab Cardiovasc Dis 2022 06 24;32(6):1470-1476. Epub 2022 Feb 24.

Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Germany; German Center for Diabetes Research (DZD), Partner Site Greifswald, Germany.

Background And Aim: While there is evidence that iron overload disorders are associated with type 2 diabetes, the relationship between hepatic iron overload and prediabetes remains unclear. We aimed to investigate the association between hepatic iron overload, as assessed by magnetic resonance imaging (MRI), and different glucose intolerance states in the population-based Study.

Methods And Results: We included data from 1622 individuals with MRI data, who did not have known type 2 diabetes (T2DM). Using an oral glucose tolerance testing, participants were classified as having isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), combined IFG and IGT (IFG + IGT) or previously unknown T2DM. Hepatic iron and fat contents were assessed through quantitative MRI. We undertook linear and multinomial logistic regression models adjusted for potential confounders and MRI-assessed hepatic fat content to examine the association of hepatic iron overload with different glucose intolerance states or continuous markers of glucose metabolism. MRI-assessed hepatic iron overload was positively associated only with both 2-h plasma glucose (β = 0.32; 95%CI 0.04-0.60) and the combined IFG + IGT category (relative risk ratio = 1.87; 95%CI 1.15-3.06). No significant associations were found between hepatic iron overload and other glucose intolerance states or biomarkers of glucose metabolism, independently of potential confounders.

Conclusions: MRI-assessed hepatic iron overload was associated with higher 2-h glucose concentrations and the combined IFG + IGT category, but not with other glucose intolerance states. Our findings suggest a weak adverse impact of hepatic iron overload on glucose metabolism, but further studies are needed to confirm these findings.
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http://dx.doi.org/10.1016/j.numecd.2022.02.013DOI Listing
June 2022

Links between ectopic and abdominal fat and systemic inflammation: New insights from the SHIP-Trend study.

Dig Liver Dis 2022 Feb 26. Epub 2022 Feb 26.

Chair of Epidemiology, University of Augsburg, University Hospital Augsburg, Stenglinstr. 2, Augsburg 86156, Germany; Independent Research Group Clinical Epidemiology, Helmholtz Zentrum München, Neuherberg D-85764, Germany.

Background: Excessive fat accumulation in adipose tissue depots and organs such as the pancreas and the liver is associated with systemic low-grade chronic inflammation.

Aims: To investigate the association between abdominal, hepatic, and pancreatic fat and the circulating level of inflammatory biomarkers.

Methods: We used data from a subsample of the Study of Health in Pomerania (SHIP-Trend, n = 469). The plasma concentration of 37 inflammatory biomarkers was measured using the Bio-Plex-Pro™-Human-Inflammation-Panel-1. Subcutaneous and visceral adipose tissue (SAT and VAT), as well as hepatic and pancreatic fat, were determined by magnetic resonance imaging. We assessed the associations between fat content and inflammatory biomarkers using multiple linear regression.

Results: Hepatic fat was associated with MMP-2 (β -0.11), PTX3 (β -0.14), and TNFSF12 (β -0.06). Pancreatic fat was associated with sTNFR1 (β 0.15), sTNFR2 (β 0.11), and sCD163 (β 0.13). VAT and SAT were associated with sCD163 (β 0.20, β 0.16), MMP-2 (β -0.12, β -0.10), OSTCN (β -0.16, β -0.10), sTNFR1 (β 0.13, β 0.13), sTNFR2 (β 0.13, β 0.12), TNFSF12 (β -0.11, β -0.08), and TNFSF14 (β 0.21, β 0.20). VAT was additionally associated with TNFSF13B (β 0.08) and CHI3L1 (β 0.07).

Conclusions: Our findings provide new insights into the involvement of hepatic and pancreatic fat on systemic inflammation.
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http://dx.doi.org/10.1016/j.dld.2022.02.003DOI Listing
February 2022

Longitudinal association of Apolipoprotein E polymorphism with lipid profile, type 2 diabetes and metabolic syndrome: Results from a 15 year follow-up study.

Diabetes Res Clin Pract 2022 Mar 12;185:109778. Epub 2022 Feb 12.

Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.

Aims: To examine the association of different APOE alleles with type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) as well as the influence of high-sensitive C-reactive protein (hs-CRP) on these associations.

Methods: We analyzed data from 3917 participants aged 20-81 years of the population-based Study of Health in Pomerania (SHIP) from Northeast Germany with a median follow-up time of 10.8 years. Linear and logistic mixed models were performed to test the association of APOE alleles with T2DM and MetS.

Results: We observed 393 T2DM and 1411 MetS events at baseline, and 576 T2DM and 1342 MetS events over the follow-up. The E4 carriers had a lower odds of developing T2DM (OR: 0.47 [0.24, 0.94]) than E3 homozygotes even after adjustment for potential confounders. The E2 carriers showed no associations. The inverse association between E4 alleles and T2DM moderately attenuated after adjustment for hs-CRP levels. The lower odds of developing T2DM in E4 carriers was more pronounced in participants without obesity, hypertension or MetS. However, both E2 and E4 carriers had higher odds of developing MetS (E2 OR: 1.45 [1.03, 2.03]; E4 OR: 1.56 [1.17, 2.09]) than E3 homozygotes.

Conclusions: While the presence of APOE E4 allele might increase the chance of MetS through its major action on lipids, E4 allele might offer a protection towards T2DM through its influence on inflammation.
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http://dx.doi.org/10.1016/j.diabres.2022.109778DOI Listing
March 2022

Association of Cardiopulmonary Exercise Capacity and Adipokines in the General Population.

Int J Sports Med 2022 Jun 3;43(7):616-624. Epub 2022 Feb 3.

Department for Internal Medicine B, Universitätsmedizin Greifswald, Greifswald, Germany.

Adipokines and cardiorespiratory fitness (CRF) are associated with the (patho)physiology of cardiometabolic diseases. Whether CRF and adipokines are related is unclear. We investigated associations of CRF with leptin, adiponectin, chemerin, resistin and vaspin. Data from the population-based Study of Health in Pomerania was used (n=1,479; median age 49 years; 51% women). Cardiopulmonary exercise testing was used to measure CRF. Circulating adipokine concentrations were measured by enzyme-linked immunosorbent assay. The association between CRF and adipokines was assessed using multivariable sex-specific quantile regression models. Higher maximum oxygen uptake was significantly associated with lower leptin (men:-0.11 ng/ml; 95%-confidence interval [CI]:-0.18 to-0.03 ng/ml; p<0.005; women:-0.17 ng/ml; 95%-CI:-0.33 to-0.02 ng/ml; p<0.05) and chemerin (men:-0.26 ng/ml; 95%-CI:-0.52 to-0.01 ng/ml; p<0.05; women:-0.41 ng/ml; 95%-CI:-0.82 to-0.01 ng/ml; p<0.05) as well as higher adiponectin concentrations (men: 0.06 µg/ml; 95%-CI: 0.02 to 0.11 µg/ml; p<0.05; women: 0.03 µg/ml; 95%-CI:-0.05 to 0.10 µg/ml; p=0.48). We found that CRF was inversely associated with leptin and chemerin in both sexes and positively associated with adiponectin only in men.
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http://dx.doi.org/10.1055/a-1699-2380DOI Listing
June 2022

Association of thyroid function with insulin resistance: data from two population-based studies.

Eur Thyroid J 2022 Feb 28;11(2). Epub 2022 Feb 28.

Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.

Objective: Thyroid dysfunction is associated with relevant disturbances in glucose metabolism. Moreover, thyroid function undergoes important changes with ageing. The objective of this study was to investigate the association of thyroid function with insulin resistance with particular consideration of possible age-related effect modifications.

Design: A sample of 4193 participants from two independent epidemiological studies, the Study of Health in Pomerania-TREND-0 and the Berlin Aging Study II, was included in this cross-sectional analysis.

Methods: Insulin resistance was estimated by homeostasis model of insulin resistance (HOMA-IR) and the insulin sensitivity index (ISI). Associations of thyroid biomarkers (thyroid-stimulating hormone, free thyroxine, and free triiodothyronine (fT3)) with parameters of glucose metabolism were analysed by regression models adjusted for age, sex, smoking status, and study site.

Results: A higher fT3 was significantly associated with higher fasting glucose and higher fasting and 2-h postload insulin levels, a higher HOMA-IR, and lower ISI. A higher fT3 was also associated with a higher risk for impaired fasting glucose (RR 1.09, 95 CI 1.02; 1.18; P = 0.017). Many of these associations between thyroid markers and parameters of glucose metabolism were significant in young and middle-aged participants but not in older individuals.

Conclusions: The main finding of this study was a consistent association of fT3 with almost all markers of insulin resistance. However, this effect seems to be wearing off in higher age highlighting a potential age-related modification of the interaction between thyroid function and glucose metabolism. Further studies are needed to clarify causal relationships.
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http://dx.doi.org/10.1530/ETJ-21-0063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8963174PMC
February 2022

Association between thyroid function and assessment of hepatic fat and iron contents by magnetic resonance imaging.

Endocr Connect 2022 Feb 16;11(2). Epub 2022 Feb 16.

Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.

The associations of thyroid function parameters with non-alcoholic fatty liver disease (NAFLD) and hepatic iron overload are not entirely clear. We have cross-sectionally investigated these associations among 2734 participants of two population-based cross-sectional studies of the Study of Health in Pomerania. Serum levels of thyroid-stimulating hormone (TSH), free tri-iodothyronine (fT3), and free thyroxine (fT4) levels were measured. Liver fat content (by proton-density fat fraction) as well as hepatic iron content (by transverse relaxation rate; R2*) were assessed by quantitative MRI. Thyroid function parameters were associated with hepatic fat and iron contents by median and logistic regression models adjusted for confounding. There were no associations between serum TSH levels and liver fat content, NAFLD, or hepatic iron overload. Serum fT4 levels were inversely associated with liver fat content, NAFLD, hepatic iron contents, and hepatic iron overload. Serum fT3 levels as well as the fT3 to fT4 ratio were positively associated with hepatic fat, NAFLD, hepatic iron contents, but not with hepatic iron overload. Associations between fT3 levels and liver fat content were strongest in obese individuals, in which we also observed an inverse association between TSH levels and NAFLD. These findings might be the result of a higher conversion of fT4 to the biologically active form fT3. Our results suggest that a subclinical hyperthyroid state may be associated with NAFLD, particularly in obese individuals. Furthermore, thyroid hormone levels seem to be more strongly associated with increased liver fat content compared to hepatic iron content.
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http://dx.doi.org/10.1530/EC-21-0566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859959PMC
February 2022

SHIP-MR and Radiology: 12 Years of Whole-Body Magnetic Resonance Imaging in a Single Center.

Healthcare (Basel) 2021 Dec 24;10(1). Epub 2021 Dec 24.

Functional Imaging Unit, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, 17475 Greifswald, Germany.

The Study of Health in Pomerania (SHIP), a population-based study from a rural state in northeastern Germany with a relatively poor life expectancy, supplemented its comprehensive examination program in 2008 with whole-body MR imaging at 1.5 T (SHIP-MR). We reviewed more than 100 publications that used the SHIP-MR data and analyzed which sequences already produced fruitful scientific outputs and which manuscripts have been referenced frequently. Upon reviewing the publications about imaging sequences, those that used T1-weighted structured imaging of the brain and a gradient-echo sequence for R2* mapping obtained the highest scientific output; regarding specific body parts examined, most scientific publications focused on MR sequences involving the brain and the (upper) abdomen. We conclude that population-based MR imaging in cohort studies should define more precise goals when allocating imaging time. In addition, quality control measures might include recording the number and impact of published work, preferably on a bi-annual basis and starting 2 years after initiation of the study. Structured teaching courses may enhance the desired output in areas that appear underrepresented.
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http://dx.doi.org/10.3390/healthcare10010033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8775435PMC
December 2021

Circulating Metabolome and White Matter Hyperintensities in Women and Men.

Circulation 2022 04 20;145(14):1040-1052. Epub 2022 Jan 20.

Lothian Birth Cohorts Group, Department of Psychology, University of Edinburgh, United Kingdom (S.E.H., I.J.D., S.R.C.).

Background: White matter hyperintensities (WMH), identified on T2-weighted magnetic resonance images of the human brain as areas of enhanced brightness, are a major risk factor of stroke, dementia, and death. There are no large-scale studies testing associations between WMH and circulating metabolites.

Methods: We studied up to 9290 individuals (50.7% female, average age 61 years) from 15 populations of 8 community-based cohorts. WMH volume was quantified from T2-weighted or fluid-attenuated inversion recovery images or as hypointensities on T1-weighted images. Circulating metabolomic measures were assessed with mass spectrometry and nuclear magnetic resonance spectroscopy. Associations between WMH and metabolomic measures were tested by fitting linear regression models in the pooled sample and in sex-stratified and statin treatment-stratified subsamples. Our basic models were adjusted for age, sex, age×sex, and technical covariates, and our fully adjusted models were also adjusted for statin treatment, hypertension, type 2 diabetes, smoking, body mass index, and estimated glomerular filtration rate. Population-specific results were meta-analyzed using the fixed-effect inverse variance-weighted method. Associations with false discovery rate (FDR)-adjusted values ()<0.05 were considered significant.

Results: In the meta-analysis of results from the basic models, we identified 30 metabolomic measures associated with WMH (<0.05), 7 of which remained significant in the fully adjusted models. The most significant association was with higher level of hydroxyphenylpyruvate in men (=1.40×10) and in both the pooled sample (=1.66×10) and statin-untreated (=1.65×10) subsample. In men, hydroxyphenylpyruvate explained 3% to 14% of variance in WMH. In men and the pooled sample, WMH were also associated with lower levels of lysophosphatidylcholines and hydroxysphingomyelins and a larger diameter of low-density lipoprotein particles, likely arising from higher triglyceride to total lipids and lower cholesteryl ester to total lipids ratios within these particles. In women, the only significant association was with higher level of glucuronate (=0.047).

Conclusions: Circulating metabolomic measures, including multiple lipid measures (eg, lysophosphatidylcholines, hydroxysphingomyelins, low-density lipoprotein size and composition) and nonlipid metabolites (eg, hydroxyphenylpyruvate, glucuronate), associate with WMH in a general population of middle-aged and older adults. Some metabolomic measures show marked sex specificities and explain a sizable proportion of WMH variance.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056892DOI Listing
April 2022
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