Publications by authors named "Maik Pietzner"

66 Publications

Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases.

Nat Med 2021 Sep 23;27(9):1564-1575. Epub 2021 Aug 23.

Human Genetics Department, Wellcome Sanger Institute (WT), Hinxton, UK.

Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N-formylmethionine (fMet), which initiates mitochondrial protein translation. In human cytoplasmic hybrid (cybrid) lines, fMet modulated both mitochondrial and cytosolic proteins on multiple levels, through transcription, post-translational modification and proteolysis by an N-degron pathway, abolishing known differences between mtDNA haplogroups. In a further 11,966 individuals, fMet levels contributed to all-cause mortality and the disease risk of several common cardiovascular disorders. Together, these findings indicate that fMet plays a key role in common age-related disease through pleiotropic effects on cell proteostasis.
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http://dx.doi.org/10.1038/s41591-021-01441-3DOI Listing
September 2021

Genetically Predicted Glucose-Dependent Insulinotropic Polypeptide (Gip) Levels and Cardiovascular Disease Risk are Driven by Distinct Causal Variants in the Gipr Region.

Diabetes 2021 Aug 23. Epub 2021 Aug 23.

MRC Epidemiology Unit, University of Cambridge, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.

There is considerable interest in GIPR agonism to enhance the insulinotropic and extra-pancreatic effects of GIP, thereby improving glycaemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the locus. Using Bayesian multi-trait colocalisation, we identified a missense variant rs1800437 (G allele; E354) as the putatively causal variant shared between fasting GIP levels, glycaemic traits and adiposity-related traits (posterior probability for colocalisation, PP>0.97; PP explained by the candidate variant; PP=1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in (rs7412; distance to E354 ∼770Kb; R with E354 = 0.004; PPcoloc>0.99; PP=1). Further, conditioning the association between E354 and CAD on the residual LD with rs7412, we observed slight attenuation in association, but it remained significant (OR per copy of E354 after adjustment 1.03; 95% CI, 1.02, 1.04; P=0.003). Instead, E354's association with CAD was completely attenuated when conditioning on an additional established CAD signal, rs1964272, (R with E354=0.27), an intronic variant in (OR for E354 after adjustment for rs1964272: 1.01; 95% CI, 0.99, 1.03; P=0.06). We demonstrate that associations with GIP, anthropometric and glycaemic traits are driven by distinct genetic signals from those driving CAD and lipid traits in the region, and higher E354-mediated fasting GIP levels are not associated with CAD risk. These findings provide evidence that the inclusion of GIPR agonism in dual GIPR/GLP-1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect which has yet to be assessed in clinical trials.
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http://dx.doi.org/10.2337/db21-0103DOI Listing
August 2021

Salivary metabolites associated with a 5-year tooth loss identified in a population-based setting.

BMC Med 2021 Jul 14;19(1):161. Epub 2021 Jul 14.

Department of Restorative Dentistry, Periodontology, Endodontology, and Preventive and Pediatric Dentistry, University Medicine Greifswald, Fleischmannstr. 42, 17475, Greifswald, Germany.

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.
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http://dx.doi.org/10.1186/s12916-021-02035-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278731PMC
July 2021

GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health.

Nat Commun 2021 07 7;12(1):4178. Epub 2021 Jul 7.

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

Mosaic loss of chromosome Y (LOY) in leukocytes is the most common form of clonal mosaicism, caused by dysregulation in cell-cycle and DNA damage response pathways. Previous genetic studies have focussed on identifying common variants associated with LOY, which we now extend to rarer, protein-coding variation using exome sequences from 82,277 male UK Biobank participants. We find that loss of function of two genes-CHEK2 and GIGYF1-reach exome-wide significance. Rare alleles in GIGYF1 have not previously been implicated in any complex trait, but here loss-of-function carriers exhibit six-fold higher susceptibility to LOY (OR = 5.99 [3.04-11.81], p = 1.3 × 10). These same alleles are also associated with adverse metabolic health, including higher susceptibility to Type 2 Diabetes (OR = 6.10 [3.51-10.61], p = 1.8 × 10), 4 kg higher fat mass (p = 1.3 × 10), 2.32 nmol/L lower serum IGF1 levels (p = 1.5 × 10) and 4.5 kg lower handgrip strength (p = 4.7 × 10) consistent with proposed GIGYF1 enhancement of insulin and IGF-1 receptor signalling. These associations are mirrored by a common variant nearby associated with the expression of GIGYF1. Our observations highlight a potential direct connection between clonal mosaicism and metabolic health.
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http://dx.doi.org/10.1038/s41467-021-24504-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263756PMC
July 2021

A metabolome-wide association study in the general population reveals decreased levels of serum laurylcarnitine in people with depression.

Mol Psychiatry 2021 Jun 4. Epub 2021 Jun 4.

Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.

Depression constitutes a leading cause of disability worldwide. Despite extensive research on its interaction with psychobiological factors, associated pathways are far from being elucidated. Metabolomics, assessing the final products of complex biochemical reactions, has emerged as a valuable tool for exploring molecular pathways. We conducted a metabolome-wide association analysis to investigate the link between the serum metabolome and depressed mood (DM) in 1411 participants of the KORA (Cooperative Health Research in the Augsburg Region) F4 study (discovery cohort). Serum metabolomics data comprised 353 unique metabolites measured by Metabolon. We identified 72 (5.1%) KORA participants with DM. Linear regression tests were conducted modeling each metabolite value by DM status, adjusted for age, sex, body-mass index, antihypertensive, cardiovascular, antidiabetic, and thyroid gland hormone drugs, corticoids and antidepressants. Sensitivity analyses were performed in subcohorts stratified for sex, suicidal ideation, and use of antidepressants. We replicated our results in an independent sample of 968 participants of the SHIP-Trend (Study of Health in Pomerania) study including 52 (5.4%) individuals with DM (replication cohort). We found significantly lower laurylcarnitine levels in KORA F4 participants with DM after multiple testing correction according to Benjamini/Hochberg. This finding was replicated in the independent SHIP-Trend study. Laurylcarnitine remained significantly associated (p value < 0.05) with depression in samples stratified for sex, suicidal ideation, and antidepressant medication. Decreased blood laurylcarnitine levels in depressed individuals may point to impaired fatty acid oxidation and/or mitochondrial function in depressive disorders, possibly representing a novel therapeutic target.
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http://dx.doi.org/10.1038/s41380-021-01176-0DOI Listing
June 2021

Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19.

Nat Med 2021 04 9;27(4):668-676. Epub 2021 Apr 9.

Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10; IFNAR2, P = 9.8 × 10 and IL-10RB, P = 2.3 × 10) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.
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http://dx.doi.org/10.1038/s41591-021-01310-zDOI Listing
April 2021

Broad Metabolome Alterations Associated with the Intake of Oral Contraceptives Are Mediated by Cortisol in Premenopausal Women.

Metabolites 2021 Mar 24;11(4). Epub 2021 Mar 24.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, D-17489 Greifswald, Germany.

The use of oral contraceptives (OCs) has been associated with elevated blood cortisol concentrations. However, metabolic downstream effects of OC intake are not well described. Here, we aimed to determine if the blood metabolome is associated with the use of OCs and to estimate if these associations might be statistically mediated by serum cortisol concentrations. Plasma metabolites measured with the Biocrates Absolute p180 Kit and serum cortisol concentrations measured by an immunoassay were determined in 391 premenopausal women (116 OC users) participating in two independent cohorts of the Study of Health in Pomerania (SHIP). After correction for multiple testing, 27 metabolites were significantly associated with OC intake in SHIP-TREND (discovery cohort), of which 25 replicated in SHIP-2. Inter alia, associated metabolites included 12 out of 38 phosphatidylcholines with diacyl residue, 7 out of 14 lysophosphatidylcholines and 5 out of 21 amino acids. The associations with phosphatidylcholines were statistically mediated by cortisol, whereas lysophosphatidylcholines showed no mediation effect. The results represent a step toward a better understanding of the metabolic consequences of OC intake. Connecting cortisol with metabolic consequences of OC intake could help to understand the mechanisms underlying adverse effects. The blood metabolome may serve as a biomarker for identifying users at high risk for developing such adverse effects.
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http://dx.doi.org/10.3390/metabo11040193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064380PMC
March 2021

Carrying asymptomatic gallstones is not associated with changes in intestinal microbiota composition and diversity but cholecystectomy with significant dysbiosis.

Sci Rep 2021 Mar 23;11(1):6677. Epub 2021 Mar 23.

Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.

Gallstone disease affects up to twenty percent of the population in western countries and is a significant contributor to morbidity and health care expenditure. Intestinal microbiota have variously been implicated as either contributing to gallstone formation or to be affected by cholecystectomy. We conducted a large-scale investigation on 404 gallstone carriers, 580 individuals post-cholecystectomy and 984 healthy controls with similar distributions of age, sex, body mass index, smoking habits, and food-frequency-score. All 1968 subjects were recruited from the population-based Study-of-Health-in-Pomerania (SHIP), which includes transabdominal gallbladder ultrasound. Fecal microbiota profiles were determined by 16S rRNA gene sequencing. No significant differences in microbiota composition were detected between gallstone carriers and controls. Individuals post-cholecystectomy exhibited reduced microbiota diversity, a decrease in the potentially beneficial genus Faecalibacterium and an increase in the opportunistic pathogen Escherichia/Shigella. The absence of an association between the gut microbiota and the presence of gallbladder stones suggests that there is no intestinal microbial risk profile increasing the likelihood of gallstone formation. Cholecystectomy, on the other hand, is associated with distinct microbiota changes that have previously been implicated in unfavorable health effects and may not only contribute to gastrointestinal infection but also to the increased colon cancer risk of cholecystectomized patients.
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http://dx.doi.org/10.1038/s41598-021-86247-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988160PMC
March 2021

Plasma metabolites to profile pathways in noncommunicable disease multimorbidity.

Nat Med 2021 03 11;27(3):471-479. Epub 2021 Mar 11.

MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.

Multimorbidity, the simultaneous presence of multiple chronic conditions, is an increasing global health problem and research into its determinants is of high priority. We used baseline untargeted plasma metabolomics profiling covering >1,000 metabolites as a comprehensive readout of human physiology to characterize pathways associated with and across 27 incident noncommunicable diseases (NCDs) assessed using electronic health record hospitalization and cancer registry data from over 11,000 participants (219,415 person years). We identified 420 metabolites shared between at least 2 NCDs, representing 65.5% of all 640 significant metabolite-disease associations. We integrated baseline data on over 50 diverse clinical risk factors and characteristics to identify actionable shared pathways represented by those metabolites. Our study highlights liver and kidney function, lipid and glucose metabolism, low-grade inflammation, surrogates of gut microbial diversity and specific health-related behaviors as antecedents of common NCD multimorbidity with potential for early prevention. We integrated results into an open-access webserver ( https://omicscience.org/apps/mwasdisease/ ) to facilitate future research and meta-analyses.
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http://dx.doi.org/10.1038/s41591-021-01266-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127079PMC
March 2021

Comparative Analysis of the Effects of Long-Term 3,5-diiodothyronine Treatment on the Murine Hepatic Proteome and Transcriptome Under Conditions of Normal Diet and High-Fat Diet.

Thyroid 2021 07 7;31(7):1135-1146. Epub 2021 Apr 7.

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Experimentelle Endokrinologie, Berlin, Germany.

The thyroid hormone (TH) metabolite 3,5-diiodothyronine (3,5-T2) is considered as a potential drug for treatment of nonalcoholic fatty liver disease (NAFLD) based on its prominent antisteatotic effects in murine models of obesity without the detrimental thyromimetic side effects known for classical TH. To expand our understanding of its mode of action, we comprehensively characterized the effects of 3,5-T2 on hepatic gene expression in a diet-induced murine model of obesity by a combined liver proteome and transcriptome analysis. Male C57BL/6 mice fed high-fat diet (HFD) to induce NAFLD or standard diet (SD) as control were treated with 2.5 μg/g body weight 3,5-T2 or saline for 4 weeks. We performed mass spectrometry analyses and integrated those proteome data with earlier published microarray-based transcriptome data from the same animals. In addition, concentrations of several sex steroids in serum and different tissues were determined by gas chromatography-tandem mass spectrometry. We observed limited concordance between transcripts and proteins exhibiting differential abundance under 3,5-T2 treatment, which was only partially explainable by methodological reasons and might, therefore, reflect noncanonical post-transcriptional events. The treatment affected the levels of more and partially different proteins under HFD as compared with SD, demonstrating response modulation by the hepatic lipid load. The hepatic physiological signatures of 3,5-T2 treatment inferable from the omics data comprised the reduction of oxidative stress and alteration of apolipoprotein profiles, both due to decreased liver fat content. In addition, induction of several classical TH target genes and genes involved in the biosynthesis of cholesterol, bile acids (BAs), and male sex steroids was observed. The latter finding was supported by hepatic sex steroid measurements. While confirming the beneficial hepatic liver fat reduction by 3,5-T2 treatment, our data suggest that besides the well-known induction of fatty acid oxidation the stimulation of cholesterol- and BA synthesis with subsequent excretion of the latter through bile might represent a further important mechanism in this context. The obvious intensified male sex steroid exposition of the liver in 3,5-T2-treated HFD animals can be predicted to cause enhanced hepatic "masculinization," with not yet clear but potentially detrimental physiological consequences.
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http://dx.doi.org/10.1089/thy.2020.0160DOI Listing
July 2021

A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity.

Nat Med 2021 04 25;27(4):659-667. Epub 2021 Feb 25.

Anaesthesiology and Intensive Care Medicine, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.

To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10), hospitalization (OR = 0.61, P = 8 × 10) and susceptibility (OR = 0.78, P = 8 × 10). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case-control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development.
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http://dx.doi.org/10.1038/s41591-021-01281-1DOI Listing
April 2021

Efficiency of a 15-Week Weight-Loss Program, Including a Low-Calorie Formula Diet, on Glycemic Control in Patients with Type 2 Diabetes Mellitus and Overweight or Obesity.

Obes Facts 2021 Feb 18:1-11. Epub 2021 Feb 18.

Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.

Introduction: Patients who are overweight or obese have an increased risk of developing type 2 diabetes mellitus (T2DM). Weight loss can have a positive effect on glycemic control.

Objective: We aimed to investigate glycemic control in patients with T2DM and overweight or obesity during a structured weight-loss program.

Methods: This was a prospective, interventional study. We recruited 36 patients (14 men and 22 women) with a median age of 58.5 years and median body mass index (BMI) of 34.1, to a 15-week structured weight-loss program with a low-calorie (800 kcal) formula diet for 6 weeks. The primary end point, HbA1c level, and secondary end points, anthropometric data, medication, and safety, were assessed weekly. Laboratory values and quality of life were assessed at baseline and after 15 weeks.

Results: HbA1c decreased from 7.3% at baseline to 6.5% at 15 weeks (p < 0.001), median body weight by 11.9 kg (p < 0.001), median BMI by 4.3 (p < 0.001) and median waist circumference by 11.0 cm (p < 0.001). Two participants discontinued insulin therapy, 4 could reduce their dosage of oral antidiabetic agents, and 6 completely discontinued their antidiabetic medication. Insulin dose decreased from 0.63 (0.38-0.89) to 0.39 (0.15-0.70) units/kg body weight (p < 0.001). No patient experienced hypoglycemic episodes or hospital emergency visits. Triglycerides and total cholesterol decreased as well as surrogate markers of liver function. However, the levels of high-density and low-density lipoprotein cholesterol (HDL-C and LDL-C) as well as uric acid remain unchanged. Regarding quality of life, the median physical health score increased from 44.5 (39.7-51.4) at baseline to 48.0 (43.1-55.3; p = 0.007), and the median mental health score decreased from 42.1 (36.1-46.7) to 37.4 (30.3-43.7; p = 0.004).

Conclusions: A structured weight-loss program is effective in the short term in reducing HbA1c, weight, and antidiabetic medication in patients with T2DM who are overweight or obese. Levels of HDL-C and LDL-C were not affected by short-term weight loss. The decline in mental health and the long-term effects of improved glycemic control require further trials.
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http://dx.doi.org/10.1159/000511453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983589PMC
February 2021

Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease.

J Hum Genet 2021 Jun 20;66(6):625-636. Epub 2021 Jan 20.

Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland.

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.
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http://dx.doi.org/10.1038/s10038-020-00895-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144017PMC
June 2021

Exocrine Pancreatic Function Modulates Plasma Metabolites Through Changes in Gut Microbiota Composition.

J Clin Endocrinol Metab 2021 Apr;106(5):e2290-e2298

Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.

Purpose: Exocrine pancreatic function is critically involved in regulating the gut microbiota composition. At the same time, its impairment acutely affects human metabolism. How these 2 roles are connected is unknown. We studied how the exocrine pancreas contributes to metabolism via modulation of gut microbiota.

Design: Fecal samples were collected in 2226 participants of the population-based Study of Health in Pomerania (SHIP/SHIP-TREND) to determine exocrine pancreatic function (pancreatic elastase enzyme-linked immunosorbent assay) and intestinal microbiota profiles (16S ribosomal ribonucleic acid gene sequencing). Plasma metabolite levels were determined by mass spectrometry.

Results: Exocrine pancreatic function was associated with changes in the abundance of 28 taxa and, simultaneously, with those of 16 plasma metabolites. Mediation pathway analysis revealed that a significant component of how exocrine pancreatic function affects the blood metabolome is mediated via gut microbiota abundance changes, most prominently, circulating serotonin and lysophosphatidylcholines.

Conclusion: These results imply that the effect of exocrine pancreatic function on intestinal microbiota composition alters the availability of microbial-derived metabolites in the blood and thus directly contributes to the host metabolic changes associated with exocrine pancreatic dysfunction.
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http://dx.doi.org/10.1210/clinem/dgaa961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186556PMC
April 2021

A cross-platform approach identifies genetic regulators of human metabolism and health.

Nat Genet 2021 01 7;53(1):54-64. Epub 2021 Jan 7.

Metabolic Research Laboratories, University of Cambridge, Cambridge, UK.

In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with β-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables the discovery of regulators of human metabolism and translation into clinical insights.
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http://dx.doi.org/10.1038/s41588-020-00751-5DOI Listing
January 2021

Genetic architecture of host proteins involved in SARS-CoV-2 infection.

Nat Commun 2020 12 16;11(1):6397. Epub 2020 Dec 16.

MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.

Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ).
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http://dx.doi.org/10.1038/s41467-020-19996-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744536PMC
December 2020

Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations.

Diabetes Care 2021 01 17;44(1):98-106. Epub 2020 Nov 17.

Unit of Nutrition and Cancer, Cancer Epidemiology Research Program and Translational Research Laboratory; Catalan Institute of Oncology - ICO, Group of Research on Nutrition and Cancer, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet of Llobregat, Barcelona, Spain.

Objective: Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes.

Research Design And Methods: We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants.

Results: We identified 11 genomic regions associated with plasma vitamin C ( < 5 × 10), with the strongest signal at , and 10 novel genetic loci including , , , , , , , , , and . Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10).

Conclusions: These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.
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http://dx.doi.org/10.2337/dc20-1328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783939PMC
January 2021

Long-term instability of the intestinal microbiome is associated with metabolic liver disease, low microbiota diversity, diabetes mellitus and impaired exocrine pancreatic function.

Gut 2021 Mar 9;70(3):522-530. Epub 2020 Nov 9.

Department of Medicine A, University Medicine Greifswald, Greifswald, Germany

Objective: The intestinal microbiome affects the prevalence and pathophysiology of a variety of diseases ranging from inflammation to cancer. A reduced taxonomic or functional diversity of the microbiome was often observed in association with poorer health outcomes or disease in general. Conversely, factors or manifest diseases that determine the long-term stability or instability of the microbiome are largely unknown. We aimed to identify disease-relevant phenotypes associated with faecal microbiota (in-)stability.

Design: A total of 2564 paired faecal samples from 1282 participants of the population-based Study of Health in Pomerania (SHIP) were collected at a 5-year (median) interval and microbiota profiles determined by gene sequencing. The changes in faecal microbiota over time were associated with highly standardised and comprehensive phenotypic data to determine factors related to microbiota (in-)stability.

Results: The overall microbiome landscape remained remarkably stable over time. The greatest microbiome instability was associated with factors contributing to metabolic syndrome such as fatty liver disease and diabetes mellitus. These, in turn, were associated with an increase in facultative pathogens such as or . Greatest stability of the microbiome was determined by higher initial alpha diversity, female sex, high household income and preserved exocrine pancreatic function. Participants who newly developed fatty liver disease or diabetes during the 5-year follow-up already displayed significant microbiota changes at study entry when the diseases were absent.

Conclusion: This study identifies distinct components of metabolic liver disease to be associated with instability of the intestinal microbiome, increased abundance of facultative pathogens and thus greater susceptibility toward dysbiosis-associated diseases.
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http://dx.doi.org/10.1136/gutjnl-2020-322753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873430PMC
March 2021

Integrating Genetics and the Plasma Proteome to Predict the Risk of Type 2 Diabetes.

Curr Diab Rep 2020 10 8;20(11):60. Epub 2020 Oct 8.

MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.

Purpose Of The Review: Proteins are the central layer of information transfer from genome to phenome and represent the largest class of drug targets. We review recent advances in high-throughput technologies that provide comprehensive, scalable profiling of the plasma proteome with the potential to improve prediction and mechanistic understanding of type 2 diabetes (T2D).

Recent Findings: Technological and analytical advancements have enabled identification of novel protein biomarkers and signatures that help to address challenges of existing approaches to predict and screen for T2D. Genetic studies have so far revealed putative causal roles for only few of the proteins that have been linked to T2D, but ongoing large-scale genetic studies of the plasma proteome will help to address this and increase our understanding of aetiological pathways and mechanisms leading to diabetes. Studies of the human plasma proteome have started to elucidate its potential for T2D prediction and biomarker discovery. Future studies integrating genomic and proteomic data will provide opportunities to prioritise drug targets and identify pathways linking genetic predisposition to T2D development.
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http://dx.doi.org/10.1007/s11892-020-01340-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543966PMC
October 2020

Associations of plasma YKL-40 concentrations with heel ultrasound parameters and bone turnover markers in the general adult population.

Bone 2020 12 6;141:115675. Epub 2020 Oct 6.

Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, University Medicine, Greifswald, Germany. Electronic address:

Objective: YKL-40, also known as chitinase-3-like protein 1, is a new proinflammatory biomarker, that might play a role in tissue remodeling and bone resorption. Here we evaluated the associations of the YKL-40 plasma concentration with heel ultrasound parameters and bone turnover markers (BTMs) in adult men and women from the general population. We tested for a causal role of YKL-40 on bone metabolism using published single nucleotide polymorphisms (SNPs) with consequences for YKL-40 expression and function.

Methods: Data were obtained from two population-based cohorts: the Study of Health in Pomerania (SHIP) and SHIP-Trend. Quantitative ultrasound (QUS) measurements at the heel were performed and bone turnover was assessed by measurement of intact amino-terminal propeptide of type I procollagen (PINP) and carboxy-terminal telopeptide of type I collagen (CTX). Associations between the YKL-40 plasma concentration and the QUS-based parameters, bone turnover marker (BTM) concentrations and 44 SNPs, including the lead SNP rs4950928, were evaluated in 382 subjects. Furthermore, we assessed the associations between the same SNPs and the QUS-based parameters (n = 5777) or the BTM concentrations (n = 7190).

Results: Sex-specific linear regression models adjusted for a comprehensive panel of interfering covariantes revealed statistically significant inverse associations between YKL-40 and all QUS-based parameters as well as positive associations with CTX in women. The rs4950928 polymorphism was associated with YKL-40 in men and women but none of the tested SNPs was associated with the QUS-based parameters or the BTMs after correction for multiple testing.

Conclusions: Plasma YKL-40 concentrations are associated with QUS-based parameters as well as CTX concentrations in women but these associations are probably not causal.
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http://dx.doi.org/10.1016/j.bone.2020.115675DOI Listing
December 2020

Insights into genetic variants associated with NASH-fibrosis from metabolite profiling.

Hum Mol Genet 2020 12;29(20):3451-3463

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, UK.

Several genetic discoveries robustly implicate five single-nucleotide variants in the progression of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis and fibrosis (NASH-fibrosis), including a recently identified variant in MTARC1. To better understand these variants as potential therapeutic targets, we aimed to characterize their impact on metabolism using comprehensive metabolomics data from two population-based studies. A total of 9135 participants from the Fenland study and 9902 participants from the EPIC-Norfolk cohort were included in the study. We identified individuals with risk alleles associated with NASH-fibrosis: rs738409C>G in PNPLA3, rs58542926C>T in TM6SF2, rs641738C>T near MBOAT7, rs72613567TA>T in HSD17B13 and rs2642438A>G in MTARC1. Circulating levels of 1449 metabolites were measured using targeted and untargeted metabolomics. Associations between NASH-fibrosis variants and metabolites were assessed using linear regression. The specificity of variant-metabolite associations were compared to metabolite associations with ultrasound-defined steatosis, gene variants linked to liver fat (in GCKR, PPP1R3B and LYPLAL1) and gene variants linked to cirrhosis (in HFE and SERPINA1). Each NASH-fibrosis variant demonstrated a specific metabolite profile with little overlap (8/97 metabolites) comprising diverse aspects of lipid metabolism. Risk alleles in PNPLA3 and HSD17B13 were both associated with higher 3-methylglutarylcarnitine and three variants were associated with lower lysophosphatidylcholine C14:0. The risk allele in MTARC1 was associated with higher levels of sphingomyelins. There was no overlap with metabolites that associated with HFE or SERPINA1 variants. Our results suggest a link between the NASH-protective variant in MTARC1 to the metabolism of sphingomyelins and identify distinct molecular patterns associated with each of the NASH-fibrosis variants under investigation.
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http://dx.doi.org/10.1093/hmg/ddaa162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116726PMC
December 2020

Genetic architecture of host proteins interacting with SARS-CoV-2.

bioRxiv 2020 Jul 1. Epub 2020 Jul 1.

MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.

Strategies to develop therapeutics for SARS-CoV-2 infection may be informed by experimental identification of viral-host protein interactions in cellular assays and measurement of host response proteins in COVID-19 patients. Identification of genetic variants that influence the level or activity of these proteins in the host could enable rapid 'in silico' assessment in human genetic studies of their causal relevance as molecular targets for new or repurposed drugs to treat COVID-19. We integrated large-scale genomic and aptamer-based plasma proteomic data from 10,708 individuals to characterize the genetic architecture of 179 host proteins reported to interact with SARS-CoV-2 proteins or to participate in the host response to COVID-19. We identified 220 host DNA sequence variants acting in (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links, evidence that putative viral interaction partners such as MARK3 affect immune response, and establish the first link between a recently reported variant for respiratory failure of COVID-19 patients at the locus and hypercoagulation, i.e. maladaptive host response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and dynamic and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ).
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http://dx.doi.org/10.1101/2020.07.01.182709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337378PMC
July 2020

Screening for New Markers to Assess Thyroid Hormone Action by OMICs Analysis of Human Samples.

Exp Clin Endocrinol Diabetes 2020 06 16;128(6-07):479-487. Epub 2020 Jun 16.

Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.

Determination of the levels of thyroid-stimulating hormone (TSH) and free thyroid hormones (fTHs) is crucial for assessing thyroid function. However, as a result of inter-individual genetic variability and different environmental factors individual set points exist for TSH and fTHs and display considerable variation. Furthermore, under specific pathophysiological conditions like central hypothyroidism, TSH secreting pituitary tumors, or thyroid hormone resistance the established markers TSH and fTH fail to reliably predict thyroid function and adequate supply of TH to peripheral organs. Even in case of overt hyper- and hypothyroidism circulating fTH concentrations do not correlate with clinical symptoms. Therefore, there is a clear need for novel, more specific biomarkers to diagnose and monitor thyroid function. OMICs screening approaches allow parallel profiling of hundreds to thousands of molecules and thus comprehensive monitoring of molecular alterations in tissues and body fluids that might be associated with changes in thyroid function. These techniques thus constitute promising tools for the identification of urgently needed novel biomarkers. This mini review summarizes the findings of OMICs studies in thyroid research with a particular focus on population-based and patient studies as well as interventional approaches investigating the effects of thyroid hormone administration.
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http://dx.doi.org/10.1055/a-1144-2636DOI Listing
June 2020

Associations between adipose tissue volume and small molecules in plasma and urine among asymptomatic subjects from the general population.

Sci Rep 2020 01 30;10(1):1487. Epub 2020 Jan 30.

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

Obesity is one of the major risk factor for cardiovascular and metabolic diseases. A disproportional accumulation of fat at visceral (VAT) compared to subcutaneous sites (SAT) has been suspected as a key detrimental event. We used non-targeted metabolomics profiling to reveal metabolic pathways associated with higher VAT or SAT amount among subjects free of metabolic diseases to identify possible contributing metabolic pathways. The study population comprised 491 subjects [mean (standard deviation): age 44.6 yrs (13.0), body mass index 25.4 kg/m² (3.6), 60.1% females] without diabetes, hypertension, dyslipidemia, the metabolic syndrome or impaired renal function. We associated MRI-derived fat amounts with mass spectrometry-derived metabolites in plasma and urine using linear regression models adjusting for major confounders. We tested for sex-specific effects using interactions terms and performed sensitivity analyses for the influence of insulin resistance on the results. VAT and SAT were significantly associated with 155 (101 urine) and 49 (29 urine) metabolites, respectively, of which 45 (27 urine) were common to both. Major metabolic pathways were branched-chain amino acid metabolism (partially independent of insulin resistance), surrogate markers of oxidative stress and gut microbial diversity, and cortisol metabolism. We observed a novel positive association between VAT and plasma levels of the potential pharmacological agent piperine. Sex-specific effects were only a few, e.g. the female-specific association between VAT and O-methylascorbate. In brief, higher VAT was associated with an unfavorable metabolite profile in a sample of healthy, mostly non-obese individuals from the general population and only few sex-specific associations became apparent.
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http://dx.doi.org/10.1038/s41598-020-58430-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992585PMC
January 2020

3,5-T2-A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action.

Front Endocrinol (Lausanne) 2019 8;10:787. Epub 2020 Jan 8.

Division of Endocrinology, Georgetown University, Washington, DC, United States.

Over the last decades, thyroid hormone metabolites (THMs) received marked attention as it has been demonstrated that they are bioactive compounds. Their concentrations were determined by immunoassay or mass-spectrometry methods. Among those metabolites, 3,5-diiodothyronine (3,5-T2), occurs at low nanomolar concentrations in human serum, but might reach tissue concentrations similar to those of T4 and T3, at least based on data from rodent models. However, the immunoassay-based measurements in human sera revealed remarkable variations depending on antibodies used in the assays and thus need to be interpreted with caution. In clinical experimental approaches in euthyroid volunteers and hypothyroid patients using the immunoassay as the analytical tool no evidence of formation of 3,5-T2 from its putative precursors T4 or T3 was found, nor was any support found for the assumption that 3,5-T2 might represent a direct precursor for serum 3-T1-AM generated by combined deiodination and decarboxylation from 3,5-T2, as previously documented for mouse intestinal mucosa. We hypothesized that lowered endogenous production of 3,5-T2 in patients requiring T4 replacement therapy after thyroidectomy or for treatment of autoimmune thyroid disease, compared to production of 3,5-T2 in individuals with intact thyroid glands might contribute to the discontent seen in a subset of patients with this therapeutic regimen. So far, our observations do not support this assumption. However, the unexpected association between high serum 3,5-T2 and elevated urinary concentrations of metabolites related to coffee consumption requires further studies for an explanation. Elevated 3,5-T2 serum concentrations were found in several situations including impaired renal function, chronic dialysis, sepsis, non-survival in the ICU as well as post-operative atrial fibrillation (POAF) in studies using a monoclonal antibody-based chemoluminescence immunoassay. Pilot analysis of human sera using LC-linear-ion-trap-mass-spectrometry yielded 3,5-T2 concentrations below the limit of quantification in the majority of cases, thus the divergent results of both methods need to be reconciliated by further studies. Although positive anti-steatotic effects have been observed in rodent models, use of 3,5-T2 as a muscle anabolic, slimming or fitness drug, easily obtained without medical prescription, must be advised against, considering its potency in suppressing the HPT axis and causing adverse cardiac side effects. 3,5-T2 escapes regular detection by commercially available clinical routine assays used for thyroid function tests, which may be seriously disrupted in individuals self-administering 3,5-T2 obtained over-the counter or from other sources.
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http://dx.doi.org/10.3389/fendo.2019.00787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960127PMC
January 2020

Genome-wide scan identifies novel genetic loci regulating salivary metabolite levels.

Hum Mol Genet 2020 03;29(5):864-875

Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.

Saliva, as a biofluid, is inexpensive and non-invasive to obtain, and provides a vital tool to investigate oral health and its interaction with systemic health conditions. There is growing interest in salivary biomarkers for systemic diseases, notably cardiovascular disease. Whereas hundreds of genetic loci have been shown to be involved in the regulation of blood metabolites, leading to significant insights into the pathogenesis of complex human diseases, little is known about the impact of host genetics on salivary metabolites. Here we report the first genome-wide association study exploring 476 salivary metabolites in 1419 subjects from the TwinsUK cohort (discovery phase), followed by replication in the Study of Health in Pomerania (SHIP-2) cohort. A total of 14 distinct locus-metabolite associations were identified in the discovery phase, most of which were replicated in SHIP-2. While only a limited number of the loci that are known to regulate blood metabolites were also associated with salivary metabolites in our study, we identified several novel saliva-specific locus-metabolite associations, including associations for the AGMAT (with the metabolites 4-guanidinobutanoate and beta-guanidinopropanoate), ATP13A5 (with the metabolite creatinine) and DPYS (with the metabolites 3-ureidopropionate and 3-ureidoisobutyrate) loci. Our study suggests that there may be regulatory pathways of particular relevance to the salivary metabolome. In addition, some of our findings may have clinical significance, such as the utility of the pyrimidine (uracil) degradation metabolites in predicting 5-fluorouracil toxicity and the role of the agmatine pathway metabolites as biomarkers of oral health.
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http://dx.doi.org/10.1093/hmg/ddz308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104674PMC
March 2020

Genetic studies of urinary metabolites illuminate mechanisms of detoxification and excretion in humans.

Nat Genet 2020 02 20;52(2):167-176. Epub 2020 Jan 20.

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

The kidneys integrate information from continuous systemic processes related to the absorption, distribution, metabolism and excretion (ADME) of metabolites. To identify underlying molecular mechanisms, we performed genome-wide association studies of the urinary concentrations of 1,172 metabolites among 1,627 patients with reduced kidney function. The 240 unique metabolite-locus associations (metabolite quantitative trait loci, mQTLs) that were identified and replicated highlight novel candidate substrates for transport proteins. The identified genes are enriched in ADME-relevant tissues and cell types, and they reveal novel candidates for biotransformation and detoxification reactions. Fine mapping of mQTLs and integration with single-cell gene expression permitted the prioritization of causal genes, functional variants and target cell types. The combination of mQTLs with genetic and health information from 450,000 UK Biobank participants illuminated metabolic mediators, and hence, novel urinary biomarkers of disease risk. This comprehensive resource of genetic targets and their substrates is informative for ADME processes in humans and is relevant to basic science, clinical medicine and pharmaceutical research.
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http://dx.doi.org/10.1038/s41588-019-0567-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484970PMC
February 2020

Integrated Analyses of Microbiome and Longitudinal Metabolome Data Reveal Microbial-Host Interactions on Sulfur Metabolism in Parkinson's Disease.

Cell Rep 2019 11;29(7):1767-1777.e8

School of Medicine, National University of Galway, Galway, Ireland; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg; Division of Microbiology, National University of Galway, Galway, Ireland; APC Microbiome Ireland, Ireland. Electronic address:

Parkinson's disease (PD) exhibits systemic effects on the human metabolism, with emerging roles for the gut microbiome. Here, we integrate longitudinal metabolome data from 30 drug-naive, de novo PD patients and 30 matched controls with constraint-based modeling of gut microbial communities derived from an independent, drug-naive PD cohort, and prospective data from the general population. Our key results are (1) longitudinal trajectory of metabolites associated with the interconversion of methionine and cysteine via cystathionine differed between PD patients and controls; (2) dopaminergic medication showed strong lipidomic signatures; (3) taurine-conjugated bile acids correlated with the severity of motor symptoms, while low levels of sulfated taurolithocholate were associated with PD incidence in the general population; and (4) computational modeling predicted changes in sulfur metabolism, driven by A. muciniphila and B. wadsworthia, which is consistent with the changed metabolome. The multi-omics integration reveals PD-specific patterns in microbial-host sulfur co-metabolism that may contribute to PD severity.
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http://dx.doi.org/10.1016/j.celrep.2019.10.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856723PMC
November 2019

Metabolomic profiling identifies novel associations with Electrolyte and Acid-Base Homeostatic patterns.

Sci Rep 2019 10 21;9(1):15088. Epub 2019 Oct 21.

Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Electrolytes have a crucial role in maintaining health and their serum levels are homeostatically maintained within a narrow range by multiple pathways involving the kidneys. Here we use metabolomics profiling (592 fasting serum metabolites) to identify molecular markers and pathways associated with serum electrolyte levels in two independent population-based cohorts. We included 1523 adults from TwinsUK not on blood pressure-lowering therapy and without renal impairment to look for metabolites associated with chloride, sodium, potassium and bicarbonate by running linear mixed models adjusting for covariates and multiple comparisons. For each electrolyte, we further performed pathway enrichment analysis (PAGE algorithm). Results were replicated in an independent cohort. Chloride, potassium, bicarbonate and sodium associated with 10, 58, 36 and 17 metabolites respectively (each P < 2.1 × 10), mainly lipids. Of all the electrolytes, serum potassium showed the most significant associations with individual fatty acid metabolites and specific enrichment of fatty acid pathways. In contrast, serum sodium and bicarbonate showed associations predominantly with amino-acid related species. In the first study to examine systematically associations between serum electrolytes and small circulating molecules, we identified novel metabolites and metabolic pathways associated with serum electrolyte levels. The role of these metabolic pathways on electrolyte homeostasis merits further studies.
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http://dx.doi.org/10.1038/s41598-019-51492-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803625PMC
October 2019
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