Publications by authors named "Matthias Laudes"

78 Publications

Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease.

Gut 2021 Apr 22. Epub 2021 Apr 22.

Department of Medicine I, Institute of Cancer Research, Medical University Vienna, Vienna, Austria.

Objective: Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date.

Design: We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry.

Results: We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix.

Conclusion: HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.
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http://dx.doi.org/10.1136/gutjnl-2020-323868DOI Listing
April 2021

Frailty in patients undergoing transcatheter aortic valve replacement: prognostic value of the Geriatric Nutritional Risk Index.

J Cachexia Sarcopenia Muscle 2021 Mar 25. Epub 2021 Mar 25.

Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, University Hospital Schleswig-Holstein Kiel, Kiel, Germany.

Background: Malnutrition is a hallmark of frailty, is common among elderly patients, and is a predictor of poor outcomes in patients with severe symptomatic aortic stenosis (AS). The Geriatric Nutritional Risk Index (GNRI) is a simple and well-established screening tool to predict the risk of morbidity and mortality in elderly patients. In this study, we evaluated whether GNRI may be used in the risk stratification and management of patients undergoing transcatheter aortic valve replacement (TAVR).

Methods: Patients with symptomatic severe AS (n = 953) who underwent transfemoral TAVR at the University Hospital Schleswig-Holstein Kiel, Germany, between 2010 and 2019 (development cohort) were divided into two groups: normal GNRI ≥ 98 (no nutrition-related risk; n = 618) versus low GNRI < 98 (at nutrition-related risk; n = 335). The results were validated in an independent (validation) cohort from another high-volume TAVR centre (n = 977).

Results: The low-GNRI group had a higher proportion of female patients (59.1% vs. 52.1%), higher median age (82.9 vs. 81.8 years), prevalence of atrial fibrillation (50.4% vs. 40.0%), median logistic EuroSCORE (17.5% vs. 15.0%) and impaired left ventricular function (<35%: 10.7% vs. 6.8%), lower median estimated glomerular filtration rate (50 vs. 57 mL/min/1.73 m ) and median albumin level (3.5 vs. 4.0 g/dL) compared with the normal-GNRI group. Among peri-procedural complications, Acute Kidney Injury Network (AKIN) Stage 3 was more common in the low-GNRI group (3.6% vs. 0.6%, p = 0.002). After a mean follow-up of 21.1 months, all-cause mortality was significantly increased in the low-GNRI group compared with the normal-GNRI group (p < 0.001). This was confirmed in the validation cohort (p < 0.001). Low GNRI < 98 was identified as an independent risk factor for all-cause mortality (hazard ratio 1.44, 95% CI 1.01-2.04, p = 0.043). Other independent risk factors included albumin level < median of 4.0 g/dL, high-sensitive troponin T in the highest quartile (> 45.0 pg/mL), N-terminal pro-B-type natriuretic peptide in the highest quartile (> 3595 pg/mL), grade III-IV tricuspid regurgitation, pulmonary arterial hypertension, life-threatening bleeding, AKIN Stage 3 and disabling stroke.

Conclusions: Low GNRI score was associated with an increased risk of all-cause mortality in patients undergoing TAVR, implying that this vulnerable group may benefit from improved preventive measures.
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http://dx.doi.org/10.1002/jcsm.12689DOI Listing
March 2021

Gliflozins for the Treatment of Congestive Heart Failure and Renal Failure in Type 2 Diabetes.

Dtsch Arztebl Int 2021 Feb 26;118(Forthcoming). Epub 2021 Feb 26.

Background: Gliflozins are effective drugs for the treatment of type 2 diabetes. They inhibit sodium glucose cotransporter 2 in the proximal renal tubule, leading to increased glucose excretion. On the basis of findings from relevant studies, gliflozins are also increasingly used in clinical practice to treat congestive heart failure and renal failure.

Methods: This review is based on pertinent publications retrieved from a selective literature search in PubMed and GoogleScholar.

Results: Cardiovascular safety studies revealed early on that gliflozins can lower the hospitalization rate of patients suffering from congestive heart failure with a reduced leftventricular ejection fraction (HFrEF). They also showed favorable effects on multiple renal endpoints. In recent years, studies such as DAPA-HF and CREDENCE have further documented the benefit of gliflozins in the treatment of congestive heart failure and renal failure in patients with type 2 diabetes, and gliflozins have accordingly been incorporated into the pertinent guidelines. In the recently published EMPEROR-Reduced trial, empagliflozin was found to significantly lower the frequency of a combined cardiovascular endpoint in patients with HFrEF (19.4 % versus 24.7%; hazard ratio [HR] 0.75; 95% confidence interval [0.65; 0.86]; number needed to treat [NNT] 19, p <0.001). In the DAPA-CKD trial, which was also recently published, dapagliflozin was found to significantly lower the frequency of a combined renal endpoint (9.2% versus 14.5%; HR 0.61 [0.51; 0.72]; NNT 19; p <0.001).

Conclusion: On the basis of findings from specific studies, gliflozins will henceforth be a major class of drug for the treatment of HFrEF and renal failure, independently of the presence of type 2 diabetes.
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http://dx.doi.org/10.3238/arztebl.m2021.0016DOI Listing
February 2021

Large-scale association analyses identify host factors influencing human gut microbiome composition.

Nat Genet 2021 02 18;53(2):156-165. Epub 2021 Jan 18.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10 < P < 5 × 10) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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http://dx.doi.org/10.1038/s41588-020-00763-1DOI Listing
February 2021

Genome-wide association study in 8,956 German individuals identifies influence of ABO histo-blood groups on gut microbiome.

Nat Genet 2021 02 18;53(2):147-155. Epub 2021 Jan 18.

Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.

The intestinal microbiome is implicated as an important modulating factor in multiple inflammatory, neurologic and neoplastic diseases. Recent genome-wide association studies yielded inconsistent, underpowered and rarely replicated results such that the role of human host genetics as a contributing factor to microbiome assembly and structure remains uncertain. Nevertheless, twin studies clearly suggest host genetics as a driver of microbiome composition. In a genome-wide association analysis of 8,956 German individuals, we identified 38 genetic loci to be associated with single bacteria and overall microbiome composition. Further analyses confirm the identified associations of ABO histo-blood groups and FUT2 secretor status with Bacteroides and Faecalibacterium spp. Mendelian randomization analysis suggests causative and protective effects of gut microbes, with clade-specific effects on inflammatory bowel disease. This holistic investigative approach of the host, its genetics and its associated microbial communities as a 'metaorganism' broaden our understanding of disease etiology, and emphasize the potential for implementing microbiota in disease treatment and management.
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http://dx.doi.org/10.1038/s41588-020-00747-1DOI Listing
February 2021

Altered Gut Microbial Metabolism of Essential Nutrients in Primary Sclerosing Cholangitis.

Gastroenterology 2021 Apr 31;160(5):1784-1798.e0. Epub 2020 Dec 31.

Norwegian Primary Sclerosing Cholangitis Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. Electronic address:

Background & Aims: To influence host and disease phenotype, compositional microbiome changes, which have been demonstrated in patients with primary sclerosing cholangitis (PSC), must be accompanied by functional changes. We therefore aimed to characterize the genetic potential of the gut microbiome in patients with PSC compared with healthy controls (HCs) and patients with inflammatory bowel disease (IBD).

Methods: Fecal DNA from 2 cohorts (1 Norwegian and 1 German), in total comprising 136 patients with PSC (58% with IBD), 158 HCs, and 93 patients with IBD without PSC, were subjected to metagenomic shotgun sequencing, generating 17 billion paired-end sequences, which were processed using HUMAnN2 and MetaPhlAn2, and analyzed using generalized linear models and random effects meta-analyses.

Results: Patients with PSC had fewer microbial genes compared with HCs (P < .0001). Compared with HCs, patients with PSC showed enrichment and increased prevalence of Clostridium species and a depletion of, for example, Eubacterium spp and Ruminococcus obeum. Patients with PSC showed marked differences in the abundance of genes related to vitamin B6 synthesis and branched-chain amino acid synthesis (Q < .05). Targeted metabolomics of plasma from an independent set of patients with PSC and controls found reduced concentrations of vitamin B6 and branched-chain amino acids in PSC (P < .0001), which strongly associated with reduced liver transplantation-free survival (log-rank P < .001). No taxonomic or functional differences were detected between patients with PSC with and without IBD.

Conclusions: The gut microbiome in patients with PSC exhibits large functional differences compared with that in HCs, including microbial metabolism of essential nutrients. Alterations in related circulating metabolites associated with disease course, suggesting that microbial functions may be relevant for the disease process in PSC.
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http://dx.doi.org/10.1053/j.gastro.2020.12.058DOI Listing
April 2021

Precision Nutrition in Chronic Inflammation.

Front Immunol 2020 23;11:587895. Epub 2020 Nov 23.

Division of Nutriinformatics, Institute of Human Nutrition and Food Science, Kiel University, Kiel, Germany.

The molecular foundation of chronic inflammatory diseases (CIDs) can differ markedly between individuals. As our understanding of the biochemical mechanisms underlying individual disease manifestations and progressions expands, new strategies to adjust treatments to the patient's characteristics will continue to profoundly transform clinical practice. Nutrition has long been recognized as an important determinant of inflammatory disease phenotypes and treatment response. Yet empirical work demonstrating the therapeutic effectiveness of patient-tailored nutrition remains scarce. This is mainly due to the challenges presented by long-term effects of nutrition, variations in inter-individual gastrointestinal microbiota, the multiplicity of human metabolic pathways potentially affected by food ingredients, nutrition behavior, and the complexity of food composition. Historically, these challenges have been addressed in both human studies and experimental model laboratory studies primarily by using individual nutrition data collection in tandem with large-scale biomolecular data acquisition (e.g. genomics, metabolomics, etc.). This review highlights recent findings in the field of precision nutrition and their potential implications for the development of personalized treatment strategies for CIDs. It emphasizes the importance of computational approaches to integrate nutritional information into multi-omics data analysis and to predict which molecular mechanisms may explain how nutrients intersect with disease pathways. We conclude that recent findings point towards the unexhausted potential of nutrition as part of personalized medicine in chronic inflammation.
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http://dx.doi.org/10.3389/fimmu.2020.587895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719806PMC
November 2020

Circulating sDPP-4 is Increased in Obesity and Insulin Resistance but Is Not Related to Systemic Metabolic Inflammation.

J Clin Endocrinol Metab 2021 Jan;106(2):e592-e601

Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine 1, University of Kiel, Kiel, Germany.

Context: Dipeptidylpeptidase (DPP)-4 is a key regulator of the incretin system. It exists in a membrane-bound form and a soluble form (sDPP-4). Initial human studies suggested sDPP-4 to be an adipokine involved in metabolic inflammation. However, recent mechanistic data in genetically modified mice has questioned these findings.

Objectives: We examined circulating sDPP-4 in a cohort of n = 451 humans with different metabolic phenotypes and during 3 different weight loss interventions (n = 101) to further clarify its role in human physiology and metabolic diseases.

Design: sDPP-4 serum concentrations were measured by enzyme-linked immunosorbent assay and related to several phenotyping data including gut microbiome analysis.

Results: sDPP-4 increased with age and body weight and was positively associated with insulin resistance and hypertriglyceridemia but was reduced in manifest type 2 diabetes. In addition, we found reduced serum concentrations of sDPP-4 in subjects with arterial hypertension. In contrast to earlier reports, we did not identify an association with systemic markers of inflammation. Impaired kidney and liver functions significantly altered sDPP-4 concentrations while no relation to biomarkers for heart failure was observed. Having found increased levels of sDPP-4 in obesity, we studied surgical (gastric bypass and sleeve gastrectomy) and nonsurgical interventions, revealing a significant association of sDPP-4 with improvement of liver function tests but not with changes in body weight.

Conclusions: Our data suggest that sDPP-4 is related to hepatic abnormalities in obesity rather than primarily functioning as an adipokine and that sDPP-4 is implicated both in glucose and in lipid metabolism, but not fundamentally in systemic inflammation.
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http://dx.doi.org/10.1210/clinem/dgaa758DOI Listing
January 2021

Autoantibody-negative insulin-dependent diabetes mellitus after SARS-CoV-2 infection: a case report.

Nat Metab 2020 10 2;2(10):1021-1024. Epub 2020 Sep 2.

Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Internal Medicine I, University Medical Centre Schleswig-Holstein, Kiel, Germany.

Here we report a case where the manifestations of insulin-dependent diabetes occurred following SARS-CoV-2 infection in a young individual in the absence of autoantibodies typical for type 1 diabetes mellitus. Specifically, a 19-year-old white male presented at our emergency department with diabetic ketoacidosis, C-peptide level of 0.62 µg l, blood glucose concentration of 30.6 mmol l (552 mg dl) and haemoglobin A1c of 16.8%. The patient´s case history revealed probable COVID-19 infection 5-7 weeks before admission, based on a positive test for antibodies against SARS-CoV-2 proteins as determined by enzyme-linked immunosorbent assay. Interestingly, the patient carried a human leukocyte antigen genotype (HLA DR1-DR3-DQ2) considered to provide only a slightly elevated risk of developing autoimmune type 1 diabetes mellitus. However, as noted, no serum autoantibodies were observed against islet cells, glutamic acid decarboxylase, tyrosine phosphatase, insulin and zinc-transporter 8. Although our report cannot fully establish causality between COVID-19 and the development of diabetes in this patient, considering that SARS-CoV-2 entry receptors, including angiotensin-converting enzyme 2, are expressed on pancreatic β-cells and, given the circumstances of this case, we suggest that SARS-CoV-2 infection, or COVID-19, might negatively affect pancreatic function, perhaps through direct cytolytic effects of the virus on β-cells.
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http://dx.doi.org/10.1038/s42255-020-00281-8DOI Listing
October 2020

Pros and Cons of Robotic Revisional Bariatric Surgery.

Visc Med 2020 Jun 15;36(3):238-245. Epub 2020 May 15.

Department of General, Visceral-, Thoracic-, Transplantation-, and Pediatric Surgery, Kurt-Semm Center for Laparoscopic and Robotic Assisted Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Introduction: Revisional procedures in bariatric surgery are regarded as technically more demanding and riskier than primary interventions. While the use of the surgical robot has not yet proven to be advantageous in primary bariatric interventions, the question remains whether its use is justified for more complex revisional procedures.

Objective: To show that revisional bariatric surgery can be performed safely using the da Vinci® Xi surgical system.

Methods: We performed a retrospective analysis of prospectively recorded data for revisional bariatric procedures between January 2016 and November 2019.

Results: Of 78 revision operations, four (5.1%) were performed by open surgery, 30 (38.5%) by laparoscopic surgery, and 44 (56.4%) by robotic surgery. A comparative analysis of robotic ( = 41) versus laparoscopic ( = 18) revisional Roux-en-Y gastric bypasses (rRYGB) revealed significant differences favoring the robotic approach for operative time (130.7 vs. 167.6 min), C-reactive protein values at days 1 (27.9 vs. 49.1 mg/L) and 2 (48.2 vs. 83.6 mg/L) after surgery, and length of stay (4.9 vs. 6.2 days). Lower complication rates (Clavien-Dindo II-V) were found after rRRYGB (7.3 vs. 22.2%, not significant).

Conclusions: Revisional bariatric surgery using a robotic system is safe. The operative time performing rRRYGB is significantly shorter than rLRYGB in our experience. Otherwise, results were largely comparable. Due to different indications, different index operations and a wide range of revisional procedures, further studies are necessary to confirm these results.
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http://dx.doi.org/10.1159/000507742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383264PMC
June 2020

Arrhythmic Gut Microbiome Signatures Predict Risk of Type 2 Diabetes.

Cell Host Microbe 2020 08 2;28(2):258-272.e6. Epub 2020 Jul 2.

ZIEL - Institute for Food & Health, Technical University of Munich, 85354 Freising, Germany; Chair of Nutrition and Immunology, Technical University of Munich, Gregor-Mendel-Str. 2, 85354 Freising, Germany. Electronic address:

Lifestyle, obesity, and the gut microbiome are important risk factors for metabolic disorders. We demonstrate in 1,976 subjects of a German population cohort (KORA) that specific microbiota members show 24-h oscillations in their relative abundance and identified 13 taxa with disrupted rhythmicity in type 2 diabetes (T2D). Cross-validated prediction models based on this signature similarly classified T2D. In an independent cohort (FoCus), disruption of microbial oscillation and the model for T2D classification was confirmed in 1,363 subjects. This arrhythmic risk signature was able to predict T2D in 699 KORA subjects 5 years after initial sampling, being most effective in combination with BMI. Shotgun metagenomic analysis functionally linked 26 metabolic pathways to the diurnal oscillation of gut bacteria. Thus, a cohort-specific risk pattern of arrhythmic taxa enables classification and prediction of T2D, suggesting a functional link between circadian rhythms and the microbiome in metabolic diseases.
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http://dx.doi.org/10.1016/j.chom.2020.06.004DOI Listing
August 2020

Differential effects of protein intake versus intake of a defined oligopeptide on FGF-21 in obese human subjects in vivo.

Clin Nutr 2021 Feb 17;40(2):600-607. Epub 2020 Jun 17.

Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Internal Medicine 1, University Hospital Schleswig-Holstein, Campus Kiel, University of Kiel, Kiel, 24105, Germany. Electronic address:

Background: FGF-21 is described as a powerful metabolic regulator with beneficial effects including glucose-lowering and improvement of insulin sensitivity without hypoglycaemia. On the other hand, FGF-21 is activated when muscle and other tissues are stressed by external effects or internal cellular pathogens that lead to shortcomings in metabolic balance. Previous results suggested that FGF-21 could be a promising target to develop future metabolic therapeutics.

Purpose: The present study was performed to gain deeper insight into the regulation of FGF-21 by protein metabolism in obese human subjects.

Methods: FGF-21 serum concentrations were measured in a cohort of n = 246 obese humans ± type 2 diabetes mellitus (T2DM) (median age 53.0 [46.0; 60.0] years and BMI 40.43 [35.11; 47.24] kg/m) and related to the nutritional protein intake. In addition, the effect of a novel oligopeptide purified from a β-casein hydrolysate on FGF-21 was examined in vitro in liver cells and in vivo in a human intervention study with the main focus on metabolic inflammation including 40 mainly obese subjects (mean age 41.08 ± 9.76 years, mean BMI 38.29 ± 9.4 kg/m) in a randomized 20 weeks double-blind cross-over design.

Main Findings: In the cohort analysis, FGF-21 serum concentrations were significant lower with higher protein intake in obese subjects without T2DM but not in obese subjects with T2DM. Furthermore, relative methionine intake was inversely related to FGF-21. While global protein intake in obesity was inversely associated with FGF-21, incubation of HepG2 cells with a β-casein oligopeptide increased FGF-21 expression in vitro. This stimulatory effect was also present in vivo, since in the clinical intervention study treatment of obese subjects with the β-casein oligopeptide for 8 weeks significantly increased FGF-21 serum levels from W0 = 23.86 pg/mL to W8 = 30.54 pg/mL (p < 0.001), while no increase was found for placebo.

Conclusion: While the total nutritional protein intake is inversely associated with FGF-21 serum levels, a purified and well characterised oligopeptide is able to induce FGF-21 serum levels in humans. These findings suggest a differential role of various components of protein metabolism on FGF-21, rather than this factor being solely a sensor of total nutritional protein intake.
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http://dx.doi.org/10.1016/j.clnu.2020.06.006DOI Listing
February 2021

Sugar-Induced Obesity and Insulin Resistance Are Uncoupled from Shortened Survival in Drosophila.

Cell Metab 2020 04 19;31(4):710-725.e7. Epub 2020 Mar 19.

MRC London Institute of Medical Sciences, Du Cane Road, London W12 0NN, UK; Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK. Electronic address:

High-sugar diets cause thirst, obesity, and metabolic dysregulation, leading to diseases including type 2 diabetes and shortened lifespan. However, the impact of obesity and water imbalance on health and survival is complex and difficult to disentangle. Here, we show that high sugar induces dehydration in adult Drosophila, and water supplementation fully rescues their lifespan. Conversely, the metabolic defects are water-independent, showing uncoupling between sugar-induced obesity and insulin resistance with reduced survival in vivo. High-sugar diets promote accumulation of uric acid, an end-product of purine catabolism, and the formation of renal stones, a process aggravated by dehydration and physiological acidification. Importantly, regulating uric acid production impacts on lifespan in a water-dependent manner. Furthermore, metabolomics analysis in a human cohort reveals that dietary sugar intake strongly predicts circulating purine levels. Our model explains the pathophysiology of high-sugar diets independently of obesity and insulin resistance and highlights purine metabolism as a pro-longevity target.
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http://dx.doi.org/10.1016/j.cmet.2020.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156915PMC
April 2020

Translation of mouse model to human gives insights into periodontitis etiology.

Sci Rep 2020 03 17;10(1):4892. Epub 2020 Mar 17.

Department of Clinical. Microbiology and Immunology, Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

To suggest candidate genes involved in periodontitis, we combined gene expression data of periodontal biopsies from Collaborative Cross (CC) mouse lines, with previous reported quantitative trait loci (QTL) in mouse and with human genome-wide association studies (GWAS) associated with periodontitis. Periodontal samples from two susceptible, two resistant and two lines that showed bone formation after periodontal infection were collected during infection and naïve status. Differential expressed genes (DEGs) were analyzed in a case-control and case-only design. After infection, eleven protein-coding genes were significantly stronger expressed in resistant CC lines compared to susceptible ones. Of these, the most upregulated genes were MMP20 (P = 0.001), RSPO4 (P = 0.032), CALB1 (P = 1.06×10), and AMTN (P = 0.05). In addition, human orthologous of candidate genes were tested for their association in a case-controls samples of aggressive (AgP) and chronic (CP) periodontitis (5,095 cases, 9,908 controls). In this analysis, variants at two loci, TTLL11/PTGS1 (rs9695213, P = 5.77×10) and RNASE2 (rs2771342, P = 2.84×10) suggested association with both AgP and CP. In the association analysis with AgP only, the most significant associations were located at the HLA loci HLA-DQH1 (rs9271850, P = 2.52×10) and HLA-DPA1 (rs17214512, P = 5.14×10). This study demonstrates the utility of the CC RIL populations as a suitable model to investigate the mechanism of periodontal disease.
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http://dx.doi.org/10.1038/s41598-020-61819-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078197PMC
March 2020

The Impact of Robotics in Learning Roux-en-Y Gastric Bypass: a Retrospective Analysis of 214 Laparoscopic and Robotic Procedures : Robotic Vs. Laparoscopic RYGB.

Obes Surg 2020 06;30(6):2403-2410

Department of General, Visceral, Thoracic, Transplantation, and Pediatric Surgery, Kurt-Semm Center for Laparoscopic and Robotic Assisted Surgery, University Hospital Schleswig Holstein, Campus Kiel, Arnold Heller Strasse 3, 24105, Kiel, Germany.

Background: Proximal Roux-en-Y gastric bypass is commonly used to manage obesity, performed using laparoscopic or robot-assisted minimally invasive surgery. As the prevalence of robotic bariatric surgery increases, further data is required to justify its use.

Methods: This was a large, retrospective analysis of prospectively recorded data for Roux-en-Y gastric bypass (RYGB) procedures performed using laparoscopic (LRYGB) or robotic (RRYGB; da Vinci Xi system, Intuitive Surgical Sàrl) surgery between January 2016 and March 2019. The surgical techniques did not differ apart from different trocar placements. Data collected included patient characteristics before and after RYGB, operative outcomes and complications.

Results: In total, 114 RRYGB and 108 LRYGB primary surgeries were performed. There were no significant differences between the groups, apart from a significantly shorter duration of surgery (116.9 vs. 128.9 min, respectively), lower C-reactive protein values at days 1 (31.1 vs. 44.1 mg/l) and 2 (50.3 vs. 77.8 mg/l) after the intervention, and overall complication rate (4.4 vs. 12.0%, Clavien-Dindo classification II-V) with RRYGB compared with LRYGB. There was a lower hemoglobin value in the postoperative course after RRYGB (12.1 vs. 12.6 g/dl, day 2).

Conclusions: In our experience, robotic RYGB has proven to be safe and efficient, with a shorter duration of surgery and lower rate of complications than laparoscopic RYGB. RRYGB is easier to learn and seems safer in less experienced centers. Increasing experience with the robotic system can reduce the duration of surgery over time. Further studies with higher evidence level are necessary to confirm our results.
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http://dx.doi.org/10.1007/s11695-020-04508-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475058PMC
June 2020

Low Postoperative Levels of C-Reactive Protein Are an Early Predictor for an Uncomplicated Course After Bariatric Surgery: A Retrospective, Validated Cohort Study.

Surg Laparosc Endosc Percutan Tech 2020 Jun;30(3):238-244

Departments of Visceral and Thoracic Surgery.

Background: Bariatric surgery is popularly used to treat or prevent morbidity in severely obese patients. Severe complications are rare, but their early detection has a significant impact on clinical outcomes. We aimed to determine whether blood tests in the first few postoperative days are reliable predictors for complications.

Methods: We retrospectively analyzed 1073 patients who underwent laparoscopic bariatric surgery between 2009 and 2018 at our center. Clinical outcome was correlated with postoperative serum C-reactive protein (CRP), white blood cell count, and vital signs, analyzed using a receiver operating characteristic (ROC) curve. A total of 570 procedures between 2009 and 2015 were used to calculate the best cutoff values (calculation group), which were validated with 330 different patients operated upon between 2016 and 2018 (validation group).

Results: Twenty-four patients (4.2%) developed anastomotic or staple-line leakages in the calculation group. The ROC curve showed a good reliability for CRP levels on day 2 (area under the ROC curve=0.86); the highest Youden index existed for a cutoff of 119 mg/L. White blood cell count and heart rate were poor predictors. Even though several characteristics differed in the validation cohort, test quality of the cutoff was high (sensitivity, 71.4%; specificity, 94.9%; positive predictive value, 23.8%; negative predictive value, 99.3%). The prediction was excellent especially for leakages appearing on days 2 to 9 (sensitivity 100.0%, negative predictive value 100%). Leakages from day 10 were rare and prediction poor (sensitivity 0%).

Conclusions: A CRP level on day 2 <120 mg/L is a good predictor of a postoperative course without leakage, even though the predictive value goes down for late-appearing events. An earlier CRP measurement added no predictive benefit. The cutoff value was validated in an internal cohort and could be applied to different populations.
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http://dx.doi.org/10.1097/SLE.0000000000000767DOI Listing
June 2020

DeepWAS: Multivariate genotype-phenotype associations by directly integrating regulatory information using deep learning.

PLoS Comput Biol 2020 02 3;16(2):e1007616. Epub 2020 Feb 3.

Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.

Genome-wide association studies (GWAS) identify genetic variants associated with traits or diseases. GWAS never directly link variants to regulatory mechanisms. Instead, the functional annotation of variants is typically inferred by post hoc analyses. A specific class of deep learning-based methods allows for the prediction of regulatory effects per variant on several cell type-specific chromatin features. We here describe "DeepWAS", a new approach that integrates these regulatory effect predictions of single variants into a multivariate GWAS setting. Thereby, single variants associated with a trait or disease are directly coupled to their impact on a chromatin feature in a cell type. Up to 61 regulatory SNPs, called dSNPs, were associated with multiple sclerosis (MS, 4,888 cases and 10,395 controls), major depressive disorder (MDD, 1,475 cases and 2,144 controls), and height (5,974 individuals). These variants were mainly non-coding and reached at least nominal significance in classical GWAS. The prediction accuracy was higher for DeepWAS than for classical GWAS models for 91% of the genome-wide significant, MS-specific dSNPs. DSNPs were enriched in public or cohort-matched expression and methylation quantitative trait loci and we demonstrated the potential of DeepWAS to generate testable functional hypotheses based on genotype data alone. DeepWAS is available at https://github.com/cellmapslab/DeepWAS.
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http://dx.doi.org/10.1371/journal.pcbi.1007616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043350PMC
February 2020

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy.

Cell 2019 09 29;178(6):1299-1312.e29. Epub 2019 Aug 29.

MRC London Institute of Medical Sciences, Du Cane Road, London W12 0NN, UK; Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK; Institute of Structural and Molecular Biology, University College London and Birkbeck, London WC1E 6BT, UK. Electronic address:

Metformin is the first-line therapy for treating type 2 diabetes and a promising anti-aging drug. We set out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, affect the effects of metformin. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransferase signaling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modeling of the microbiota in metformin-treated type 2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.cell.2019.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736778PMC
September 2019

PTH Immunoassay Interference Due to Human Anti-Mouse Antibodies in a Subject With Obesity With Normal Parathyroid Function.

J Clin Endocrinol Metab 2019 12;104(12):5840-5842

Institute of Clinical Chemistry, University Hospital of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.

Context: Immunoassay interference has been most often found with prolactin measurement. However, only few data exist on immunoassay interference for other hormones.

Case Description: A 36-year-old woman with obesity (body mass index, 31 kg/m2) had regularly attended our endocrine unit for type 2 diabetes therapy. When she was included as a control subject in a study for obesity management, detailed laboratory testing was performed, including PTH. In the absence of clinical symptoms, she presented with normal calcium, phosphate, and vitamin D levels. However, the PTH levels were >5000 ng/L. These results were obtained using the Roche Elecsys electrochemiluminescence assay. Repeated measurements with this assay (mouse antibody) led to the same findings. However, using an Euroimmun assay (goat antibody), the exact PTH values were measured at 18.0 ng/L. After pretreatment with a heterophilic antibody blocking reagent, the results of the Roche assay had decreased to a normal level. This phenomenon was explained by the detection of human anti-mouse antibodies in the proband's serum.

Conclusions: In cases of prolactin immunoassay interference, endogenous antibodies will bind to the hormone in vivo, resulting in complexes of a high molecular weight that are less efficiently cleared by the kidneys and, thus, accumulate in the blood. In contrast, the PTH values >5000 ng/L detected in our subject most likely had resulted from the specific interference of the human anti-mouse antibodies present in the proband's serum with the assay antibody, resulting in artificial stimulation of the Roche assay detection system ex vivo.
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http://dx.doi.org/10.1210/jc.2019-01321DOI Listing
December 2019

Obese Individuals with and without Type 2 Diabetes Show Different Gut Microbial Functional Capacity and Composition.

Cell Host Microbe 2019 08 6;26(2):252-264.e10. Epub 2019 Aug 6.

Biostatistics Department, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02115, USA.

Obesity and type 2 diabetes (T2D) are metabolic disorders that are linked to microbiome alterations. However, their co-occurrence poses challenges in disentangling microbial features unique to each condition. We analyzed gut microbiomes of lean non-diabetic (n = 633), obese non-diabetic (n = 494), and obese individuals with T2D (n = 153) from German population and metabolic disease cohorts. Microbial taxonomic and functional profiles were analyzed along with medical histories, serum metabolomics, biometrics, and dietary data. Obesity was associated with alterations in microbiome composition, individual taxa, and functions with notable changes in Akkermansia, Faecalibacterium, Oscillibacter, and Alistipes, as well as in serum metabolites that correlated with gut microbial patterns. However, microbiome associations were modest for T2D, with nominal increases in Escherichia/Shigella. Medications, including antihypertensives and antidiabetics, along with dietary supplements including iron, were significantly associated with microbiome variation. These results differentiate microbial components of these interrelated metabolic diseases and identify dietary and medication exposures to consider in future studies.
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http://dx.doi.org/10.1016/j.chom.2019.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720933PMC
August 2019

The IL-6-neutralizing sIL-6R-sgp130 buffer system is disturbed in patients with type 2 diabetes.

Am J Physiol Endocrinol Metab 2019 08 25;317(2):E411-E420. Epub 2019 Jun 25.

Department of Pathology, Medical Faculty, Otto von Guericke University Magdeburg, Magdeburg, Germany.

Serum levels of interleukin-6 (IL-6) are increased in patients with type 2 diabetes (T2D). IL-6 exerts its pleiotropic effects via the IL-6 α-receptor (IL-6R), which exists in membrane-bound and soluble (sIL-6R) forms and activates cells via the β-receptor glycoprotein 130 (gp130). The nonsynonymous single-nucleotide polymorphism (SNP) rs2228145 (Asp358Ala) within the locus is associated with T2D. The aim of this study was to determine whether sIL-6R in combination with soluble gp130 (sgp130) is able to form an IL-6-neutralizing buffer in healthy subjects and whether this is disturbed in T2D. We found that sIL-6R-sgp130 indeed forms an IL-6-neutralizing buffer in the serum of healthy humans, whose capacity is controlled by the SNP of the IL-6R. Circulating sIL-6R-sgp130 levels were lower in T2D subjects ( < 0.001), whereas IL-6 was high and inversely correlated with sIL-6R ( = -0.57, < 0.001), indicating a severe disturbance of the buffer. This phenomenon is also observed in sex- and age-matched patients with both T2D and atherosclerosis but not in patients with atherosclerosis alone. In conclusion, sIL-6R and sgp130 serum levels were significantly lower in T2D patients compared with healthy subjects or atherosclerosis patients, although IL-6 levels were high. These data suggest that disturbance of the protective buffer may be closely associated with T2D pathophysiology.
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http://dx.doi.org/10.1152/ajpendo.00166.2019DOI Listing
August 2019

Dietary patterns associated with inflammatory biomarkers in a Northern German population.

Eur J Nutr 2020 Jun 21;59(4):1433-1441. Epub 2019 May 21.

Department of Nutrition and Food Sciences, Nutritional Epidemiology, University of Bonn, Bonn, Germany.

Purpose: The aim of the present study was to derive overall and sex-specific dietary patterns associated with inflammatory biomarkers in a general population sample from Northern Germany.

Methods: The present analysis included 1158 participants (477 men, 681 women, mean age: 53.1 years; mean body mass index: 26.2 kg/m) of the Food Chain Plus (FoCus) cohort in Kiel, Germany. Participants completed a semi-quantitative food frequency questionnaire and provided blood samples. Reduced rank regression with C-reactive protein (CRP) and Interleukin 6 (IL-6) as response variables was used to derive dietary patterns. After a mean follow-up of 1.7 years, a second blood sample was obtained in a subsample of 112 individuals. Multiple regression models were used to examine the association between dietary patterns at baseline and inflammatory biomarkers at follow-up.

Results: The overall pattern characterised by high intakes of soft drinks, meat, potatoes and sauce, and low intakes of other cereals (except pasta/rice), wine, nuts, seeds, vegetarian dishes, vegetable oil, and fish was positively associated with CRP (OR 2.20; 95% CI 1.12, 4.35) and IL-6 (OR 3.14; 95% CI 1.26, 7.87) at follow-up. In men, the dietary pattern was higher in soft drinks, processed meat and low in cereals and plant-based fats. In women, the pattern was characterised by soft drinks, meat, vegetables and low in other cereals, wine, nuts, and seeds. The association between sex-specific patterns with inflammatory biomarkers was weaker for CRP.

Conclusion: We identified dietary patterns positively associated with established biomarkers of chronic low-grade inflammation.
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http://dx.doi.org/10.1007/s00394-019-02000-wDOI Listing
June 2020

Activation of Toll-like Receptor 2 (TLR2) induces Interleukin-6 trans-signaling.

Sci Rep 2019 05 13;9(1):7306. Epub 2019 May 13.

Institute of Biochemistry, Kiel University, Kiel, Germany.

Signaling of the pleiotropic cytokine Interleukin-6 (IL-6) via its soluble IL-6R (sIL-6R) has been termed trans-signaling and is thought to be responsible for the pro-inflammatory properties of IL-6. The sIL-6R can be generated by alternative mRNA splicing or proteolytic cleavage of the membrane-bound IL-6R. However, which stimuli induce sIL-6R release and which endogenous signaling pathways are required for this process is poorly understood. Here, we show that activation of Toll-like receptor 2 (TLR2) on primary human peripheral blood mononuclear cells (PBMCs) and on the monocytic cell line THP-1 induces expression and secretion of IL-6 and the generation of sIL-6R. We show by flow cytometry that monocytes are a PBMC subset that expresses TLR2 in conjunction with the IL-6R and are the major cellular source for both IL-6 and sIL-6R. Mechanistically, we find that the metalloproteases ADAM10 and ADAM17 are responsible for cleavage of the IL-6R and therefore sIL-6R generation. Finally, we identify the Extracellular-signal Regulated Kinase (ERK) cascade as a critical pathway that differentially regulates both IL-6 and sIL-6R generation in monocytes.
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http://dx.doi.org/10.1038/s41598-019-43617-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513869PMC
May 2019

Adjustment of triple shellac coating for precise release of bioactive substances with different physico-chemical properties in the ileocolonic region.

Int J Pharm 2019 Jun 13;564:472-484. Epub 2019 Apr 13.

Division of Food Technology, Kiel University, Heinrich-Hecht-Platz 10, 24118 Kiel, Germany.

Formulations for the controlled release of substances in the human terminal ileum and colon are essential to target the gut microbiome and its interactions with the intestinal mucosa. In contrast to pharmaceutical enteric coatings, reliable food-grade alternatives are still scarce. Shellac coatings have been used for various active ingredients, but their stability is affected by the physicochemical properties of the encapsulated substances. It is well known, that shellac release can be modulated by an acidic subcoating. Here, we hypothesized that a triple shellac coating with an adjusted intermediate coating (acidic or alkaline) can be effectively used to counteract the differences in pH value of various encapsulated substances, allowing a precise targeting of the desired release pH value. First, the system was tested with riboflavin 5'-monophosphate sodium salt dihydrate (RMSD) as a characteristic model substance. Secondly, it was transferred to nicotinic acid (NA) and nicotinamide (NAM) as bioactive compounds with different physio-chemical properties: NAM, an alkaline crystalline and highly water-soluble substance, led to a premature release from conventional shellac microcapsules, whereas RMSD and NA with their medium solubility and neutral to acidic pH properties delayed the shellac dissolution. A precise modulation of the release profile of each substance was possible by the addition of different intermediate subcoatings: an acidic layer with citric acid counteracted the premature release of the alkaline and highly soluble NAM. In contrast, an alkaline sodium bicarbonate intermediate subcoating enhanced shellac swelling and delayed the release of NA and RMSD. In conclusion, the novel triple-layer shellac coating provides a much higher adaptability and reliability for nutritional formulations aiming at a targeted release in the ileocolonic region.
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http://dx.doi.org/10.1016/j.ijpharm.2019.04.039DOI Listing
June 2019

Secreted frizzled-related protein 5 serum levels in human periodontitis-A nested case-control study.

J Clin Periodontol 2019 05 22;46(5):522-528. Epub 2019 Apr 22.

Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.

Aim: Recombinant secreted frizzled-related protein 5 (sFRP5) improved periodontal status in mice. Thus, this study aimed to investigate this finding in human periodontitis using an epidemiological approach.

Materials And Methods: sFRP5 and wnt5a concentrations were determined in human serum from the Food Chain Plus cohort using ELISAs. A total of 128 patients with periodontitis and tooth loss and 245 patients with periodontitis without tooth loss were compared to 373 sex-, smoker-, age- and BMI-matched individuals in a nested case-control design.

Results: Systemic sFRP5 serum levels were significantly lower in patients with periodontitis and tooth loss (2.5 [0.0-10.4] ng/ml, median [IQR]) compared to patients with periodontitis without tooth loss (6.0 [2.5-15.8] ng/ml, median [IQR], p = 0.04] and matched controls (7.0 [2.5-18.3] ng/ml, median [IQR], p = 0.02). No significant differences in sFRP5 serum levels were found among patients with periodontitis without tooth loss (6.0 [2.5-15.8] ng/ml, median [IQR]) and controls (3.1 [0.0-10.6] ng/ml, median [IQR], p = 0.06).

Conclusions: sFRP5 might serve as a novel biomarker for periodontitis severity. Modulating the inflammatory background of severe forms of periodontitis, in the time of precision medicine, needs to be revealed in further studies.
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http://dx.doi.org/10.1111/jcpe.13087DOI Listing
May 2019

Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.

Lancet Respir Med 2019 03 5;7(3):227-238. Epub 2018 Dec 5.

Medstar Health, Washington, DC, USA.

Background: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.

Methods: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.

Findings: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity.

Interpretation: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.

Funding: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.
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http://dx.doi.org/10.1016/S2213-2600(18)30409-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391516PMC
March 2019

Meta-analysis of genome-wide association studies of aggressive and chronic periodontitis identifies two novel risk loci.

Eur J Hum Genet 2019 01 14;27(1):102-113. Epub 2018 Sep 14.

Department of Periodontology and Synoptic Dentistry, Institute of Health, Institute for Dental and Craniofacial Sciences, Charité-University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. It is classified into the widespread moderate form chronic periodontitis (CP) and the rare early-onset and severe phenotype aggressive periodontitis (AgP). These different disease manifestations are thought to share risk alleles and predisposing environmental factors. To obtain novel insights into the shared genetic etiology and the underlying molecular mechanisms of both forms, we performed a two step-wise meta-analysis approach using genome-wide association studies of both phenotypes. Genotypes from imputed genome-wide association studies (GWAS) of AgP and CP comprising 5,095 cases and 9,908 controls of North-West European genetic background were included. Two loci were associated with periodontitis at a genome-wide significance level. They located within the pseudogene MTND1P5 on chromosome 8 (rs16870060-G, P = 3.69 × 10, OR = 1.36, 95% CI = [1.23-1.51]) and intronic of the long intergenic non-coding RNA LOC107984137 on chromosome 16, downstream of the gene SHISA9 (rs729876-T, P = 9.77 × 10, OR = 1.24, 95% CI = [1.15-1.34]). This study identified novel risk loci of periodontitis, adding to the genetic basis of AgP and CP.
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http://dx.doi.org/10.1038/s41431-018-0265-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303247PMC
January 2019

Genome-wide association meta-analysis of coronary artery disease and periodontitis reveals a novel shared risk locus.

Sci Rep 2018 09 12;8(1):13678. Epub 2018 Sep 12.

Charité - University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute for Dental and Craniofacial Sciences, Department of Periodontology and Synoptic Dentistry, Berlin, Germany.

Evidence for a shared genetic basis of association between coronary artery disease (CAD) and periodontitis (PD) exists. To explore the joint genetic basis, we performed a GWAS meta-analysis. In the discovery stage, we used a German aggressive periodontitis sample (AgP-Ger; 680 cases vs 3,973 controls) and the CARDIoGRAMplusC4D CAD meta-analysis dataset (60,801 cases vs 123,504 controls). Two SNPs at the known CAD risk loci ADAMTS7 (rs11634042) and VAMP8 (rs1561198) passed the pre-assigned selection criteria (P < 0.05; P < 5 × 10; concordant effect direction) and were replicated in an independent GWAS meta-analysis dataset of PD (4,415 cases vs 5,935 controls). SNP rs1561198 showed significant association (PD[Replication]: P = 0.008 OR = 1.09, 95% CI = [1.02-1.16]; PD [Discovery + Replication]: P = 0.0002, OR = 1.11, 95% CI = [1.05-1.17]). For the associated haplotype block, allele specific cis-effects on VAMP8 expression were reported. Our data adds to the shared genetic basis of CAD and PD and indicate that the observed association of the two disease conditions cannot be solely explained by shared environmental risk factors. We conclude that the molecular pathway shared by CAD and PD involves VAMP8 function, which has a role in membrane vesicular trafficking, and is manipulated by pathogens to corrupt host immune defense.
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http://dx.doi.org/10.1038/s41598-018-31980-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135769PMC
September 2018