Publications by authors named "Wolfgang Lieb"

282 Publications

Microbial Diversity and Abundance of Mediate the Associations Between Higher Intake of Flavonoid-Rich Foods and Lower Blood Pressure.

Hypertension 2021 Sep 23;78(4):1016-1026. Epub 2021 Aug 23.

Institute for Global Food Security, Queen's University Belfast, Northern Ireland (A.J., A.C.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.17441DOI Listing
September 2021

Sex-specific genetic factors affect the risk of early-onset periodontitis in Europeans.

J Clin Periodontol 2021 Aug 18. Epub 2021 Aug 18.

Department of Periodontology, Oral Medicine and Oral Surgery, Charité - University Medicine Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute for Dental and Craniofacial Sciences, Berlin, Germany.

Aims: Various studies have reported that young European women are more likely to develop early-onset periodontitis compared to men. A potential explanation for the observed variations in sex and age of disease onset is the natural genetic variation within the autosomal genomes. We hypothesized that genotype-by-sex (G × S) interactions contribute to the increased prevalence and severity.

Materials And Methods: Using the case-only design, we tested for differences in genetic effects between men and women in 896 North-West European early-onset cases, using imputed genotypes from the OmniExpress genotyping array. Population-representative 6823 controls were used to verify that the interacting variables G and S were uncorrelated in the general population.

Results: In total, 20 loci indicated G × S associations (P < 0.0005), 3 of which were previously suggested as risk genes for periodontitis (ABLIM2, CDH13, and NELL1). We also found independent G × S interactions of the related gene paralogs MACROD1/FLRT1 (chr11) and MACROD2/FLRT3 (chr20). G × S-associated SNPs at CPEB4, CDH13, MACROD1, and MECOM were genome-wide-associated with heel bone mineral density (CPEB4, MECOM), waist-to-hip ratio (CPEB4, MACROD1), and blood pressure (CPEB4, CDH13).

Conclusions: Our results indicate that natural genetic variation affects the different heritability of periodontitis among sexes and suggest genes that contribute to inter-sex phenotypic variation in early-onset periodontitis.
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http://dx.doi.org/10.1111/jcpe.13538DOI Listing
August 2021

[Idiopathic orbital inflammation].

Authors:
Wolfgang E Lieb

Ophthalmologe 2021 Aug 29;118(8):777-786. Epub 2021 Jul 29.

ViDia Christliche Kliniken Karlsruhe, St. Vincentius-Kliniken, Steinhäuserstr. 18, 76135, Karlsruhe, Deutschland.

Background: Orbital inflammatory disease encompasses a spectrum of disorders. Idiopathic orbital inflammation (IOI) is often a diagnosis of exclusion, which needs to be differentiated from infections, systemic inflammatory disease, and neoplasms. IOI includes anterior inflammation with dacryoadenitis, myositis, perineuritis of the optic nerve, periscleritis, diffuse sclerosing inflammation, and orbital apex inflammation.

Objective: A differential diagnostic overview of IOI is presented, including its subcategories, diagnosis, and treatment.

Conclusion: The diagnosis of IOI is often made by exclusion with typical clinical findings, CT and MRI scans, and pathology. Treatment includes corticosteroids, immunomodulators, immunosuppressants, and radiotherapy.
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http://dx.doi.org/10.1007/s00347-021-01459-5DOI Listing
August 2021

Large-Scale Imputation of KIR Copy Number and HLA Alleles in North American and European Psoriasis Case-Control Cohorts Reveals Association of Inhibitory KIR2DL2 With Psoriasis.

Front Immunol 2021 11;12:684326. Epub 2021 Jun 11.

Department of Dermatology, University of California, San Francisco, San Francisco, CA, United States.

Killer cell immunoglobulin-like receptors (KIR) regulate immune responses in NK and CD8+ T cells interaction with HLA ligands. KIR genes, including KIR2DS1, KIR3DL1, and KIR3DS1 have previously been implicated in psoriasis susceptibility. However, these previous studies were constrained to small sample sizes, in part due to the time and expense required for direct genotyping of KIR genes. Here, we implemented KIR*IMP to impute KIR copy number from single-nucleotide polymorphisms (SNPs) on chromosome 19 in the discovery cohort (n=11,912) from the PAGE consortium, University of California San Francisco, and the University of Dundee, and in a replication cohort (n=66,357) from Kaiser Permanente Northern California. Stratified multivariate logistic regression that accounted for patient ancestry and high-risk HLA alleles revealed that KIR2DL2 copy number was significantly associated with psoriasis in the discovery cohort (p ≤ 0.05). The KIR2DL2 copy number association was replicated in the Kaiser Permanente replication cohort. This is the first reported association of KIR2DL2 copy number with psoriasis and highlights the importance of KIR genetics in the pathogenesis of psoriasis.
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http://dx.doi.org/10.3389/fimmu.2021.684326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231283PMC
June 2021

The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome.

J Cell Mol Med 2021 Aug 24;25(16):8047-8061. Epub 2021 Jun 24.

Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland.

Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.
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http://dx.doi.org/10.1111/jcmm.16736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358858PMC
August 2021

Identification of two novel bullous pemphigoid- associated alleles, HLA-DQA1*05:05 and -DRB1*07:01, in Germans.

Orphanet J Rare Dis 2021 05 19;16(1):228. Epub 2021 May 19.

CRIS, Center for Research On Inflammation of the Skin, University of Lübeck, Lübeck, Germany.

Bullous pemphigoid (BP) is the most common autoimmune skin blistering disease characterized by autoimmunity against the hemidesmosomal proteins BP180, type XVII collagen, and BP230. To elucidate the genetic basis of susceptibility to BP, we performed the first genome-wide association study (GWAS) in Germans. This GWAS was combined with HLA locus targeted sequencing in an additional independent BP cohort. The strongest association with BP in Germans tested in this study was observed in the two HLA loci, HLA-DQA1*05:05 and HLA-DRB1*07:01. Further studies with increased sample sizes and complex studies integrating multiple pathogenic drivers will be conducted.
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http://dx.doi.org/10.1186/s13023-021-01863-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136166PMC
May 2021

Post-diagnostic reliance on plant-compared with animal-based foods and all-cause mortality in omnivorous long-term colorectal cancer survivors.

Am J Clin Nutr 2021 08;114(2):441-449

Institute of Epidemiology, University Hospital Schleswig-Holstein, University of Kiel, Kiel, Germany.

Background: Plant-rich diets are associated with lower cardiometabolic risks and longer survival in the general population, but their association with mortality in cancer survivors is still unclear.

Objectives: We aimed to examine the associations of 3 postdiagnostic plant-based diet indices with all-cause mortality in omnivorous long-term colorectal cancer (CRC) survivors.

Methods: Diet was assessed with FFQs at a median of 6 years after diagnosis in 1404 CRC survivors (56% male; median age, 69 years) in a Northern German prospective cohort study. An overall, a healthful plant-based, and an unhealthful plant-based diet index were derived by scoring intakes of animal foods reversely and intakes of healthy (whole grains, vegetables, fruits, legumes, nuts, oils, tea/coffee) and less healthy plant foods (refined grains, fruit juices, sugar-sweetened beverages, potatoes, sweets/desserts) positively or reversely, depending on the index. Vital status follow-up was conducted via population registries. Cox proportional hazards regression was applied to estimate HRs for all-cause mortality according to plant-based diet adherence.

Results: Within 7 years (median) after diet assessment, 204 deaths occurred. The overall plant-based diet index displayed a significant, inverse association with all-cause mortality (HR per 10-point increase in diet index, 0.72; 95% CI, 0.57-0.91). Although not statistically significant, higher healthful plant-based diet scores showed a strong tendency towards lower mortality (HR, 0.82; 95% CI, 0.67-1.01). The unhealthful plant-based diet index was associated with higher mortality, but lost statistical significance after multivariable adjustment (HR, 1.19; 95% CI, 0.96-1.48). A subgroup analysis revealed that the tendency towards a positive association of the unhealthful plant-based diet with mortality was restricted to less physically active individuals (<95 metabolic equivalent of task hours/week).

Conclusions: An overall plant-based diet was inversely associated with all-cause mortality in long-term CRC survivors. However, more research is needed to further disentangle the impacts of different qualities of plant-based diets on cancer survivors' health.
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http://dx.doi.org/10.1093/ajcn/nqab061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326049PMC
August 2021

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292596PMC
April 2021

Patient Reported Outcomes in Chronic Inflammatory Diseases: Current State, Limitations and Perspectives.

Front Immunol 2021 18;12:614653. Epub 2021 Mar 18.

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

Chronic inflammatory diseases (CID) are emerging disorders which do not only affect specific organs with respective clinical symptoms but can also affect various aspects of life, such as emotional distress, anxiety, fatigue and quality of life. These facets of chronic disease are often not recognized in the therapy of CID patients. Furthermore, the symptoms and patient-reported outcomes often do not correlate well with the actual inflammatory burden. The discrepancy between patient-reported symptoms and objectively assessed disease activity can indeed be instructive for the treating physician to draw an integrative picture of an individual's disease course. This poses a challenge for the design of novel, more comprehensive disease assessments. In this mini-review, we report on the currently available patient-reported outcomes, the unmet needs in the field of chronic inflammatory diseases and the challenges of addressing these.
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http://dx.doi.org/10.3389/fimmu.2021.614653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012677PMC
June 2021

Genetic architectures of proximal and distal colorectal cancer are partly distinct.

Gut 2021 Jul 25;70(7):1325-1334. Epub 2021 Feb 25.

Cancer Prevention and Control Program, Catalan Institute of Oncology - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.

Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.

Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.

Results: We identified 13 loci that reached genome-wide significance (p<5×10) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.

Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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http://dx.doi.org/10.1136/gutjnl-2020-321534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223655PMC
July 2021

Exome-Wide Association Study Identifies FN3KRP and PGP as New Candidate Longevity Genes.

J Gerontol A Biol Sci Med Sci 2021 04;76(5):786-795

Institute of Clinical Molecular Biology, Kiel University, University Hospital Schleswig-Holstein, Germany.

Despite enormous research efforts, the genetic component of longevity has remained largely elusive. The investigation of common variants, mainly located in intronic or regulatory regions, has yielded only little new information on the heritability of the phenotype. Here, we performed a chip-based exome-wide association study investigating 62 488 common and rare coding variants in 1248 German long-lived individuals, including 599 centenarians and 6941 younger controls (age < 60 years). In a single-variant analysis, we observed an exome-wide significant association between rs1046896 in the gene fructosamine-3-kinase-related-protein (FN3KRP) and longevity. Noteworthy, we found the longevity allele C of rs1046896 to be associated with an increased FN3KRP expression in whole blood; a database look-up confirmed this effect for various other human tissues. A gene-based analysis, in which potential cumulative effects of common and rare variants were considered, yielded the gene phosphoglycolate phosphatase (PGP) as another potential longevity gene, though no single variant in PGP reached the discovery p-value (1 × 10E-04). Furthermore, we validated the previously reported longevity locus cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1). Replication of our results in a French longevity cohort was only successful for rs1063192 in CDKN2B-AS1. In conclusion, we identified 2 new potential candidate longevity genes, FN3KRP and PGP which may influence the phenotype through their role in metabolic processes, that is, the reverse glycation of proteins (FN3KRP) and the control of glycerol-3-phosphate levels (PGP).
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http://dx.doi.org/10.1093/gerona/glab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087267PMC
April 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

Association of antecedent cardiovascular risk factor levels and trajectories with cardiovascular magnetic resonance-derived cardiac function and structure.

J Cardiovasc Magn Reson 2021 01 4;23(1). Epub 2021 Jan 4.

Institute of Epidemiology, Kiel University, Kiel, Germany.

Background: The association of longitudinal trajectories of cardiovascular risk factors with cardiovascular magnetic resonance (CMR)-measures of cardiac structure and function in the community is not well known. Therefore we aimed to relate risk factor levels from different examination cycles to CMR-measures of the left ventricle (LV) and right ventricle in a population-based cohort.

Methods: We assessed conventional cardiovascular disease risk factors in 349 participants (143 women; aged 25-59 years) at three examination cycles (Exam 1 [baseline], at Exam 2 [7-years follow-up] and at Exam 3 [14-years follow-up]) of the KORA S4 cohort and related single-point measurements of individual risk factors and longitudinal trajectories of these risk factors to various CMR-measures obtained at Exam 3.

Results: High levels of diastolic blood pressure, waist circumference, and LDL-cholesterol at the individual exams were associated with worse cardiac function and structure. Trajectory clusters representing higher levels of the individual risk factors were associated with worse cardiac function and structure compared to low risk trajectory clusters of individual risk factors. Multivariable (combining different risk factors) trajectory clusters were associated with different cardiac parameters in a graded fashion (e.g. decrease of LV stroke volume for middle risk cluster β = - 4.91 ml/m, 95% CI - 7.89; - 1.94, p < 0.01 and high risk cluster β = - 7.00 ml/m, 95% CI - 10.73; - 3.28, p < 0.001 compared to the low risk cluster). The multivariable longitudinal trajectory clusters added significantly to explain variation in CMR traits beyond the multivariable risk profile obtained at Exam 3.

Conclusions: Cardiovascular disease risk factor levels, measured over a time period of 14 years, were associated with CMR-derived measures of cardiac structure and function. Longitudinal multivariable trajectory clusters explained a greater proportion of the inter-individual variation in cardiac traits than multiple risk factor assessed contemporaneous with the CMR exam.
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http://dx.doi.org/10.1186/s12968-020-00698-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780638PMC
January 2021

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

Gastroenterology 2021 04 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

Blood Metabolomic Profiling Confirms and Identifies Biomarkers of Food Intake.

Metabolites 2020 Nov 17;10(11). Epub 2020 Nov 17.

Unit of Nutritional Epidemiology, Department of Nutrition and Food Sciences, Rheinische Friedrich-Wilhelms-University Bonn, 53115 Bonn, Germany.

Metabolomics can be a tool to identify dietary biomarkers. However, reported food-metabolite associations have been inconsistent, and there is a need to explore further associations. Our aims were to confirm previously reported food-metabolite associations and to identify novel food-metabolite associations. We conducted a cross-sectional analysis of data from 849 participants (57% men) of the PopGen cohort. Dietary intake was obtained using FFQ and serum metabolites were profiled by an untargeted metabolomics approach. We conducted a systematic literature search to identify previously reported food-metabolite associations and analyzed these associations using linear regression. To identify potential novel food-metabolite associations, datasets were split into training and test datasets and linear regression models were fitted to the training datasets. Significant food-metabolite associations were evaluated in the test datasets. Models were adjusted for covariates. In the literature, we identified 82 food-metabolite associations. Of these, 44 associations were testable in our data and confirmed associations of coffee with 12 metabolites, of fish with five, of chocolate with two, of alcohol with four, and of butter, poultry and wine with one metabolite each. We did not identify novel food-metabolite associations; however, some associations were sex-specific. Potential use of some metabolites as biomarkers should consider sex differences in metabolism.
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http://dx.doi.org/10.3390/metabo10110468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698441PMC
November 2020

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.

Kidney Int 2021 04 31;99(4):926-939. Epub 2020 Oct 31.

Division of Nephrology, University of Washington, Seattle, Washington, USA; Kidney Research Institute, University of Washington, Seattle, Washington, USA.

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
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http://dx.doi.org/10.1016/j.kint.2020.09.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010357PMC
April 2021

Shared Genetics of Multiple System Atrophy and Inflammatory Bowel Disease.

Mov Disord 2021 02 27;36(2):449-459. Epub 2020 Oct 27.

Rita Lila Weston Institute, University College London, London, UK.

Background: Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by intracellular accumulations of α-synuclein and nerve cell loss in striatonigral and olivopontocerebellar structures. Epidemiological and clinical studies have reported potential involvement of autoimmune mechanisms in MSA pathogenesis. However, genetic etiology of this interaction remains unknown. We aimed to investigate genetic overlap between MSA and 7 autoimmune diseases and to identify shared genetic loci.

Methods: Genome-wide association study summary statistics of MSA and 7 autoimmune diseases were combined in cross-trait conjunctional false discovery rate analysis to explore overlapping genetic background. Expression of selected candidate genes was compared in transgenic MSA mice and wild-type mice. Genetic variability of candidate genes was further investigated using independent whole-exome genotyping data from large cohorts of MSA and autoimmune disease patients and healthy controls.

Results: We observed substantial polygenic overlap between MSA and inflammatory bowel disease and identified 3 shared genetic loci with leading variants upstream of the DENND1B and RSP04 genes, and in intron of the C7 gene. Further, the C7 gene showed significantly dysregulated expression in the degenerating midbrain of transgenic MSA mice compared with wild-type mice and had elevated burden of protein-coding variants in independent MSA and inflammatory bowel disease cohorts.

Conclusion: Our study provides evidence of shared genetic etiology between MSA and inflammatory bowel disease with an important role of the C7 gene in both phenotypes, with the implication of immune and gut dysfunction in MSA pathophysiology. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28338DOI Listing
February 2021

Premature Parental Cardiovascular Disease and Subclinical Disease Burden in the Offspring.

J Am Heart Assoc 2020 09 8;9(18):e015406. Epub 2020 Sep 8.

Framingham Heart Study Framingham MA.

Background Offspring of parents with premature cardiovascular disease (CVD) have an increased risk of developing subclinical and clinical CVD. It is unclear whether this association differs by vascular beds in the offspring or by the age cut points used to define premature parental CVD. Methods and Results Using 3 generations of Framingham Heart Study participants, we assessed prevalent coronary artery calcification, the progression of coronary artery calcification over 6.1 years (median), carotid intima media thickness and the ankle-brachial index in 1046 offspring of parents with premature CVD before age 70 years, in 1618 offspring with both parents free of CVD and in 923 offspring with parents with CVD after age 70 years. We used different age cut points (55, 60, 65, and 70 years) to define premature parental CVD. In multivariable-adjusted models, offspring of parents with premature CVD (onset before age 65 years) displayed greater odds for prevalent coronary artery calcification (odds ratio [OR], 1.81; 95% CI, 1.35-2.43), higher carotid intima media thickness (OR, 1.50; 95% CI, 0.92-2.44) and lower ankle-brachial index (OR, 1.89; 95% CI, 1.00-3.58). These associations were generally consistent across different age cut points used to define premature parental CVD. The association with the progression of coronary artery calcification was less consistent. Conclusions Parental premature CVD is associated with increased subclinical CVD burden in the offspring, with consistent relations across different vascular beds and for different age cut points used to define premature parental CVD. Future studies should evaluate whether screening for subclinical CVD traits is warranted in offspring with premature parental CVD.
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http://dx.doi.org/10.1161/JAHA.119.015406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727015PMC
September 2020

Plasma Lithium Levels in a General Population: A Cross-Sectional Analysis of Metabolic and Dietary Correlates.

Nutrients 2020 Aug 18;12(8). Epub 2020 Aug 18.

Institute of Epidemiology, Kiel University, 24105 Kiel, Germany.

Initial evidence suggests that lithium might affect life expectancy and the risk for different disease conditions, but most studies were conducted in patients on lithium medication. Little is known about the association of blood lithium levels within the physiological range with cardiometabolic risk factors and diet. We measured plasma lithium in a community-based sample from Northern Germany (samples taken between 2010 and 2012). All participants (aged 25-82 years) underwent standardized examinations and completed a semi-quantitative food frequency questionnaire. Of several variables tested, the estimated glomerular filtration rate (eGFR) was statistically significantly (inversely) associated with lithium levels, mainly in individuals with slightly impaired renal function (eGFR < 75 mL/min/1.73 m). Besides, lithium levels were positively associated with age and alcohol intake. Using reduced rank regression, we identified a dietary pattern explaining 8.63% variation in plasma lithium levels. Higher lithium levels were associated with higher intakes of potatoes, leafy vegetables, root vegetables, fruits, tea, beer, wine and dietetic products and lower intakes of pasta, rice, pork, chocolate, sweets, soft drinks, other alcoholic beverages, sauces and snacks. Our observations suggest that plasma lithium levels are associated inversely with kidney function, particularly in individuals with slightly impaired renal function, and positively with age and alcohol intake. Lithium at physiological levels was moderately related to an exploratory dietary pattern.
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http://dx.doi.org/10.3390/nu12082489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468710PMC
August 2020

An update on genetic risk scores for coronary artery disease: are they useful for predicting disease risk and guiding clinical decisions?

Expert Rev Cardiovasc Ther 2020 08 9;18(8):443-447. Epub 2020 Aug 9.

The Framingham Heart Study , Framingham, MA, USA.

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http://dx.doi.org/10.1080/14779072.2020.1797489DOI Listing
August 2020

Adherence to a plant-based diet in relation to adipose tissue volumes and liver fat content.

Am J Clin Nutr 2020 08;112(2):354-363

Institute of Epidemiology, University of Kiel, Kiel, Germany.

Background: Better adherence to plant-based diets has been linked to lower risk of metabolic diseases but the effect on abdominal fat distribution and liver fat content is unclear.

Objectives: We aimed to examine the association between different plant-based diet indices and measures of abdominal fat distribution and liver fat content.

Methods: In a population-based sample of 578 individuals from Northern Germany (57% male, median age 62 y), diet was assessed with a validated FFQ and an overall, a healthy, and an unhealthy plant-based diet index were derived. Participants underwent MRI to assess volumes of visceral and subcutaneous abdominal adipose tissue and liver signal intensity (LSI), a measure of liver fat content. Fatty liver disease (FLD) was defined as log LSI ≥3.0. Cross-sectional associations of the plant-based diet indices with visceral and subcutaneous abdominal fat volumes, LSI, and FLD were assessed in linear and logistic regression analyses. The most comprehensive model adjusted for age, sex, education, smoking, alcohol, physical activity, energy intake, diabetes, hyperlipidemia, and BMI.

Results: Higher overall and healthy plant-based diet indices both revealed statistically significant associations with lower visceral and subcutaneous abdominal adipose tissue volumes and with lower odds of FLD in multivariable-adjusted models without BMI. Upon additional adjustment for BMI, only the association of the healthy plant-based diet with visceral adipose tissue remained statistically significant (per 10-point higher healthy plant-based diet index, percentage change in visceral adipose tissue: -4.9%, 95% CI: -8.6%, -2.0%). None of the plant-based diet indices was associated with LSI. The unhealthy plant-based diet index was unrelated to any of the abdominal or liver fat parameters.

Conclusions: Adherence to healthy plant-based diets was associated with lower visceral adipose tissue. None of the other examined associations remained statistically significant after adjustment for BMI.
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http://dx.doi.org/10.1093/ajcn/nqaa119DOI Listing
August 2020

Inhibition of Tumor Cell Growth and Cancer Stem Cell Expansion by a Bispecific Antibody Targeting EGFR and HER3.

Mol Cancer Ther 2020 07 19;19(7):1474-1485. Epub 2020 May 19.

Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.

The frequent activation of HER3 signaling as a resistance mechanism to EGFR-targeted therapy has motivated the development of combination therapies that block more than one receptor tyrosine kinase. Here, we have developed a novel tetravalent, bispecific single-chain diabody-Fc fusion protein targeting EGFR and HER3 (also known as ErbB3) that integrates the antigen-binding sites of a humanized version of cetuximab as well as a recently developed anti-HER3 antibody, IgG 3-43. This bispecific antibody combines the binding and neutralizing properties of the parental antibodies, as observed in biochemical and two-dimensional and three-dimensional cell culture assays, and gave rise to long-lasting growth suppression in a subcutaneous xenograft head and neck tumor model. In triple-negative breast cancer (TNBC) cell lines, treatment with the bispecific antibody inhibited the proliferation and oncosphere formation efficiency driven by HER3 signaling. In an orthotopic MDA-MB-468 tumor model, this translated into antitumor effects superior to those obtained by the parental antibodies alone or in combination and was associated with a reduced number of cells with stem-like properties. These findings demonstrate that the bispecific antibody efficiently blocks not only TNBC proliferation, but also the survival and expansion of the cancer stem cell population, holding promise for further preclinical development.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-1095DOI Listing
July 2020

A disease-specific decline of the relative abundance of Bifidobacterium in patients with autoimmune hepatitis.

Aliment Pharmacol Ther 2020 06 7;51(12):1417-1428. Epub 2020 May 7.

1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: The pathogenesis of autoimmune hepatitis (AIH) is poorly understood and little is known about enteric microbiota in AIH.

Aim: To investigate disease-specific microbiome alterations in AIH.

Methods: The V1-V2 variable regions of the 16S rRNA gene were sequenced in faecal samples from 347 patients with AIH and controls (AIH n = 72, healthy controls (HC) n = 95, primary biliary cholangitis (PBC) n = 99 and ulcerative colitis (UC) n = 81).

Results: Biodiversity (Shannon entropy) was decreased in AIH patients compared to HC (P = 0.016), which was partially reversed by azathioprine (P = 0.011). Regarding between-sample diversity, AIH patients separated from HC, PBC and UC individuals (all P = 0.001). Compared to HC, decreased relative abundance of anaerobic genera such as Faecalibacterium and an increase of Veillonella and the facultative anaerobic genera Streptococcus and Lactobacillus were detected. Importantly, a disease-specific decline of relative abundance of Bifidobacterium was observed in AIH patients. Lack of Bifidobacterium was associated with failure to achieve remission of AIH (P < 0.001). Of potential therapeutic implication, Bifidobacterium abundance correlated with average protein intake (P < 0.001). Random forests classification between AIH and PBC on the microbiome signature yielded an area under receiver operating characteristic curve (AUC) of 0.787 in the training cohort, and an AUC of 0.849 in an external validation cohort.

Conclusion: Disease-specific faecal microbial alterations were identified in patients with AIH. Intestinal dysbiosis in AIH was characterised by a decline of Bifidobacterium, which was associated with increased disease activity. These results point to the contribution of intestinal microbiota to AIH pathogenesis and to novel therapeutic targets.
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http://dx.doi.org/10.1111/apt.15754DOI Listing
June 2020

Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood.

Eur J Epidemiol 2020 Jul 7;35(7):685-697. Epub 2020 May 7.

Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Lund University, 21741, Malmö, Sweden.

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (β = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.
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http://dx.doi.org/10.1007/s10654-020-00638-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867117PMC
July 2020

Prevalence and risk factors of perirenal hyperintensities on T2-weighted MR imaging.

Abdom Radiol (NY) 2020 08;45(8):2518-2525

Department of Radiology, Ludwig Maximilian University Hospital, Pettenkoferstr. 8a, 80336, Munich, Germany.

Objectives: To assess the prevalence and severity of perirenal hyperintensities (PRHs) on T2-weighted magnetic resonance imaging (MRI) and their risk factors in the general population.

Methods: 1752 participants (910 women, 842 men, median age: 52 years) of the Study of Health in Pomerania were included. A visual classification system was established to assess the severity of PRHs (stage 0: no PRHs visible to stage 3: extensive PRHs visible). The MRI-derived thickness of the perirenal and posterior pararenal space and additional risk factors were determined and associated with PRH stages.

Results: The overall prevalence of PRHs was 40.7% and was higher in men than in women. PRHs were more common around the left compared to the right kidney (p < 0.001). On both sides, the presence of PRHs was associated with age (p < 0.001). Multivariable-adjusted regression models revealed male sex (OR = 13.2, 95%CI 9.7; 17.9, p < 0.001), older age (OR = 1.1, 95%CI 1.1; 1.1, p < 0.001), higher body mass index (BMI; OR = 1.1, 95%CI 1.0; 1.1, p < 0.001), current smoking status (OR = 1.9, 95%CI 1.4; 2.6, p < 0.001), and greater thickness of the posterior pararenal space (OR = 1.2, 95%CI 1.2; 1.2, p < 0.001) as independent significant risk factors of left-sided PRHs. The same risk factors were confirmed for right PRHs. Glomerular filtration rate was not associated with PRHs on either sides (OR = 1.00, 95%CI 1.0;1.0, p > 0.05).

Conclusions: PRHs are common in the general population, with a higher prevalence in men, elderly individuals, and around the left kidney. Furthermore, BMI, posterior pararenal space thickness, and current smoking, but not renal function itself, are associated with the presence of PRHs.
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http://dx.doi.org/10.1007/s00261-020-02569-5DOI Listing
August 2020

Exome sequencing in 38 patients with intracranial aneurysms and subarachnoid hemorrhage.

J Neurol 2020 Sep 4;267(9):2533-2545. Epub 2020 May 4.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Objective: Genetic risk factors for unruptured intracranial aneurysms (UIA) and aneurysmal subarachnoid hemorrhage (aSAH) are poorly understood. We aimed to verify recently reported risk genes and to identify novel sequence variants involved in the etiology of UIA/aSAH.

Methods: We performed exome sequencing (ES) in 35 unrelated individuals and 3 family members, each with a history of UIA and/or aSAH. We searched for sequence variants with minor allele frequency (MAF) ≤ 5% in the reported risk genes ADAMTS15, ANGPTL6, ARHGEF17, LOXL2, PCNT, RNF213, THSD1 and TMEM132B. To identify novel putative risk genes we looked for unknown (MAF = 0) variants shared by the three relatives.

Results: We identified 20 variants with MAF ≤ 5% in 18 individuals: 9 variants in PCNT (9 patients), 4 in RNF213 (3 patients), 3 in THSD1 (6 patients), 2 in ANGPTL6 (3 patients), 1 in ADAMTS15 (1 patient) and 1 in TMEM132B (1 patient). In the affected family, prioritization of shared sequence variants yielded five novel putative risk genes. Based on predicted pathogenicity of identified variants, population genetics data and a high functional relevance for vascular biology, EDIL3 was selected as top candidate and screened in additional 37 individuals with UIA and/or aSAH: a further very rare EDIL3 sequence variant in two unrelated sporadic patients was identified.

Conclusions: Our data support a role of sequence variants in PCNT, RNF213 and THSD1 as susceptibility factors for cerebrovascular disease. The documented function in vascular wall integrity, the crucial localization of affected amino acids and gene/variant association tests suggest EDIL3 as a further valid candidate disease gene for UIA/aSAH.
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http://dx.doi.org/10.1007/s00415-020-09865-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419486PMC
September 2020

Rare Variants in Specific Lysosomal Genes Are Associated With Parkinson's Disease.

Mov Disord 2020 07 8;35(7):1245-1248. Epub 2020 Apr 8.

Department of Neurology, Universitätsklinikum Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany.

Objective: Impaired lysosomal degradation of α-synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD.

Methods: We investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next-generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes.

Results: We confirm the association of rare variants in GBA with PD and report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, and VPS13C.

Conclusion: Rare variants in selected lysosomal genes, first and foremost GBA, are associated with PD. Rare variants in ATP13A2 and VPC13C previously linked to monogenic PD and more common variants in TMEM175 and VPS13C previously linked to sporadic PD in genome-wide association studies are associated with PD. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28037DOI Listing
July 2020
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