Publications by authors named "Thomas Illig"

464 Publications

Optical genome mapping identifies rare structural variations as predisposition factors associated with severe COVID-19.

iScience 2022 Jan 10:103760. Epub 2022 Jan 10.

Department of Pathology, Medical College of Georgia, Augusta University, GA, 30912, U.S.A.

Impressive global efforts have identified both rare and common gene variants associated with severe COVID-19 using sequencing technologies. However, these studies lack the sensitivity to accurately detect several classes of variants, especially large structural variants (SVs), which account for a substantial proportion of genetic diversity including clinically relevant variation. We performed optical genome mapping on 52 severely-ill COVID-19 patients to identify rare/unique SVs as decisive predisposition factors associated with COVID-19. We identified 7 SVs involving genes implicated in two key host-viral interaction pathways: innate immunity and inflammatory response, and viral replication and spread in 9 patients, of which SVs in and genes are the most intriguing candidates. This study is the first to systematically assess the potential role of SVs in the pathogenesis of COVID-19 severity and highlights the need to evaluate SVs along with sequencing variants to comprehensively associate genomic information with inter-individual variability in COVID-19 phenotypes.
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http://dx.doi.org/10.1016/j.isci.2022.103760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8744399PMC
January 2022

Validation and clinical application of transactivation assays for RUNX1 variant classification.

Blood Adv 2022 Jan 13. Epub 2022 Jan 13.

Hannover Medical School, Hannover, Germany.

Familial platelet disorder with associated myeloid malignancies (RUNX1-FPD) is caused by heterozygous pathogenic germline variants of RUNX1. In the present study, we evaluate the applicability of transactivation assays to investigate RUNX1 variants in different regions of the protein. We studied 11 variants to independently validate transactivation assays supporting variant classification following the ClinGen Myeloid Malignancies variant curation expert panel guidelines. Variant classification is key for the translation of genetic findings. We showed that new assays need to be developed to assess C-terminal RUNX1 variants. Two variants of uncertain significance (VUS) were reclassified to likely pathogenic. Additionally, our analyses supported the (likely) pathogenic classification of two other variants. We demonstrated functionality of four VUS, but reclassification to (likely) benign was challenging and suggested the need to reevaluate current classification guidelines. Finally, clinical utility of our assays was illustrated in the context of seven families. Our data confirmed RUNX1-FPD suspicion in three families with RUNX1-FPD-specific family history. Whereas for three variants identified in non RUNX1-FPD-typical families, no functional defect was detected. Applying functional assays to support RUNX1 variant classification can be essential for adequate care of index patients and their relatives at risk. It facilitates translation of genetic data into personalized medicine.
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http://dx.doi.org/10.1182/bloodadvances.2021006161DOI Listing
January 2022

Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function.

Nat Genet 2022 Jan 3;54(1):18-29. Epub 2022 Jan 3.

Research Unit Protein Science, Helmholtz Zentrum München, German Research Centre for Environmental Health, Munich, Germany.

We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP-CpG associations (methylation quantitative trait loci (meQTL), P < 10), including 467,915 meQTL that operate in trans. The meQTL are enriched for functionally relevant characteristics, including shared chromatin state, High-throuhgput chromosome conformation interaction, and association with gene expression, metabolic variation and clinical traits. We use molecular interaction and colocalization analyses to identify multiple nuclear regulatory pathways linking meQTL loci to phenotypic variation, including UBASH3B (body mass index), NFKBIE (rheumatoid arthritis), MGA (blood pressure) and COMMD7 (white cell counts). For rs6511961 , chromatin immunoprecipitation followed by sequencing (ChIP-seq) validates zinc finger protein (ZNF)333 as the likely trans acting effector protein. Finally, we used interaction analyses to identify population- and lineage-specific meQTL, including rs174548 in FADS1, with the strongest effect in CD8 T cells, thus linking fatty acid metabolism with immune dysregulation and asthma. Our study advances understanding of the potential pathways linking genetic variation to human phenotype.
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http://dx.doi.org/10.1038/s41588-021-00969-xDOI Listing
January 2022

Ago-RIP Sequencing Identifies New MicroRNA-449a-5p Target Genes Increasing Sorafenib Efficacy in Hepatocellular Carcinoma.

J Cancer 2022 1;13(1):62-75. Epub 2022 Jan 1.

Department of Human Genetics, Hannover Medical School, Hannover, Germany.

Patients with hepatocellular carcinoma (HCC) have very limited treatment options. For the last fourteen years, the multi-tyrosine kinase inhibitor sorafenib has been used as standard-of-care therapeutic agent in advanced HCC. Unfortunately, drug resistance develops in many cases. Therefore, we aimed to find a way to mitigate drug resistance and to improve the sorafenib efficacy in HCC cells. MicroRNAs play a significant role in targeting genes involved in tumor control suggesting microRNA/sorafenib combination therapy as a promising treatment option in advanced HCC. MiR-449a-5p target genes were identified by Ago-RIP sequencing and validated by luciferase reporter assays and expression analyses Target gene expression and survival data were analyzed in public HCC datasets. Tumor-relevant functional effects of miR-449a-5p and its target genes as well as their impact on the effects of sorafenib were analyzed using assays. An indirect transwell co-culture system was used to survey anti-angiogenic effects of miR-449a-5p. and were identified as direct target genes of miR-449a-5p. Overexpression of these genes correlated with a poor outcome of HCC patients. Transfection with miR-449a-5p and repression of miR-449a-5p target genes inhibited cell proliferation and angiogenesis, induced apoptosis and reduced AKT and ERK signaling in HLE and Huh7 cells. Importantly, miR-449a-5p potentiated the efficacy of sorafenib in HCC cells via downregulation of and This study provides detailed insights into the targetome and regulatory network of miR-449a-5p. Our results demonstrate for the first time that targeting and via miR-449a overexpression could have significant implications in counteracting sorafenib resistance suggesting miR-449a-5p as a promising candidate for a microRNA/sorafenib combination therapy.
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http://dx.doi.org/10.7150/jca.66016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8692677PMC
January 2022

Children and Adolescents' Behavioral Patterns in Response to Escalating COVID-19 Restriction Reveal Sex and Age Differences.

J Adolesc Health 2021 Nov 24. Epub 2021 Nov 24.

Department of Pediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany. Electronic address:

Purpose: The COVID-19 pandemic affects students in a myriad of different ways. Our prospective, longitudinal study in a cohort of students in Hannover, Germany explores behavioral patterns during escalating COVID-19 restrictions.

Methods: In total, 777 students between the age of 9 and 20 were assessed for their activity engagement, travel patterns, and self-assessed compliance with protective recommendations at six time points between June 2020 and June 2021 (3,564 observations) and were monitored for severe acute respiratory syndrome coronavirus 2 infection by nasal swab polymerase chain reaction and serum antibody titers.

Results: Activity engagement decreased, but self-assessed compliance with measures such as mask wearing and social distancing was stable during escalating restrictions. Although we found no sex difference during the summer break, when incidence was lowest, females engaged in a higher variety of activities than males for all other time points. Older students engaged in more activities and self-assigned themselves lower compliance values than younger ones. Greater involvement in different activities was seen in households which traveled more frequently. Infection rate in our cohort was low (0.03% acute infections, 1.94% positive seroprevalence).

Discussion: Our study supports the view that, overall, students show high compliance with COVID-19 recommendations and restrictions. The identification of subsets, such as female and older students, with higher risk behavioral patterns should be considered when implementing public information campaigns. In light of the low infection rate in our cohort, we conclude that in-person learning can occur safely if extensive protective measures are in place and the incidence in the general population remains moderate.
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http://dx.doi.org/10.1016/j.jadohealth.2021.11.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610846PMC
November 2021

Discrimination of SARS-CoV-2 Infections From Other Viral Respiratory Infections by Scent Detection Dogs.

Front Med (Lausanne) 2021 18;8:749588. Epub 2021 Nov 18.

Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Hannover, Germany.

Testing of possibly infected individuals remains cornerstone of containing the spread of SARS-CoV-2. Detection dogs could contribute to mass screening. Previous research demonstrated canines' ability to detect SARS-CoV-2-infections but has not investigated if dogs can differentiate between COVID-19 and other virus infections. Twelve dogs were trained to detect SARS-CoV-2 positive samples. Three test scenarios were performed to evaluate their ability to discriminate SARS-CoV-2-infections from viral infections of a different aetiology. Naso- and oropharyngeal swab samples from individuals and samples from cell culture both infected with one of 15 viruses that may cause COVID-19-like symptoms were presented as distractors in a randomised, double-blind study. Dogs were either trained with SARS-CoV-2 positive saliva samples (test scenario I and II) or with supernatant from cell cultures (test scenario III). When using swab samples from individuals infected with viruses other than SARS-CoV-2 as distractors (test scenario I), dogs detected swab samples from SARS-CoV-2-infected individuals with a mean diagnostic sensitivity of 73.8% (95% CI: 66.0-81.7%) and a specificity of 95.1% (95% CI: 92.6-97.7%). In test scenario II and III cell culture supernatant from cells infected with SARS-CoV-2, cells infected with other coronaviruses and non-infected cells were presented. Dogs achieved mean diagnostic sensitivities of 61.2% (95% CI: 50.7-71.6%, test scenario II) and 75.8% (95% CI: 53.0-98.5%, test scenario III), respectively. The diagnostic specificities were 90.9% (95% CI: 87.3-94.6%, test scenario II) and 90.2% (95% CI: 81.1-99.4%, test scenario III), respectively. In all three test scenarios the mean specificities were above 90% which indicates that dogs can distinguish SARS-CoV-2-infections from other viral infections. However, compared to earlier studies our scent dogs achieved lower diagnostic sensitivities. To deploy COVID-19 detection dogs as a reliable screening method it is therefore mandatory to include a variety of samples from different viral respiratory tract infections in dog training to ensure a successful discrimination process.
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http://dx.doi.org/10.3389/fmed.2021.749588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636992PMC
November 2021

Transcriptional and Mutational Profiling of B-Other Acute Lymphoblastic Leukemia for Improved Diagnostics.

Cancers (Basel) 2021 Nov 12;13(22). Epub 2021 Nov 12.

Institute of Human Genetics, Hannover Medical School (MHH), 30625 Hannover, Germany.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common cancer in children, and significant progress has been made in diagnostics and the treatment of this disease based on the subtypes of BCP-ALL. However, in a large proportion of cases (B-other), recurrent BCP-ALL-associated genomic alterations remain unidentifiable by current diagnostic procedures. In this study, we performed RNA sequencing and analyzed gene fusions, expression profiles, and mutations in diagnostic samples of 185 children with BCP-ALL. Gene expression clustering showed that a subset of B-other samples partially clusters with some of the known subgroups, particularly -positive. Mutation analysis coupled with gene expression profiling revealed the presence of distinctive BCP-ALL subgroups, characterized by the presence of mutations in known ALL driver genes, e.g., and . Moreover, we identified novel fusion partners of lymphoid lineage transcriptional factors , and . In addition, we report on low blast count detection thresholds and show that the use of EDTA tubes for sample collection does not have adverse effects on sequencing and downstream analysis. Taken together, our findings demonstrate the applicability of whole-transcriptome sequencing for personalized diagnostics in pediatric ALL, including tentative classification of the B-other cases that are difficult to diagnose using conventional methods.
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http://dx.doi.org/10.3390/cancers13225653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616234PMC
November 2021

Impaired immune response mediated by prostaglandin E2 promotes severe COVID-19 disease.

PLoS One 2021 4;16(8):e0255335. Epub 2021 Aug 4.

Department of Cardiology and Angiology, Hannover Medical School, Hanover, Germany.

The SARS-CoV-2 coronavirus has led to a pandemic with millions of people affected. The present study finds that risk-factors for severe COVID-19 disease courses, i.e. male sex, older age and sedentary life style are associated with higher prostaglandin E2 (PGE2) serum levels in blood samples from unaffected subjects. In COVID-19 patients, PGE2 blood levels are markedly elevated and correlate positively with disease severity. SARS-CoV-2 induces PGE2 generation and secretion in infected lung epithelial cells by upregulating cyclo-oxygenase (COX)-2 and reducing the PG-degrading enzyme 15-hydroxyprostaglandin-dehydrogenase. Also living human precision cut lung slices (PCLS) infected with SARS-CoV-2 display upregulated COX-2. Regular exercise in aged individuals lowers PGE2 serum levels, which leads to increased Paired-Box-Protein-Pax-5 (PAX5) expression, a master regulator of B-cell survival, proliferation and differentiation also towards long lived memory B-cells, in human pre-B-cell lines. Moreover, PGE2 levels in serum of COVID-19 patients lowers the expression of PAX5 in human pre-B-cell lines. The PGE2 inhibitor Taxifolin reduces SARS-CoV-2-induced PGE2 production. In conclusion, SARS-CoV-2, male sex, old age, and sedentary life style increase PGE2 levels, which may reduce the early anti-viral defense as well as the development of immunity promoting severe disease courses and multiple infections. Regular exercise and Taxifolin treatment may reduce these risks and prevent severe disease courses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255335PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336874PMC
August 2021

MicroRNA-192-5p inhibits migration of triple negative breast cancer cells and directly regulates Rho GTPase activating protein 19.

Genes Chromosomes Cancer 2021 Nov 6;60(11):733-742. Epub 2021 Aug 6.

Department of Human Genetics, Hannover Medical School, Hannover, Germany.

Among the different breast cancer subtypes, triple-negative breast cancer (TNBC) is associated with a poor prognosis, low survival rates, and high expression of histone deacetylases. Treatment with histone deacetylase inhibitor trichostatin A (TSA) leads to an increased expression of potential tumor-suppressive miRNAs. Characterization of these miRNAs can help to find new molecular targets for treatment of TNBC. We identified differentially expressed miRNAs by microarray analyses after treatment with TSA in the TNBC cell lines HCC38, HCC1395, and HCC1935. The gene locus of hsa-miRNA-192-5p (miR-192) and hsa-miR-194-2 (miR-194-2) with its host gene, long noncoding RNA miR-194-2HG, has been linked to inhibition of migration in different tumor types. Therefore, we examined tumor-relevant functional effects using WST-1-based proliferation, capsase-3/7-based apoptosis, and trans-well migration assays after transfection with miRNA mimics or specific siRNAs. We demonstrated the tumor-suppressive capacity of miR-192 in TNBC cells, which was exerted through inhibition of proliferation, induction of apoptosis, and reduction of migration. Gene expression and bioinformatics analyses of TNBC cell lines transfected with miR-192 mimics, identified a number of genes involved in migration including the Rho GTPase Activating Protein ARHGAP19. Through RNA immunoprecipitation we demonstrated the direct binding of miR-192 and ARHGAP19. Downregulation of ARHGAP19 expression by either miR-192 or siRNA inhibited migration of TNBC cells significantly. Our findings demonstrate that overexpression of epigenetically deregulated miR-192 decreases proliferation, promotes apoptosis, and inhibits migration of TNBC cell lines.
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http://dx.doi.org/10.1002/gcc.22982DOI Listing
November 2021

Synergistic effect of genetic polymorphisms in and genes on the risk of pulmonary tuberculosis in a Moldavian population.

Innate Immun 2021 07 18;27(5):365-376. Epub 2021 Jul 18.

Hannover Unified Biobank, 9177Hannover Medical School, Hannover Medical School, Germany.

Polymorphisms in genes that control immune function and regulation may influence susceptibility to pulmonary tuberculosis (TB). In this study, 14 polymorphisms in 12 key genes involved in the immune response (, , , , , , , , , , , and ) were tested for their association with pulmonary TB in 271 patients with TB and 251 community-matched controls from the Republic of Moldova. In addition, gene-gene interactions involved in TB susceptibility were analyzed for a total of 43 genetic loci. Single nucleotide polymorphism (SNP) analysis revealed a nominal association between rs1800629 and pulmonary TB (Fisher exact test  = 0.01843). In the pairwise interaction analysis, the combination of the genotypes rs5743810 GA and rs11096957 GT was significantly associated with an increased genetic risk of pulmonary TB (OR = 2.48, 95% CI = 1.62-3.85; Fisher exact test value = 1.5 × 10, significant after Bonferroni correction). In conclusion, the rs5743810 and rs11096957 two-locus interaction confers a significantly higher risk for pulmonary TB; due to its high frequency in the population, this SNP combination may serve as a novel biomarker for predicting TB susceptibility.
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http://dx.doi.org/10.1177/17534259211029996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419295PMC
July 2021

Plasma Metabolome Signature Indicative of Germline Status Independent of Cancer Incidence.

Front Oncol 2021 7;11:627217. Epub 2021 Apr 7.

Department of Human Genetics, Hannover Medical School, Hannover, Germany.

Individuals carrying a pathogenic germline variant in the breast cancer predisposition gene (g+) are prone to developing breast cancer. Apart from its well-known role in DNA repair, BRCA1 has been shown to powerfully impact cellular metabolism. While, in general, metabolic reprogramming was named a hallmark of cancer, disrupted metabolism has also been suggested to drive cancer cell evolution and malignant transformation by critically altering microenvironmental tissue integrity. Systemic metabolic effects induced by germline variants in cancer predisposition genes have been demonstrated before. Whether or not systemic metabolic alterations exist in g+ individuals independent of cancer incidence has not been investigated yet. We therefore profiled the plasma metabolome of 72 g+ women and 72 age-matched female controls, none of whom (carriers and non-carriers) had a prior cancer diagnosis and all of whom were cancer-free during the follow-up period. We detected one single metabolite, pyruvate, and two metabolite ratios involving pyruvate, lactate, and a metabolite of yet unknown structure, significantly altered between the two cohorts. A machine learning signature of metabolite ratios was able to correctly distinguish between g+ and controls in ~82%. The results of this study point to innate systemic metabolic differences in g+ women independent of cancer incidence and raise the question as to whether or not constitutional alterations in energy metabolism may be involved in the etiology of -associated breast cancer.
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http://dx.doi.org/10.3389/fonc.2021.627217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058469PMC
April 2021

Association between Single Nucleotide Polymorphisms and Weight Reduction in Behavioural Interventions-A Pooled Analysis.

Nutrients 2021 Mar 2;13(3). Epub 2021 Mar 2.

Clinic of Internal Medicine II, University Hospital of Regensburg, 93053 Regensburg, Germany.

Knowledge of the association between single nucleotide polymorphisms (SNPs) and weight loss is limited. The aim was to analyse whether selected obesity-associated SNPs within the fat mass and obesity-associated (), transmembrane protein 18 (), melanocortin-4 receptor (), SEC16 homolog B (), and brain-derived neurotrophic factor () gene are associated with anthropometric changes during behavioural intervention for weight loss. genetic and anthropometric data from 576 individuals with overweight and obesity from four lifestyle interventions were obtained. A genetic predisposition score (GPS) was calculated. Our results show that study participants had a mean age of 48.2 ± 12.6 years and a mean baseline body mass index of 33.9 ± 6.4 kg/m. Mean weight reduction after 12 months was -7.7 ± 10.9 kg. After 12 months of intervention, the SNPs rs571312 and rs17782313 were significantly associated with a greater decrease in body weight and BMI ( 0.012, = 0.011, respectively). The investigated SNPs within the other four genetic loci showed no statistically significant association with changes in anthropometric parameters. The GPS showed no statistically significant association with weight reduction. In conclusion there was no consistent evidence for statistically significant associations of SNPs with anthropometric changes during a behavioural intervention. It seems that other factors play a more significant in weight management than the investigated SNPs.
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http://dx.doi.org/10.3390/nu13030819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998423PMC
March 2021

Exploring beyond clinical routine SARS-CoV-2 serology using MultiCoV-Ab to evaluate endemic coronavirus cross-reactivity.

Nat Commun 2021 02 19;12(1):1152. Epub 2021 Feb 19.

Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany.

The humoral immune response to SARS-CoV-2 is a benchmark for immunity and detailed analysis is required to understand the manifestation and progression of COVID-19, monitor seroconversion within the general population, and support vaccine development. The majority of currently available commercial serological assays only quantify the SARS-CoV-2 antibody response against individual antigens, limiting our understanding of the immune response. To overcome this, we have developed a multiplex immunoassay (MultiCoV-Ab) including spike and nucleocapsid proteins of SARS-CoV-2 and the endemic human coronaviruses. Compared to three broadly used commercial in vitro diagnostic tests, our MultiCoV-Ab achieves a higher sensitivity and specificity when analyzing a well-characterized sample set of SARS-CoV-2 infected and uninfected individuals. We find a high response against endemic coronaviruses in our sample set, but no consistent cross-reactive IgG response patterns against SARS-CoV-2. Here we show a robust, high-content-enabled, antigen-saving multiplex assay suited to both monitoring vaccination studies and facilitating epidemiologic screenings for humoral immunity towards pandemic and endemic coronaviruses.
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http://dx.doi.org/10.1038/s41467-021-20973-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896075PMC
February 2021

Unbalanced translocation der(5;17) resulting in a TP53 loss as recurrent aberration in myelodysplastic syndrome and acute myeloid leukemia with complex karyotype.

Genes Chromosomes Cancer 2021 Jun 19;60(6):452-457. Epub 2021 Feb 19.

Department of Human Genetics, Hannover Medical School, Hannover, Germany.

A complex karyotype, detected in myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), is associated with a reduced median survival. The most frequent chromosomal aberrations in complex karyotypes are deletions of 5q and 17p harboring the tumor suppressor gene TP53. The unbalanced translocation der(5;17) involving chromosome 5q and 17p is a recurrent aberration in MDS/AML, resulting in TP53 loss. We analyzed the karyotypes of 178 patients with an unbalanced translocation der(5;17) using fluorescence R-/G-banding analysis. Whenever possible, fluorescence in situ hybridization (FISH) (n = 138/141), multicolor FISH (n = 8), telomere length measurement (n = 9), targeted DNA sequencing (n = 13), array-CGH (n = 7) and targeted RNA sequencing (n = 2) were conducted. The der(5;17) aberration was accompanied with loss of genetic material in 7q (53%), -7 (27%), gain of 21q (29%), +8 (17%) and - 18 (16%) and all analyzed patients (n = 13) showed a (likely) pathogenic variant inTP53. The der(5;17) cohort showed significantly shortened telomeres in comparison to the healthy age-matched controls (P < .05), but there was no significant telomere shortening in comparison to MDS/AML patients with a complex karyotype without der(5;17). No fusion genes resulted from the unbalanced translocation. This study demonstrates that the unbalanced translocation der(5;17) is associated with a biallelic inactivation of TP53 due to a deletion of TP53 in one allele and a pathogenic variant of the second TP53 allele. Since the breakpoints are located within (near-) heterochromatic regions, alterations of DNA methylation or histone modifications may be involved in the generation of der(5;17).
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http://dx.doi.org/10.1002/gcc.22938DOI Listing
June 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Smokers with COPD Show a Shift in Energy and Nitrogen Metabolism at Rest and During Exercise.

Int J Chron Obstruct Pulmon Dis 2020 6;15:1-13. Epub 2020 Jan 6.

Fraunhofer ITEM, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover, Germany.

Purpose: There is an ongoing demand for easily accessible biomarkers that reflect the physiological and pathophysiological mechanisms of COPD. To test if an exercise challenge could help to identify clinically relevant metabolic biomarkers in COPD.

Patients And Methods: We performed two constant-load exercise challenges separated by 4 weeks including smokers with COPD (n=23/19) and sex- and age-matched healthy smokers (n=23/20). Two hours after a standardized meal venous blood samples were obtained before, 5 mins after the start, at the end of submaximal exercise, and following a recovery of 20 mins. Data analysis was performed using mixed- effects model, with the metabolite level as a function of disease, time point and interaction terms and using each individual's resting level as reference.

Results: Exercise duration was longer in healthy smokers but lactate levels were comparable between groups at all four time points. Glucose levels were increased in COPD. Glutamine was lower, while glutamate and arginine were higher in COPD. Branched-chain amino acids showed a stronger decline during exercise in healthy smokers. Carnitine and the acyl-carnitines C16 and C18:1 were increased in COPD. These metabolite levels and changes were reproducible in the second challenge.

Conclusion: Higher serum glucose, evidence for impaired utilization of amino acids during exercise and a shift of energy metabolism to enhanced consumption of lipids could be early signs for a developing metabolic syndrome in COPD. In COPD patients, deviations of energy and nitrogen metabolism are amplified by an exercise challenge.
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http://dx.doi.org/10.2147/COPD.S217474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956026PMC
February 2021

A comparison of curated gene sets versus transcriptomics-derived gene signatures for detecting pathway activation in immune cells.

BMC Bioinformatics 2020 Jan 28;21(1):28. Epub 2020 Jan 28.

Hannover Medical School, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Carl-Neuberg-Straße, Hannover, 30625, Germany.

Background: Despite the significant contribution of transcriptomics to the fields of biological and biomedical research, interpreting long lists of significantly differentially expressed genes remains a challenging step in the analysis process. Gene set enrichment analysis is a standard approach for summarizing differentially expressed genes into pathways or other gene groupings. Here, we explore an alternative approach to utilizing gene sets from curated databases. We examine the method of deriving custom gene sets which may be relevant to a given experiment using reference data sets from previous transcriptomics studies. We call these data-derived gene sets, "gene signatures" for the biological process tested in the previous study. We focus on the feasibility of this approach in analyzing immune-related processes, which are complicated in their nature but play an important role in the medical research.

Results: We evaluate several statistical approaches to detecting the activity of a gene signature in a target data set. We compare the performance of the data-derived gene signature approach with comparable GO term gene sets across all of the statistical tests. A total of 61 differential expression comparisons generated from 26 transcriptome experiments were included in the analysis. These experiments covered eight immunological processes in eight types of leukocytes. The data-derived signatures were used to detect the presence of immunological processes in the test data with modest accuracy (AUC = 0.67). The performance for GO and literature based gene sets was worse (AUC = 0.59). Both approaches were plagued by poor specificity.

Conclusions: When investigators seek to test specific hypotheses, the data-derived signature approach can perform as well, if not better than standard gene-set based approaches for immunological signatures. Furthermore, the data-derived signatures can be generated in the cases that well-defined gene sets are lacking from pathway databases and also offer the opportunity for defining signatures in a cell-type specific manner. However, neither the data-derived signatures nor standard gene-sets can be demonstrated to reliably provide negative predictions for negative cases. We conclude that the data-derived signature approach is a useful and sometimes necessary tool, but analysts should be weary of false positives.
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http://dx.doi.org/10.1186/s12859-020-3366-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986093PMC
January 2020

PedCAPNETZ - prospective observational study on community acquired pneumonia in children and adolescents.

BMC Pulm Med 2019 Dec 9;19(1):238. Epub 2019 Dec 9.

Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Carl-Neuberg-Straße 1, D -, 30625, Hannover, Germany.

Background: Pediatric community acquired pneumonia (pedCAP) is one of the leading causes for childhood morbidity accounting for up to 20% of pediatric hospital admissions in high income countries. In spite of its high morbidity, updated epidemiological and pathogen data after introduction of preventive vaccination and novel pathogen screening strategies are limited. Moreover, there is a need for validated recommendations on diagnostic and treatment regimens in pedCAP. Through collection of patient data and analysis of pathogen and host factors in a large sample of unselected pedCAP patients in Germany, we aim to address and substantially improve this situation.

Methods: pedCAPNETZ is an observational, multi-center study on pedCAP. Thus far, nine study centers in hospitals, outpatient clinics and practices have been initiated and more than 400 patients with radiologically confirmed pneumonia have been enrolled, aiming at a total of 1000 study participants. Employing an online data base, information on disease course, treatment as well as demographical and socioeconomical data is recorded. Patients are followed up until day 90 after enrollment; Comprehensive biosample collection and a central pedCAPNETZ biobank allow for in-depth analyses of pathogen and host factors. Standardized workflows to assure sample logistics and data management in more than fifteen future study centers have been established.

Discussion: Through comprehensive epidemiological, clinical and biological analyses, pedCAPNETZ fills an important gap in pediatric and infection research. To secure dissemination of the registry, we will raise clinical and scientific awareness at all levels. We aim at participating in decision making processes for guidelines and prevention strategies. Ultimately, we hope the results of the pedCAPNETZ registry will help to improve care and quality of life in pedCAP patients in the future.
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http://dx.doi.org/10.1186/s12890-019-1013-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902429PMC
December 2019

Decreased plasma phospholipid concentrations and increased acid sphingomyelinase activity are accurate biomarkers for community-acquired pneumonia.

J Transl Med 2019 11 11;17(1):365. Epub 2019 Nov 11.

Research Group "Biomarkers for Infectious Diseases", TWINCORE Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Str. 7, 30625, Hannover, Germany.

Background: There continues to be a great need for better biomarkers and host-directed treatment targets for community-acquired pneumonia (CAP). Alterations in phospholipid metabolism may constitute a source of small molecule biomarkers for acute infections including CAP. Evidence from animal models of pulmonary infections and sepsis suggests that inhibiting acid sphingomyelinase (which releases ceramides from sphingomyelins) may reduce end-organ damage.

Methods: We measured concentrations of 105 phospholipids, 40 acylcarnitines, and 4 ceramides, as well as acid sphingomyelinase activity, in plasma from patients with CAP (n = 29, sampled on admission and 4 subsequent time points), chronic obstructive pulmonary disease exacerbation with infection (COPD, n = 13) as a clinically important disease control, and 33 age- and sex-matched controls.

Results: Phospholipid concentrations were greatly decreased in CAP and normalized along clinical improvement. Greatest changes were seen in phosphatidylcholines, followed by lysophosphatidylcholines, sphingomyelins and ceramides (three of which were upregulated), and were least in acylcarnitines. Changes in COPD were less pronounced, but also differed qualitatively, e.g. by increases in selected sphingomyelins. We identified highly accurate biomarkers for CAP (AUC ≤ 0.97) and COPD (AUC ≤ 0.93) vs. Controls, and moderately accurate biomarkers for CAP vs. COPD (AUC ≤ 0.83), all of which were phospholipids. Phosphatidylcholines, lysophosphatidylcholines, and sphingomyelins were also markedly decreased in S. aureus-infected human A549 and differentiated THP1 cells. Correlations with C-reactive protein and procalcitonin were predominantly negative but only of mild-to-moderate extent, suggesting that these markers reflect more than merely inflammation. Consistent with the increased ceramide concentrations, increased acid sphingomyelinase activity accurately distinguished CAP (fold change = 2.8, AUC = 0.94) and COPD (1.75, 0.88) from Controls and normalized with clinical resolution.

Conclusions: The results underscore the high potential of plasma phospholipids as biomarkers for CAP, begin to reveal differences in lipid dysregulation between CAP and infection-associated COPD exacerbation, and suggest that the decreases in plasma concentrations are at least partially determined by changes in host target cells. Furthermore, they provide validation in clinical blood samples of acid sphingomyelinase as a potential treatment target to improve clinical outcome of CAP.
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http://dx.doi.org/10.1186/s12967-019-2112-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849224PMC
November 2019

MTF1 binds to metal-responsive element e within the ATP7B promoter and is a strong candidate in regulating the ATP7B expression.

Ann Hum Genet 2020 03 9;84(2):195-200. Epub 2019 Oct 9.

Department of Human Genetics, Hannover Medical School, Hannover, Germany.

Wilson's disease is an autosomal recessive disorder resulting from copper excess. Some patients with clinical Wilson's disease symptoms exhibit no or only heterozygous pathogenic variants in the coding region of the disease-causing ATP7B gene. Therefore, the ATP7B promoter region is of special interest. Metal-responsive elements (MREs) located in the ATP7B promoter are promising motifs in modulating the ATP7B expression. We studied protein interaction of MREe, MREc, and MREd by electrophoretic mobility shift assays and revealed specific interactions for all MREs. We further narrowed down the specific binding site. Proteins potentially binding to the three MREs were identified by MatInspector analyses. Metal regulatory transcription factor 1 (MTF1) could be validated to bind to MREe by electrophoretic mobility shift assays. ATP7B promoter-driven reporter gene expression was significantly increased because of this interaction. MTF1 is a strong candidate in regulating the ATP7B expression through MREe binding.
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http://dx.doi.org/10.1111/ahg.12355DOI Listing
March 2020

Wnt status-dependent oncogenic role of BCL9 and BCL9L in hepatocellular carcinoma.

Hepatol Int 2020 May 22;14(3):373-384. Epub 2019 Aug 22.

Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover, 30625, Germany.

Background: Activation of Wnt/β-catenin pathway is a frequent event in hepatocellular carcinoma and is associated with enhanced cell survival and proliferation. Therefore, targeting this signaling pathway is discussed as an attractive therapeutic approach for HCC treatment. BCL9 and BCL9L, two homologous coactivators of the β-catenin transcription factor complex, have not yet been comprehensively characterized in HCC. We aimed to elucidate the roles of BCL9 and BCL9L, especially regarding Wnt/β-catenin signaling and their prognostic value in HCC.

Methods: Expression of BCL9/BCL9L was determined in HCC cell lines (HLE, HLF, Huh7, HepG2, Hep3B, and Huh6) and normal liver cell lines (THLE-2 and THLE-3). To analyze proliferation and apoptosis, BCL9 and/or BCL9L were knocked down in Wnt-inactive HLE and Wnt-active HepG2 and Huh6 cells using siRNA. Subsequently, Wnt reporter assays were performed in HepG2 and Huh6 cells. BCL9 and BCL9L expression, clinicopathological and survival data of public HCC datasets were analyzed, taking the Wnt signaling status into account.

Results: Knockdown of BCL9L, but not of BCL9, reduced Wnt signaling activity. Knockdown of BCL9 and/or BCL9L reduced cell viability and increased apoptosis of Wnt-inactive HCC cells, but had no effect in Wnt-active cells. Expression of BCL9 and BCL9L was upregulated in human HCC and increased with progressing dedifferentiation. For BCL9L, higher expression was observed in tumors of larger size. Overexpression of BCL9 and BCL9L correlated with poor overall survival, especially in HCC without activated Wnt signaling.

Conclusion: Oncogenic BCL9 proteins represent promising targets for cancer therapy and inhibiting them may be particularly beneficial in Wnt-inactive HCCs.
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http://dx.doi.org/10.1007/s12072-019-09977-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220899PMC
May 2020

Quality Assessment of the Preanalytical Workflow in Liquid Biobanking: Taurine as a Serum-Specific Quality Indicator for Preanalytical Process Variations.

Biopreserv Biobank 2019 Oct 24;17(5):458-467. Epub 2019 Jul 24.

Institute of Clinical Chemistry and Laboratory Diagnostics and Integrated Biobank Jena (IBBJ), Jena University Hospital, Jena, Germany.

The scientific impact of translational biomedical research largely depends on the availability of high-quality biomaterials. However, evidence-based and robust quality indicators (QIs) covering the most relevant preanalytical variations are still lacking. The aim of this study was to identify and validate a QI suitable for assessing time-to-centrifugation (TTC) delays in human liquid biospecimens originating from both healthy and diseased individuals. Serum and plasma samples with varying TTCs were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in a pilot cohort of healthy individuals to identify a suitable QI candidate. Taurine (TAU), as a TTC QI candidate, was validated in healthy individuals and patients with rheumatologic and cardiologic diseases, considering the (1) preanalytical handling temperature, (2) platelet count, and (3) postcentrifugation delay. For discrimination of high TTC (TTC >60 minutes) from low TTC serum specimens, a probability calculation tool was developed (Triple-T-cutoff-model). TTC-dependent changes in healthy individuals were observed for amino acids, particularly TAU. Validation of the TAU levels in an independent cohort of healthy individuals revealed a time-dependent increase in serum, but not in plasma, for a TTC delay of 30-240 minutes. TAU increases were dependent on the handling temperature and platelet count and volume. By contrast, no changes in TAU concentrations were observed for additional postcentrifugation delays. Validation of TAU and the Triple-T-cutoff-model, in rheumatologic/cardiologic patient collectives, allowed the discrimination of samples with TTC ≤60 min/>60 min with estimated AUROC (area under the receiver operating characteristic curve) values of 89% [78%-100%]/86% [71%-100%] and 91% [79%-100%]/84% [68%-100%], respectively. Considering the preanalytical handling temperature and platelet count and volume, TAU and the Triple-T-cutoff-model represent reliable QIs for TTC >60 minutes in serum samples from healthy individuals and selected rheumatologic/cardiologic patients. However, further studies in larger patient collectives with various diseases are needed to assess the robustness and potential of the QIs presented in this article as biobanking quality assurance/quality control tools to support high-quality biomedical research.
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http://dx.doi.org/10.1089/bio.2019.0004DOI Listing
October 2019

Self-reported diabetes and herpes zoster are associated with a weak humoral response to the seasonal influenza A H1N1 vaccine antigen among the elderly.

BMC Infect Dis 2019 Jul 23;19(1):656. Epub 2019 Jul 23.

Helmholtz Centre for Infection Research, Braunschweig, Germany.

Background: The immune response to seasonal influenza vaccines decreases with advancing age. Therefore, an adjuvanted inactivated trivalent influenza vaccine (Fluad®) exists for elderly individuals. Fluad® is more immunogenic and efficacious than conventional influenza vaccines. However, the immune response varies and may still result in high frequencies of poor responders. Therefore, we aimed to a) examine the prevalence of a weak response to Fluad® and b) identify potential risk factors.

Methods: A prospective population-based study among individuals 65-80 years old was conducted in 2015/2016 in Hannover, Germany (n = 200). Hemagglutination-inhibition titers 21 days after vaccination with Fluad® served as indicator of vaccine responsiveness.

Results: The percentage of vaccinees with an inadequate vaccine response varied depending on the influenza strain: it was lowest for H3N2 (13.5%; 95% CI, 9.4-18.9%), intermediate for B strain (37.0%; 30.6-43.9%), and highest for H1N1 (49.0%; 42.2-55.9%). The risk of a weak response to the influenza A H1N1 strain was independently associated with self-reported diabetes (AOR, 4.64; 95% CI, 1.16-18.54), a history of herpes zoster (2.27; 1.01-5.10) and, to a much lesser extent, increasing age (change per year, 1.08; 0.99-1.16). In addition, herpes zoster was the only risk factor for a weak response to the H3N2 antigen (AOR, 3.12; 1.18-8.23). We found no significant association between sex, Body Mass Index, cancer, hypertension, heart attack and CMV seropositivity and a weak response to these two influenza A antigens. Despite its occurence in over one third of vaccinees, none of the variables examined proved to be risk factors for a weak response to the B antigen.

Conclusions: A considerable proportion of elderly individuals displayed a weak vaccine response to this adjuvanted seasonal influenza vaccine and further efforts are thus needed to improve immune responses to influenza vaccination among the elderly. Diabetes and herpes zoster were identified as potentially modifiable risk factors for a poor vaccine response against influenza A antigens, but the results also reveal the need for broader investigations to identify risk factors for inadequate responses to influenza B antigens.

Trial Registration: No. NCT02362919 (ClinicalTrials.gov, date of registration: 09.02.2015).
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http://dx.doi.org/10.1186/s12879-019-4214-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651912PMC
July 2019

Whole blood microRNA levels associate with glycemic status and correlate with target mRNAs in pathways important to type 2 diabetes.

Sci Rep 2019 06 20;9(1):8887. Epub 2019 Jun 20.

Department of Clinical Chemistry, Pirkanmaa Hospital District, Fimlab Laboratories, and the Finnish Cardiovascular Research Center, Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

We analyzed the associations between whole blood microRNA profiles and the indices of glucose metabolism and impaired fasting glucose and examined whether the discovered microRNAs correlate with the expression of their mRNA targets. MicroRNA and gene expression profiling were performed for the Young Finns Study participants (n = 871). Glucose, insulin, and glycated hemoglobin (HbA1c) levels were measured, the insulin resistance index (HOMA2-IR) was calculated, and the glycemic status (normoglycemic [n = 534]/impaired fasting glucose [IFG] [n = 252]/type 2 diabetes [T2D] [n = 24]) determined. Levels of hsa-miR-144-5p, -122-5p, -148a-3p, -589-5p, and hsa-let-7a-5p associated with glycemic status. hsa-miR-144-5p and -148a-3p associated with glucose levels, while hsa-miR-144-5p, -122-5p, -184, and -339-3p associated with insulin levels and HOMA2-IR, and hsa-miR-148a-3p, -15b-3p, -93-3p, -146b-5p, -221-3p, -18a-3p, -642a-5p, and -181-2-3p associated with HbA1c levels. The targets of hsa-miR-146b-5p that correlated with its levels were enriched in inflammatory pathways, and the targets of hsa-miR-221-3p were enriched in insulin signaling and T2D pathways. These pathways showed indications of co-regulation by HbA1c-associated miRNAs. There were significant differences in the microRNA profiles associated with glucose, insulin, or HOMA-IR compared to those associated with HbA1c. The HbA1c-associated miRNAs also correlated with the expression of target mRNAs in pathways important to the development of T2D.
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http://dx.doi.org/10.1038/s41598-019-43793-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586838PMC
June 2019

Homozygous frame shift variant in ATP7B exon 1 leads to bypass of nonsense-mediated mRNA decay and to a protein capable of copper export.

Eur J Hum Genet 2019 06 5;27(6):879-887. Epub 2019 Feb 5.

Department of Human Genetics, Hannover Medical School, Hannover, Germany.

Wilson disease (WD) is an autosomal recessive disease of copper excess due to pathogenic variants in the ATP7B gene coding for a copper-transporting ATPase. We present a 5-year-old girl with the homozygous frame shift variant NM_000053.3: c.19_20del in exon 1 of ATP7B (consecutive exon numbering with c.1 as first nucleotide of exon 1), detected by whole-exome sequencing as a secondary finding. The variant leads to a premature termination codon in exon 2. The girl exhibited no WD symptoms and no abnormalities in liver biopsy. ATP7B liver mRNA expression was comparable to healthy controls suggesting that nonsense-mediated mRNA decay (NMD) could be bypassed by the mechanism of translation reinitiation. To verify this hypothesis, a CMV-driven ATP7B minigene (pcDNA3) was equipped with the authentic ATP7B 5' untranslated region  and a truncated intron 2. We introduced c.19_20del by site-directed mutagenesis and overexpressed the constructs in HEK293T cells. We analyzed ATP7B expression by qRT-PCR, northern and western blot, and examined protein function by copper export capacity assays. Northern blot, qRT-PCR, and western blot revealed that c.19_20del ATP7B mRNA and protein is expressed in size and amount comparable to wild-type. Copper export capacity was also comparable to wild-type. Our results indicate that c.19_20del in ATP7B is able to bypass NMD by translation reinitiation, demonstrating that the classification of truncating variants as pathogenic without additional investigations should be done carefully.
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http://dx.doi.org/10.1038/s41431-019-0345-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777614PMC
June 2019

Disentangling the genetics of lean mass.

Am J Clin Nutr 2019 02;109(2):276-287

Icelandic Heart Association Holtasmari, Kopavogur, Iceland.

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.

Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.

Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).

Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.

Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.
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http://dx.doi.org/10.1093/ajcn/nqy272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500901PMC
February 2019
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