Publications by authors named "Jeanette Erdmann"

251 Publications

A Novel Missense Mutation in Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family.

Genes (Basel) 2021 08 21;12(8). Epub 2021 Aug 21.

Institute for Cardiogenetics, University of Lübeck, 23562 Lübeck, Germany.

Cardiac conduction disease (CCD), which causes altered electrical impulse propagation in the heart, is a life-threatening condition with high morbidity and mortality. It exhibits genetic and clinical heterogeneity with diverse pathomechanisms, but in most cases, it disrupts the synchronous activity of impulse-generating nodes and impulse-conduction underlying the normal heartbeat. In this study, we investigated a consanguineous Pakistani family comprised of four patients with CCD. We applied whole exome sequencing (WES) and co-segregation analysis, which identified a novel homozygous missense mutation (c.1531T>C;(p.Ser511Pro)) in the highly conserved kinase domain of the cardiac troponin I-interacting kinase (TNNI3K) encoding gene. The behaviors of mutant and native TNNI3K were compared by performing all-atom long-term molecular dynamics simulations, which revealed changes at the protein surface and in the hydrogen bond network. Furthermore, intra and intermolecular interaction analyses revealed that p.Ser511Pro causes structural variation in the ATP-binding pocket and the homodimer interface. These findings suggest p.Ser511Pro to be a pathogenic variant. Our study provides insights into how the variant perturbs the TNNI3K structure-function relationship, leading to a disease state. This is the first report of a recessive mutation in and the first mutation in this gene identified in the Pakistani population.
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http://dx.doi.org/10.3390/genes12081282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395014PMC
August 2021

Identification of a Functional Variant at the Chromosome 4q27 Coronary Artery Disease Locus in an Extended Myocardial Infarction Family.

Circulation 2021 Aug 23;144(8):662-665. Epub 2021 Aug 23.

Department of Cardiology, German Heart Centre Munich (T.A.D., T.K., J.W., H.B.S., H.S.), Technical University of Munich, Germany.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052975DOI Listing
August 2021

The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets.

Nat Commun 2021 06 7;12(1):3352. Epub 2021 Jun 7.

Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany.

Platelets contribute to the regulation of tissue neovascularization, although the specific factors underlying this function are unknown. Here, we identified the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) on platelets as a negative regulatory mechanism of vessel formation. We showed that platelets expressing C5aR1 exert an inhibitory effect on endothelial cell functions such as migration and 2D and 3D tube formation. Growth factor- and hypoxia-driven vascularization was markedly increased in C5ar1 mice. Platelet-specific deletion of C5aR1 resulted in a proangiogenic phenotype with increased collateralization, capillarization and improved pericyte coverage. Mechanistically, we found that C5a induced preferential release of CXC chemokine ligand 4 (CXCL4, PF4) from platelets as an important antiangiogenic paracrine effector molecule. Interfering with the C5aR1-CXCL4 axis reversed the antiangiogenic effect of platelets both in vitro and in vivo.In conclusion, we identified a mechanism for the control of tissue neovascularization through C5a/C5aR1 axis activation in platelets and subsequent induction of the antiangiogenic factor CXCL4.
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http://dx.doi.org/10.1038/s41467-021-23499-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185003PMC
June 2021

Effect of Differences in the Microbiome of -Deficient Mice on Atherosclerotic Background.

Cells 2021 05 23;10(6). Epub 2021 May 23.

Institute for Cardiogenetics, University of Lübeck, 23562 Lübeck, Germany.

CYP17A1 is a cytochrome P450 enzyme that has 17-alpha-hydroxylase and C17,20-lyase activities. deficiency is associated with high body mass and visceral fat deposition in atherosclerotic female ApoE knockout (KO, d/d or -/-) mice. In the present study, we aimed to investigate the effects of diet and genotype on the gut microbiome. Female (d/d) × ApoE (d/d) (DKO) and ApoE (d/d) (controls) were fed either standard chow or a Western-type diet (WTD), and we demonstrated the effects of genetics and diet on the body mass of the mice and composition of their gut microbiome. We found a significantly lower alpha diversity after accounting for the ecological network structure in DKO mice and WTD-fed mice compared with chow-fed ApoE(d/d). Furthermore, we found a strong significant positive association of the vs. ratio with body mass and the circulating total cholesterol and triglyceride concentrations of the mice when feeding the WTD, independent of the genotype. Further pathway enrichment and network analyses revealed a substantial effect of genotype on associated cardiovascular and obesity-related pathways involving aspartate and L-arginine. Future studies are required to validate these findings and further investigate the role of aspartate/L-arginine pathways in the obesity and body fat distribution in our mouse model.
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http://dx.doi.org/10.3390/cells10061292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224745PMC
May 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

Cis-epistasis at the LPA locus and risk of cardiovascular diseases.

Cardiovasc Res 2021 Apr 20. Epub 2021 Apr 20.

Estonian Genome Center, Institute of Genomics, University of Tartu, 51010, Tartu, Estonia.

Aims: Coronary artery disease (CAD) has a strong genetic predisposition. However, despite substantial discoveries made by genome-wide association studies (GWAS), a large proportion of heritability awaits identification. Non-additive genetic-effects might be responsible for part of the unaccounted genetic variance. Here we attempted a proof-of-concept study to identify non-additive genetic effects, namely epistatic interactions, associated with CAD.

Methods And Results: We tested for epistatic interactions in ten CAD case-control studies and UK Biobank with focus on 8,068 SNPs at 56 loci with known associations with CAD risk. We identified a SNP pair located in cis at the LPA locus, rs1800769 and rs9458001, to be jointly associated with risk for CAD (odds ratio [OR]=1.37, p = 1.07 × 10-11), peripheral arterial disease (OR = 1.22, p = 2.32 × 10-4), aortic stenosis (OR = 1.47, p = 6.95 × 10-7), hepatic lipoprotein(a) (Lp(a)) transcript levels (beta = 0.39, p = 1.41 × 10-8), and Lp(a) serum levels (beta = 0.58, p = 8.7 × 10-32), while individual SNPs displayed no association. Further exploration of the LPA locus revealed a strong dependency of these associations on a rare variant, rs140570886, that was previously associated with Lp(a) levels. We confirmed increased CAD risk for heterozygous (relative OR = 1.46, p = 9.97 × 10-32) and individuals homozygous for the minor allele (relative OR = 1.77, p = 0.09) of rs140570886. Using forward model selection, we also show that epistatic interactions between rs140570886, rs9458001, and rs1800769 modulate the effects of the rs140570886 risk allele.

Conclusions: These results demonstrate the feasibility of a large-scale knowledge-based epistasis scan and provide rare evidence of an epistatic interaction in a complex human disease. We were directed to a variant (rs140570886) influencing risk through additive genetic as well as epistatic effects. In summary, this study provides deeper insights into the genetic architecture of a locus important for cardiovascular diseases.

Translational Perspective: Genetic variants identified by GWAS studies explain about a quarter of the heritability of coronary artery disease by additive genetic effects. Our study demonstrates that non-additive effects contribute to the genetic architecture of the disease as well and identifies complex interaction patterns at the LPA locus, which affect LPA expression, Lp(a) plasma levels and risk of atherosclerosis. This proof-of-concept study encourages systematic searches for epistatic interactions in further studies to shed new light on the aetiology of the disease.
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http://dx.doi.org/10.1093/cvr/cvab136DOI Listing
April 2021

A proteomic atlas of the neointima identifies novel druggable targets for preventive therapy.

Eur Heart J 2021 05;42(18):1773-1785

Department of Cardiology, German Heart Centre Munich, Technical University of Munich, Munich, Germany.

Aims: In-stent restenosis is a complication after coronary stenting associated with morbidity and mortality. Here, we sought to investigate the molecular processes underlying neointima formation and to identify new treatment and prevention targets.

Methods And Results: Neointima formation was induced by wire injury in mouse femoral arteries. High-accuracy proteomic measurement of single femoral arteries to a depth of about 5000 proteins revealed massive proteome remodelling, with more than half of all proteins exhibiting expression differences between injured and non-injured vessels. We observed major changes in the composition of the extracellular matrix and cell migration processes. Among the latter, we identified the classical transient receptor potential channel 6 (TRPC6) to drive neointima formation. While Trpc6-/- mice presented reduced neointima formation compared to wild-type mice (1.44 ± 0.39 vs. 2.16 ± 0.48, P = 0.01), activating or repressing TRPC6 in human vascular smooth muscle cells resulted in increased [vehicle 156.9 ± 15.8 vs. 1-oleoyl-2-acetyl-sn-glycerol 179.1 ± 8.07 (103 pixels), P = 0.01] or decreased migratory capacity [vehicle 130.0 ± 26.1 vs. SAR7334 111.4 ± 38.0 (103 pixels), P = 0.04], respectively. In a cohort of individuals with angiographic follow-up (n = 3068, males: 69.9%, age: 59 ± 11 years, follow-up 217.1 ± 156.4 days), homozygous carriers of a common genetic variant associated with elevated TRPC6 expression were at increased risk of restenosis after coronary stenting (adjusted odds ratio 1.49, 95% confidence interval 1.08-2.05; P = 0.01).

Conclusions: Our study provides a proteomic atlas of the healthy and injured arterial wall that can be used to define novel factors for therapeutic targeting. We present TRPC6 as an actionable target to prevent neointima formation secondary to vascular injury and stent implantation.
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http://dx.doi.org/10.1093/eurheartj/ehab140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104955PMC
May 2021

Induced Pluripotent Stem Cells (iPSCs) in Vascular Research: from Two- to Three-Dimensional Organoids.

Stem Cell Rev Rep 2021 10 18;17(5):1741-1753. Epub 2021 Mar 18.

Institute for Cardiogenetics, University of Luebeck, Ratzeburger Allee 160, 23562, Luebeck, Germany.

Stem cell technology has been around for almost 30 years and in that time has grown into an enormous field. The stem cell technique progressed from the first successful isolation of mammalian embryonic stem cells (ESCs) in the 1990s, to the production of human induced-pluripotent stem cells (iPSCs) in the early 2000s, to finally culminate in the differentiation of pluripotent cells into highly specialized cell types, such as neurons, endothelial cells (ECs), cardiomyocytes, fibroblasts, and lung and intestinal cells, in the last decades. In recent times, we have attained a new height in stem cell research whereby we can produce 3D organoids derived from stem cells that more accurately mimic the in vivo environment. This review summarizes the development of stem cell research in the context of vascular research ranging from differentiation techniques of ECs and smooth muscle cells (SMCs) to the generation of vascularized 3D organoids. Furthermore, the different techniques are critically reviewed, and future applications of current 3D models are reported.
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http://dx.doi.org/10.1007/s12015-021-10149-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972819PMC
October 2021

sGC Activity and Regulation of Blood Flow in a Zebrafish Model System.

Front Physiol 2021 25;12:633171. Epub 2021 Feb 25.

Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.

Soluble guanylyl cyclase (sGC) protein is a heterodimer formed by two subunits encoded by and genes. The chromosomal locus 4q32.1 harbors both of these genes, which has been previously significantly associated with coronary artery disease, myocardial infarction, and high blood pressure. Blood pressure is influenced by both the environment and genetics and is complemented by several biological pathways. The underlying mechanisms associated with this locus and its genes still need to be investigated. In the current study, we aimed to establish the zebrafish as a model organism to investigate the mechanisms surrounding sGC activity and blood pressure. A zebrafish mutant line was generated using the CRISPR-Cas9 system by inducing a 4-bp deletion frameshift mutation. This mutation resulted in a reduction of expression in both heterozygote and homozygote zebrafish. Blood flow parameters (blood flow, arterial pulse, linear velocity, and vessel diameter) investigated in the mutants showed a significant increase in blood flow and linear velocity, which was augmented in the homozygotes. No significant differences were observed for the blood flow parameters measured from larvae with individual morpholino downregulation of and , but an increase in blood flow and linear velocity was observed after co-morpholino downregulation of both genes. In addition, the pharmacological sGC stimulator BAY41-2272 rescued the impaired cGMP production in the zebrafish mutant larvae. Downregulation of gene did not show any significant difference on the blood flow parameters in both wild-type and background larvae. In summary, we successfully established a zebrafish platform for investigating sGC-associated pathways and underlying mechanisms in depth. This model system will have further applications, including for potential drug screening experiments.
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http://dx.doi.org/10.3389/fphys.2021.633171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946990PMC
February 2021

Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23.

Eur Heart J 2021 05;42(20):2000-2011

Université de Paris, INSERM, UMR-S970, Integrative Epidemiology of cardiovascular disease, Paris, France.

Aims: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure.

Methods And Results: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene.

Conclusion: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
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http://dx.doi.org/10.1093/eurheartj/ehab030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139853PMC
May 2021

The CAD risk locus 9p21 increases the risk of vascular calcification in an iPSC-derived VSMC model.

Stem Cell Res Ther 2021 03 6;12(1):166. Epub 2021 Mar 6.

Institute for Cardiogenetics, University of Luebeck, Ratzeburger Allee 160, 23562, Luebeck, Germany.

Background: Coronary artery disease (CAD) is the leading cause of death worldwide. Chromosome locus 9p21 was the first to be associated with increased risk of CAD and coronary artery calcification (CAC). Vascular calcification increases the risk for CAD. Vascular smooth muscle cells (VSMCs) are one of the major cell types involved in the development of vascular calcification.

Methods: So far, mainly animal models or primary SMCs have been used to model human vascular calcification. In this study, a human in vitro assay using iPSC-derived VSMCs was developed to examine vascular calcification. Human iPSCs were derived from a healthy non-risk (NR) and risk (R) donor carrying SNPs in the 9p21 locus. Additionally, 9p21 locus knockouts of each donor iPSC line (NR and R) were used. Following differentiation, the iPSC-derived VSMCs were characterized based on cell type, proliferation, and migration rate, along with calcium phosphate (CaP) deposits. CaP deposits were confirmed using Calcein and Alizarin Red S staining and then quantified.

Results: The data demonstrated significantly more proliferation, migration, and CaP deposition in VSMCs derived from the R and both KO iPSC lines than in those derived from the NR line. Molecular analyses confirmed upregulation of calcification markers. These results are consistent with recent data demonstrating increased calcification when the 9p21 murine ortholog is knocked-out.

Conclusion: Therefore, in conclusion, genetic variation or deletion of the CAD risk locus leads to an increased risk of vascular calcification. This in vitro human iPSC model of calcification could be used to develop new drug screening strategies to combat CAC.
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http://dx.doi.org/10.1186/s13287-021-02229-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936418PMC
March 2021

Current Developments of Clinical Sequencing and the Clinical Utility of Polygenic Risk Scores in Inflammatory Diseases.

Front Immunol 2020 29;11:577677. Epub 2021 Jan 29.

Department of Dermatology, Quincke Research Center, University Hospital Schleswig-Holstein, Kiel, Germany.

In this mini-review, we highlight selected research by the Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence "Precision Medicine in Chronic Inflammation" focusing on clinical sequencing and the clinical utility of polygenic risk scores as well as its implication on precision medicine in the field of the inflammatory diseases inflammatory bowel disease, atopic dermatitis and coronary artery disease. Additionally, we highlight current developments and discuss challenges to be faced in the future. Exemplary, we point to residual challenges in detecting disease-relevant variants resulting from difficulties in the interpretation of candidate variants and their potential interactions. While polygenic risk scores represent promising tools for the stratification of patient groups, currently, polygenic risk scores are not accurate enough for clinical setting. Precision medicine, incorporating additional data from genomics, transcriptomics and proteomics experiments, may enable the identification of distinct disease pathogeneses. In the future, data-intensive biomedical innovation will hopefully lead to improved patient stratification for personalized medicine.
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http://dx.doi.org/10.3389/fimmu.2020.577677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901950PMC
June 2021

Unfolding and disentangling coronary vascular disease through genome-wide association studies.

Eur Heart J 2021 03;42(9):934-937

Laboratory of Clinical Chemistry and Hematology, Division of Laboratories and Pharmacy, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.

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http://dx.doi.org/10.1093/eurheartj/ehaa1089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936521PMC
March 2021

What can we learn from common variants associated with unexpected phenotypes in rare genetic diseases?

Authors:
Jeanette Erdmann

Orphanet J Rare Dis 2021 01 21;16(1):41. Epub 2021 Jan 21.

Institute for Cardiogenetics, University of Lübeck, Ratzeburger Allee 160, Building 67, 23562, Lübeck, Germany.

The purpose of this article is to stimulate discussion about whether a phenome-wide association study is a suitable tool for uncovering late-onset risks in patients with monogenic disorders that are not yet fully recognized because the life expectancy of people with such conditions has only recently extended, and they now reach older ages when they may develop additional complications.
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http://dx.doi.org/10.1186/s13023-021-01684-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818908PMC
January 2021

Qtlizer: comprehensive QTL annotation of GWAS results.

Sci Rep 2020 11 24;10(1):20417. Epub 2020 Nov 24.

Institute for Cardiogenetics, University of Lübeck, 23562, Lübeck, Germany.

Exploration of genetic variant-to-gene relationships by quantitative trait loci such as expression QTLs is a frequently used tool in genome-wide association studies. However, the wide range of public QTL databases and the lack of batch annotation features complicate a comprehensive annotation of GWAS results. In this work, we introduce the tool "Qtlizer" for annotating lists of variants in human with associated changes in gene expression and protein abundance using an integrated database of published QTLs. Features include incorporation of variants in linkage disequilibrium and reverse search by gene names. Analyzing the database for base pair distances between best significant eQTLs and their affected genes suggests that the commonly used cis-distance limit of 1,000,000 base pairs might be too restrictive, implicating a substantial amount of wrongly and yet undetected eQTLs. We also ranked genes with respect to the maximum number of tissue-specific eQTL studies in which a most significant eQTL signal was consistent. For the top 100 genes we observed the strongest enrichment with housekeeping genes (P = 2 × 10) and with the 10% highest expressed genes (P = 0.005) after grouping eQTLs by r > 0.95, underlining the relevance of LD information in eQTL analyses. Qtlizer can be accessed via https://genehopper.de/qtlizer or by using the respective Bioconductor R-package ( https://doi.org/10.18129/B9.bioc.Qtlizer ).
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http://dx.doi.org/10.1038/s41598-020-75770-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687904PMC
November 2020

Population Bias in Polygenic Risk Prediction Models for Coronary Artery Disease.

Circ Genom Precis Med 2020 12 10;13(6):e002932. Epub 2020 Nov 10.

Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck (D.G., I.R.K.).

Background: Individual risk prediction based on genome-wide polygenic risk scores (PRSs) using millions of genetic variants has attracted much attention. It is under debate whether PRS models can be applied-without loss of precision-to populations of similar ethnic but different geographic background than the one the scores were trained on. Here, we examine how PRS trained in population-specific but European data sets perform in other European subpopulations in distinguishing between coronary artery disease patients and healthy individuals.

Methods: We use data from UK and Estonian biobanks (UKB, EB) as well as case-control data from the German population (DE) to develop and evaluate PRS in the same and different populations.

Results: PRSs have the highest performance in their corresponding population testing data sets, whereas their performance significantly drops if applied to testing data sets from different European populations. Models trained on DE data revealed area under the curves in independent testing sets in DE: 0.6752, EB: 0.6156, and UKB: 0.5989; trained on EB and tested on EB: 0.6565, DE: 0.5407, and UKB: 0.6043; trained on UKB and tested on UKB: 0.6133, DE: 0.5143, and EB: 0.6049.

Conclusions: This result has a direct impact on the clinical usability of PRS for risk prediction models using PRS: a population effect must be kept in mind when applying risk estimation models, which are based on additional genetic information even for individuals from different European populations of the same ethnicity.
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http://dx.doi.org/10.1161/CIRCGEN.120.002932DOI Listing
December 2020

Studies in Zebrafish Demonstrate That and Are Most Likely the Causal Genes at the Blood Pressure-Associated Locus on Human Chromosome 10q24.32.

Front Cardiovasc Med 2020 2;7:135. Epub 2020 Sep 2.

Institute for Cardiogenetics, University of Luebeck, Luebeck, Germany.

Globally, high blood pressure (BP) is the most important risk factor for cardiovascular disease. Several genome-wide association studies (GWAS) have identified variants associated with BP traits at more than 535 chromosomal loci with genome-wide significance. The post-GWAS challenge is to annotate the most likely causal gene(s) at each locus. Chromosome 10q24.32 is a locus associated with BP that encompasses five genes: , and and warrants investigation to determine the specific gene or genes responsible for the phenotype. To identify the most likely causal gene(s) associated with BP at the 10q24.32 locus using zebrafish as an animal model. We report significantly higher blood flow, increased arterial pulse, and elevated linear velocity in zebrafish larvae with and knocked down using gene-specific splice modification transcriptional morpholinos, compared with controls. No differences in blood-flow parameters were observed after , or knockdown. There was no effect on vessel diameter in animals with any of the four genes knocked down. At the molecular level, expression of hypertension markers ( and ) was significantly increased in and knockdown larvae. Further, the results obtained by morpholino knockdown were validated using zebrafish knockout (KO) lines with and deficiency, again resulting in higher blood flow, increased arterial pulse, and elevated linear velocity. Analysis of KO larvae demonstrated that lack of this gene resulted in reduced expression of , with reciprocal downregulation of in KO larvae. Staining of whole-blood smears from mutants revealed that KO of this gene might be associated with an acute lymphoblastic leukemia phenotype, consistent with literature reports. Additional experiments were designed based on previous literature on mutant zebrafish revealed impaired renal function, high levels of renin, and significantly increased expression of the gene, leading us to hypothesize that the observed elevated blood-flow parameters may be attributable to triggering of the renin-angiotensin-aldosterone signaling pathway. Our zebrafish data establish and as the most likely causal genes at the 10q24.32 BP locus and indicate that they trigger separate downstream mechanistic pathways.
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http://dx.doi.org/10.3389/fcvm.2020.00135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492806PMC
September 2020

Heterozygous Gene Deficiency and Risk of Coronary Artery Disease.

Circ Genom Precis Med 2020 10 30;13(5):417-423. Epub 2020 Aug 30.

Center for Genomic Medicine (C.A.E., P.N., N.G., S.G., A.V.K., S.K.), Massachusetts General Hospital, Boston.

Background: Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency-homozygous loss-of-function (LoF) variants-in the or genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of or -as occurs in heterozygous carriers of LoF variants-on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.

Methods: We first recruited 9 sitosterolemia families, identified causative LoF variants in or , and evaluated the associations of these or LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in or in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in or with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1% in or .

Results: In sitosterolemia families, 7 pedigrees harbored causative LoF variants in and 2 pedigrees in . Homozygous LoF variants in either or led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in and in was ≈0.1% each. heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14-35]; =1.1×10) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27-3.35]; =0.004). By contrast, heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.

Conclusions: Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.
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http://dx.doi.org/10.1161/CIRCGEN.119.002871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983048PMC
October 2020

Increased Serum Levels of Asymmetric Dimethylarginine and Symmetric Dimethylarginine and Decreased Levels of Arginine in Sudanese Patients with Essential Hypertension.

Kidney Blood Press Res 2020 19;45(5):727-736. Epub 2020 Aug 19.

Department of Biochemistry, Faculty of Medicine, University of Khartoum, Khartoum, Sudan.

Introduction: Essential hypertension (EH) is a disease caused by various environmental and genetic factors. Nitric oxide (NO) is important for the functional integrity of the endothelium. It is produced in endothelial cells by endothelial NO synthase (eNOS) that mediates the conversion of the amino acid arginine into NO and citrulline. Asymmetric dimethylarginine (ADMA) acts as an inhibitor of eNOS. In contrast, symmetric dimethylarginine (SDMA) has no direct effect on eNOS but plays an important role competing with arginine for transport across the amino acid transporter. ADMA and SDMA have been found to play a central role in the development of cardiovascular diseases. Serum ADMA levels may serve as a future diagnostic marker and a target of therapy in hypertensive patients in the Sudanese population. This study aimed to investigate the relation between serum arginine, ADMA, and SDMA levels with EH in the Sudanese population.

Methods: Patients (n = 260) with established hypertension and controls (n = 144) with normal blood pressure were included in this case-control study. Serum blood samples were analyzed for arginine, ADMA, and SDMA, using high-performance liquid chromatography-tandem mass spectrometry. Other laboratory data were measured using routine methods. Mann-Whitney's U test and χ2 tests were used for continuous and categorical data, respectively. A multivariate logistic regression analysis was conducted to investigate the independent effect of multiple variables on the development of hypertension.

Results: Serum arginine levels were significantly lower in the patient group than in the control group (p < 0.001). ADMA and SDMA levels were significantly higher in the patient group than the control group (p < 0.001, p = 0.001, respectively). Multivariate logistic regression analysis showed that only older age, being a male, and arginine levels are independent factors controlling the development of hypertension (p < 0.001, p < 0.001, and p = 0.046, respectively). ADMA and SDMA levels were not independent factors for the development of hypertension.

Conclusions: This study demonstrated increased serum levels of ADMA and SDMA and decreased arginine levels in Sudanese patients with EH. Lowering serum ADMA levels or increasing the arginine levels might be a novel therapeutic target in these individuals.
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http://dx.doi.org/10.1159/000508695DOI Listing
May 2021

New technologies for intensive prevention programs after myocardial infarction: rationale and design of the NET-IPP trial.

Clin Res Cardiol 2021 Feb 30;110(2):153-161. Epub 2020 Jul 30.

Medical Clinic II, Lübeck University Heart Center, Ratzeburger Allee 160, 23538, Lübeck, Germany.

Introduction: Current health care data reveal suboptimal prevention in patients with coronary artery disease and an unmet need to develop effective preventive strategies. The New Technologies for Intensive Prevention Programs (NET-IPP) Trial will investigate if a long-term web-based prevention program after myocardial infarction (MI) will reduce clinical events and risk factors. In a genetic sub study the impact of disclosure of genetic risk using polygenic risk scores (PRS) will be assessed.

Study Design: Patients hospitalized for MI will be prospectively enrolled and assigned to either a 12-months web-based intensive prevention program or standard care. The web-based program will include telemetric transmission of risk factor data, e-learning and electronic contacts between a prevention assistant and the patients. The combined primary study endpoint will comprise severe adverse cardiovascular events after 2 years. Secondary endpoints will be risk factor control, adherence to medication and quality of life. In a genetic sub study genetic risk will be assessed in all patients of the web-based intensive prevention program group by PRS and patients will be randomly assigned to genetic risk disclosure vs. no disclosure. The study question will be if disclosure of genetic risk has an impact on patient motivation and cardiovascular risk factor control.

Conclusions: The randomized multicenter NET-IPP study will evaluate for the first time the effects of a long-term web-based prevention program after MI on clinical events and risk factor control. In a genetic sub study the impact of disclosure of genetic risk using PRS will be investigated.
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http://dx.doi.org/10.1007/s00392-020-01695-wDOI Listing
February 2021

Dare to Compare. Development of Atherosclerotic Lesions in Human, Mouse, and Zebrafish.

Front Cardiovasc Med 2020 30;7:109. Epub 2020 Jun 30.

Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.

Cardiovascular diseases, such as atherosclerosis, are the leading cause of death worldwide. Although mice are currently the most commonly used model for atherosclerosis, zebrafish are emerging as an alternative, especially for inflammatory and lipid metabolism studies. Here, we review the history of atherosclerosis models and highlight the potential for future studies on inflammatory responses in lipid deposits in zebrafish, based on known immune reactions in humans and mice, in anticipation of new zebrafish models with more advanced atherosclerotic plaques.
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http://dx.doi.org/10.3389/fcvm.2020.00109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344238PMC
June 2020

Genomewide Association Study of Severe Covid-19 with Respiratory Failure.

N Engl J Med 2020 10 17;383(16):1522-1534. Epub 2020 Jun 17.

From the Institute of Clinical Molecular Biology, Christian-Albrechts-University (D.E., F.D., J.K., S. May, M. Wendorff, L.W., F.U.-W., X.Y., A.T., A. Peschuck, C.G., G.H.-S., H.E.A., M.C.R., M.E.F.B., M. Schulzky, M. Wittig, N.B., S.J., T.W., W.A., M. D'Amato, A.F.), and University Hospital Schleswig-Holstein, Campus Kiel (N.B., A.F.), Kiel, the Institute for Cardiogenetics, University of Lübeck, Lübeck (J.E.), the German Research Center for Cardiovascular Research, partner site Hamburg-Lübeck-Kiel (J.E.), the University Heart Center Lübeck (J.E.), and the Institute of Transfusion Medicine, University Hospital Schleswig-Holstein (S.G.), Lübeck, Stefan-Morsch-Stiftung, Birkenfeld (M. Schaefer, W.P.), and the Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Plön (O.O., T.L.L.) - all in Germany; Novo Nordisk Foundation Center for Protein Research, Disease Systems Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen (D.E.); the Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute-Donostia University Hospital-University of the Basque Country (L.B., K.G.-E., L.I.-S., P.M.R., J.M.B.), Osakidetza Basque Health Service, Donostialdea Integrated Health Organization, Clinical Biochemistry Department (A.G.C., B.N.J.), and the Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute (M. D'Amato), San Sebastian, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III (L.B., M. Buti, A. Albillos, A. Palom, F.R.-F., B.M., L. Téllez, K.G.-E., L.I.-S., F.M., L.R., M.R.-B., M. Rodríguez-Gandía, P.M.R., M. Romero-Gómez, J.M.B.), the Departments of Gastroenterology (A. Albillos, B.M., L. Téllez, F.M., M. Rodríguez-Gandía), Intensive Care (R.P., A.B.O.), Respiratory Diseases (D.J., A.S., R.N.), Infectious Diseases (C.Q., E.N.), and Anesthesiology (D. Pestaña, N. Martínez), Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, University of Alcalá, and Histocompatibilidad y Biologia Molecular, Centro de Transfusion de Madrid (F.G.S.), Madrid, the Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus (M. Buti, A. Palom, L.R., M.R.-B.), Hospital Clinic, University of Barcelona, and the August Pi i Sunyer Biomedical Research Institute (J.F., F.A., E.S., J.F.-A., L.M., M.H.-T., P.C.), the European Foundation for the Study of Chronic Liver Failure (J.F.), Vall d'Hebron Institut de Recerca (A. Palom, F.R.-F., A.J., S. Marsal), and the Departments of Biochemistry (A.-E.G.-F., F.R.-F., A.C.-G., C.C., A.B.-G.), Intensive Care (R.F.), and Microbiology (T.P.), University Hospital Vall d'Hebron, the Immunohematology Department, Banc de Sang i Teixits, Autonomous University of Barcelona (E.M.-D.), Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, Consortium for Biomedical Research in Epidemiology and Public Health and University of Barcelona, l'Hospitalet (V. Moreno), and Autonoma University of Barcelona (T.P.), Barcelona, Universitat Autònoma de Barcelona, Bellatera (M. Buti, F.R.-F., M.R.-B.), GenomesForLife-GCAT Lab Group, Germans Trias i Pujol Research Institute (A.C.N., I.G.-F., R.C.), and High Content Genomics and Bioinformatics Unit, Germans Trias i Pujol Research Institute (L. Sumoy), Badalona, Institute of Parasitology and Biomedicine Lopez-Neyra, Granada (J.M., M.A.-H.), the Digestive Diseases Unit, Virgen del Rocio University Hospital, Institute of Biomedicine of Seville, University of Seville, Seville (M. Romero-Gómez), and Ikerbasque, Basque Foundation for Science, Bilbao (M. D'Amato, J.M.B.) - all in Spain; the Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca (P.I., C.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (D. Prati, G.B., A.Z., A. Bandera, A.G., A.L.F., A. Pesenti, C.P., F.C., F.M.-B., F.P., F.B., G.G., G. Costantino, L. Terranova, L. Santoro, L. Scudeller, M. Carrabba, M. Baldini, M.M., N. Montano, R.G., S.P., S. Aliberti, V. Monzani, S. Bosari, L.V.), the Department of Biomedical Sciences, Humanitas University (R.A., A. Protti, A. Aghemo, A. Lleo, E.M.P., G. Cardamone, M. Cecconi, V.R., S.D.), Humanitas Clinical and Research Center, IRCCS (R.A., A. Protti, A. Aghemo, A. Lleo, A.V., C.A., E.M.P., H.K., I.M., M. Cecconi, M. Ciccarelli, M. Bocciolone, P.P., P.O., P.T., S. Badalamenti, S.D.), University of Milan (A.Z., A. Bandera, A.G., A.L.F., A. Pesenti, F.M.-B., F.P., F.B., G.G., G. Costantino, M.M., N. Montano, R.G., S.P., S. Aliberti, S. Bosari, L.V.), and the Center of Bioinformatics, Biostatistics, and Bioimaging (M.G.V.) and the Phase 1 Research Center (M. Cazzaniga), School of Medicine and Surgery, and the Departments of Emergency, Anesthesia, and Intensive Care (G.F.), Pneumologia (P.F.), and Infectious Diseases (P.B.); University of Milano-Bicocca, Milan, the European Reference Network on Hepatological Diseases (P.I., C.M.) and the Infectious Diseases Unit (P.B.), San Gerardo Hospital, Monza, the Pediatric Departement and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM-Ospedale, San Gerardo (A. Biondi, L.R.B., M. D'Angiò), the Gastroenterology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (A. Latiano, O.P.), the Department of Medical Sciences, Università degli Studi di Torino, Turin (S. Aneli, G.M.), and the Italian Bone Marrow Donor Registry, E.O. Ospedali Galliera, Genoa (N.S.) - all in Italy; the Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases, and Transplantation, and the Research Institute for Internal Medicine, Division of Surgery, Inflammatory Diseases, and Transplantation, Oslo University Hospital Rikshospitalet and University of Oslo (M.M.G., J.R.H., T.F., T.H.K.), and the Section for Gastroenterology, Department of Transplantation Medicine, Division for Cancer Medicine, Surgery, and Transplantation, Oslo University Hospital Rikshospitalet (J.R.H., T.F., T.H.K.), Oslo; the School of Biological Sciences, Monash University, Clayton, VIC, Australia (T.Z., M. D'Amato); Private University in the Principality of Liechtenstein (C.G.); the Institute of Biotechnology, Vilnius University, Vilnius, Lithuania (S.J.); and the Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm (M. D'Amato).

Background: There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19.

Methods: We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case-control panels.

Results: We detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10) in the meta-analysis of the two case-control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P = 1.15×10; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P = 4.95×10, respectively). At locus 3p21.31, the association signal spanned the genes , , , , and . The association signal at locus 9q34.2 coincided with the blood group locus; in this cohort, a blood-group-specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P = 1.48×10) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P = 1.06×10).

Conclusions: We identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.).
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http://dx.doi.org/10.1056/NEJMoa2020283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315890PMC
October 2020

CYP17A1 deficient XY mice display susceptibility to atherosclerosis, altered lipidomic profile and atypical sex development.

Sci Rep 2020 05 29;10(1):8792. Epub 2020 May 29.

Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.

CYP17A1 is a cytochrome P450 enzyme with 17-alpha-hydroxylase and C17,20-lyase activities. CYP17A1 genetic variants are associated with coronary artery disease, myocardial infarction and visceral and subcutaneous fat distribution; however, the underlying pathological mechanisms remain unknown. We aimed to investigate the function of CYP17A1 and its impact on atherosclerosis in mice. At 4-6 months, CYP17A1-deficient mice were viable, with a KO:Het:WT ratio approximating the expected Mendelian ratio of 1:2:1. All Cyp17a1 knockout (KO) mice were phenotypically female; however, 58% were Y chromosome-positive, resembling the phenotype of human CYP17A1 deficiency, leading to 46,XY differences/disorders of sex development (DSD). Both male and female homozygous KO mice were infertile, due to abnormal genital organs. Plasma steroid analyses revealed a complete lack of testosterone in XY-KO mice and marked accumulation of progesterone in XX-KO mice. Elevated corticosterone levels were observed in both XY and XX KO mice. In addition, Cyp17a1 heterozygous mice were also backcrossed onto an Apoe KO atherogenic background and fed a western-type diet (WTD) to study the effects of CYP17A1 on atherosclerosis. Cyp17a1 x Apoe double KO XY mice developed more atherosclerotic lesions than Apoe KO male controls, regardless of diet (standard or WTD). Increased atherosclerosis in CYP17A1 XY KO mice lacking testosterone was associated with altered lipid profiles. In mice, CYP17A1 deficiency interferes with sex differentiation. Our data also demonstrate its key role in lipidomic profile, and as a risk factor in the pathogenesis of atherosclerosis.
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http://dx.doi.org/10.1038/s41598-020-65601-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260244PMC
May 2020

Retraction notice to "Differentiation of human iPSCs into VSMCs and generation of VSMC-derived calcifying vascular cells" [Stem Cell Res. 31 (2018) 62-70].

Stem Cell Res 2020 05 24;45:101830. Epub 2020 May 24.

Institute for Cardiogenetics, University of Luebeck, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Germany; University Heart Centre Luebeck, 23562 Luebeck, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.scr.2020.101830DOI Listing
May 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

A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.

PLoS Genet 2020 04 13;16(4):e1008629. Epub 2020 Apr 13.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.
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http://dx.doi.org/10.1371/journal.pgen.1008629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200007PMC
April 2020

White Blood Cells and Blood Pressure: A Mendelian Randomization Study.

Circulation 2020 04 9;141(16):1307-1317. Epub 2020 Mar 9.

Department of Internal and Agricultural Medicine, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland (M.S., E.J., T.J.G.).

Background: High blood pressure (BP) is a risk factor for cardiovascular morbidity and mortality. While BP is regulated by the function of kidney, vasculature, and sympathetic nervous system, recent experimental data suggest that immune cells may play a role in hypertension.

Methods: We studied the relationship between major white blood cell types and blood pressure in the UK Biobank population and used Mendelian randomization (MR) analyses using the ≈750 000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies to examine which leukocyte populations may be causally linked to BP.

Results: A positive association between quintiles of lymphocyte, monocyte, and neutrophil counts, and increased systolic BP, diastolic BP, and pulse pressure was observed (eg, adjusted systolic BP mean±SE for 1st versus 5th quintile respectively: 140.13±0.08 versus 141.62±0.07 mm Hg for lymphocyte, 139.51±0.08 versus 141.84±0.07 mm Hg for monocyte, and 137.96±0.08 versus 142.71±0.07 mm Hg for neutrophil counts; all <10). Using 121 single nucleotide polymorphisms in MR, implemented through the inverse-variance weighted approach, we identified a potential causal relationship of lymphocyte count with systolic BP and diastolic BP (causal estimates: 0.69 [95% CI, 0.19-1.20] and 0.56 [95% CI, 0.23-0.90] of mm Hg per 1 SD genetically elevated lymphocyte count, respectively), which was directionally concordant to the observational findings. These inverse-variance weighted estimates were consistent with other robust MR methods. The exclusion of rs3184504 SNP in the locus attenuated the magnitude of the signal in some of the MR analyses. MR in the reverse direction found evidence of positive effects of BP indices on counts of monocytes, neutrophils, and eosinophils but not lymphocytes or basophils. Subsequent MR testing of lymphocyte count in the context of genetic correlation with renal function or resting and postexercise heart rate demonstrated a positive association of lymphocyte count with urine albumin-to-creatinine ratio.

Conclusions: Observational and genetic analyses demonstrate a concordant, positive and potentially causal relationship of lymphocyte count with systolic BP and diastolic BP.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.045102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176352PMC
April 2020

miR-128a Acts as a Regulator in Cardiac Development by Modulating Differentiation of Cardiac Progenitor Cell Populations.

Int J Mol Sci 2020 Feb 10;21(3). Epub 2020 Feb 10.

Department of Cardiovascular Surgery, German Heart Center Munich at the Technische Universität München, 80636 Munich, Germany.

MicroRNAs (miRs) appear to be major, yet poorly understood players in regulatory networks guiding cardiogenesis. We sought to identify miRs with unknown functions during cardiogenesis analyzing the miR-profile of multipotent enhancer cardiac progenitor cells (NkxCE-CPCs). Besides well-known candidates such as miR-1, we found about 40 miRs that were highly enriched in NkxCE-CPCs, four of which were chosen for further analysis. Knockdown in zebrafish revealed that only miR-128a affected cardiac development and function robustly. For a detailed analysis, loss-of-function and gain-of-function experiments were performed during in vitro differentiations of transgenic murine pluripotent stem cells. MiR-128a knockdown (1) increased , , and (cardiac transcription factors) but reduced at the onset of cardiogenesis, (2) upregulated -positive CPCs, whereas NkxCE-positive CPCs were downregulated, and (3) increased the expression of the ventricular cardiomyocyte marker accompanied by a reduced beating frequency of early cardiomyocytes. Overexpression of miR-128a (4) diminished the expression of , , , and , but increased , (5) enhanced NkxCE-positive CPCs, and (6) favored nodal-like cardiomyocytes (, , ) accompanied by increased beating frequencies. In summary, we demonstrated that miR-128a plays a so-far unknown role in early heart development by affecting the timing of CPC differentiation into various cardiomyocyte subtypes.
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http://dx.doi.org/10.3390/ijms21031158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038042PMC
February 2020
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