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RL-SKAT: An exact and efficient score test for heritability and set tests [article]

Regev Schweiger, Omer Weissbrod, Elior Rahmani, Martina Müller-Nurasyid, Sonja Kunze, Christian Gieger, Melanie Waldenberger, Saharon Rosset, Eran Halperin
<span title="2017-06-03">2017</span> <i title="Cold Spring Harbor Laboratory"> bioRxiv </i> &nbsp; <span class="release-stage" >pre-print</span>
Testing for the existence of variance components in linear mixed models is a fundamental task in many applicative fields. In statistical genetics, the score test has recently become instrumental in the task of testing an association between a set of genetic markers and a phenotype. With few markers, this amounts to set-based variance component tests, which attempt to increase power in association studies by aggregating weak individual effects. When the entire genome is considered, it allows
more &raquo; ... ing for the heritability of a phenotype, defined as the proportion of phenotypic variance explained by genetics. In the popular score-based Sequence Kernel Association Test (SKAT) method, the assumed distribution of the score test statistic is uncalibrated in small samples, with a correction being computationally expensive. This may cause severe inflation or deflation of p-values, even when the null hypothesis is true. Here, we characterize the conditions under which this discrepancy holds, and show it may occur also in large real datasets, such as a dataset from the Wellcome Trust Case Control Consortium 2 (n=13,950) study, and in particular when the individuals in the sample are unrelated. In these cases the SKAT approximation tends to be highly over-conservative and therefore underpowered. To address this limitation, we suggest an efficient method to calculate exact p-values for the score test in the case of a single variance component and a continuous response vector, which can speed up the analysis by orders of magnitude. Our results enable fast and accurate application of the score test in heritability and in set-based association tests. Our method is available in http://github.com/cozygene/RL-SKAT.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/140889">doi:10.1101/140889</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/fwzggdx5xnb4lks5nnk47sdykm">fatcat:fwzggdx5xnb4lks5nnk47sdykm</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20180723064609/https://www.biorxiv.org/content/biorxiv/early/2017/06/11/140889.full.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/81/d1/81d19896907052328069c20d5f6d0615119350e0.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/140889"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> biorxiv.org </button> </a>

RL-SKAT: An Exact and Efficient Score Test for Heritability and Set Tests

Regev Schweiger, Omer Weissbrod, Elior Rahmani, Martina Müller-Nurasyid, Sonja Kunze, Christian Gieger, Melanie Waldenberger, Saharon Rosset, Eran Halperin
<span title="2017-10-12">2017</span> <i title="Genetics Society of America"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/j4jbzoikwjh4nhplkbx7xsr32y" style="color: black;">Genetics</a> </i> &nbsp;
Testing for the existence of variance components in linear mixed models is a fundamental task in many applicative fields. In statistical genetics, the score test has recently become instrumental in the task of testing an association between a set of genetic markers and a phenotype. With few markers, this amounts to set-based variance component tests, which attempt to increase power in association studies by aggregating weak individual effects. When the entire genome is considered, it allows
more &raquo; ... ing for the heritability of a phenotype, defined as the proportion of phenotypic variance explained by genetics. In the popular score-based Sequence Kernel Association Test (SKAT) method, the assumed distribution of the score test statistic is uncalibrated in small samples, with a correction being computationally expensive. This may cause severe inflation or deflation of P-values, even when the null hypothesis is true. Here, we characterize the conditions under which this discrepancy holds, and show it may occur also in large real datasets, such as a dataset from the Wellcome Trust Case Control Consortium 2 (n = 13,950) study, and, in particular, when the individuals in the sample are unrelated. In these cases, the SKAT approximation tends to be highly overconservative and therefore underpowered. To address this limitation, we suggest an efficient method to calculate exact P-values for the score test in the case of a single variance component and a continuous response vector, which can speed up the analysis by orders of magnitude. Our results enable fast and accurate application of the score test in heritability and in set-based association tests. Our method is available in http://github.com/cozygene/RL-SKAT.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1534/genetics.117.300395">doi:10.1534/genetics.117.300395</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/29025915">pmid:29025915</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC5714447/">pmcid:PMC5714447</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/wzs4j4fhxvbyva7z4amieii5iq">fatcat:wzs4j4fhxvbyva7z4amieii5iq</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20190427131925/http://www.genetics.org/content/genetics/207/4/1275.full.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/0e/3a/0e3acec6a84d640da13b6459c8395f3ef00d20b6.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1534/genetics.117.300395"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> Publisher / doi.org </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714447" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

Deoxyribonuclease 1 Q222R single nucleotide polymorphism and long-term mortality after acute myocardial infarction

Thomas M Hofbauer, Andreas Mangold, Anna S Ondracek, Adelheid Panzenböck, Thomas Scherz, Julian Müller, Klaus Distelmaier, Veronika Seidl, Stefan Kastl, Martina Müller-Nurasyid, Annette Peters, Konstantin Strauch (+4 others)
<span title="2021-04-23">2021</span> <i title="Springer-Verlag"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/654qviva6vfghnyoskuy7twaru" style="color: black;">Basic Research in Cardiology</a> </i> &nbsp;
Upon activation, neutrophils release neutrophil extracellular traps (NETs), which contribute to circulating DNA burden and thrombosis, including ST-segment elevation myocardial infarction (STEMI). Deoxyribonuclease (DNase) 1 degrades circulating DNA and NETs. Lower DNase activity correlates with NET burden and infarct size. The DNase 1 Q222R single nucleotide polymorphism (SNP), impairing DNase 1 function, is linked with myocardial infarction. We assessed whether the Q222R SNP is connected to
more &raquo; ... creased NET burden in STEMI and influences long-term outcomes. We enrolled 711 STEMI patients undergoing primary percutaneous coronary intervention (pPCI), and 1422 controls. Genotyping was performed for DNase 1 Q222R SNP. DNase activity, double-stranded (ds)DNA and citrullinated histone H3 were determined in culprit site and peripheral plasma during pPCI. The association of the Q222R variant on cardiovascular and all-cause mortality was assessed by multivariable Cox regression adjusted for cardiovascular risk factors. Homozygous Q222R DNase 1 variant was present in 64 (9.0%) STEMI patients, at the same frequency as in controls. Patients homozygous for Q222R displayed less DNase activity and increased circulating DNA burden. In overall patients, median survival was 60 months. Homozygous Q222R variant was independently associated with cardiovascular and all-cause mortality after STEMI. dsDNA/DNase ratio independently predicted cardiovascular and all-cause mortality. These findings highlight that the Q222R DNase 1 SNP is associated with increased NET burden and decreased compensatory DNase activity, and may serve as an independent risk factor for poor outcome after STEMI.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1007/s00395-021-00864-w">doi:10.1007/s00395-021-00864-w</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/33891165">pmid:33891165</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC8064981/">pmcid:PMC8064981</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/2emnndyjqrbzzmvrxyzplzd7de">fatcat:2emnndyjqrbzzmvrxyzplzd7de</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20210717190654/https://link.springer.com/content/pdf/10.1007/s00395-021-00864-w.pdf?error=cookies_not_supported&amp;code=fab55812-27c8-46d5-95b7-b8aaafef24b3" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/48/1a/481a2e374957306cc08271f2e911c378a9d28a6b.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1007/s00395-021-00864-w"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> springer.com </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064981" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

Controversial association results for INSIG2 on body mass index may be explained by interactions with age and with MC4R

Dörthe Malzahn, Martina Müller-Nurasyid, Iris M Heid, H-Erich Wichmann, Heike Bickeböller
<span title="2014-02-12">2014</span> <i title="Springer Nature"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/pmvuapr27ngvveh4i2dhb3i3ce" style="color: black;">European Journal of Human Genetics</a> </i> &nbsp;
Among the single-nucleotide polymorphisms (SNPs) previously reported to be associated with body mass index (BMI) and obesity, we focus on a common risk variant rs7566605 upstream of the insulin-induced gene 2 (INSIG2) gene and a rare protective variant rs2229616 on the melanocortin-4 receptor (MC4R) gene. INSIG2 is involved in adipogenesis and MC4R effects hormonal appetite control in response to the amount of adipose tissue. The influence of rs2229616 (MC4R) on BMI and obesity has been
more &raquo; ... d repeatedly and insight into the underlying mechanism provided. However, a main effect of rs7566605 (INSIG2) is under debate because of inconsistent replications of association. Interaction of rs7566605 with age may offer an explanation. SNP-age and SNP-SNP interaction models were tested on independent individuals from three population-based longitudinal cohorts, restricting the analysis to an observed age of 25-74 years. KORA S3/F3, KORA S4/F4 (and Framingham-Offspring data (Framingham, USA, 1971-2001 were analysed, with a total sample size of N ¼ 6926 in the joint analysis. The effect of interaction between rs7566605 and age on BMI and obesity status is significant and consistent across studies. This new evidence for rs7566605 (INSIG2) complements previous research. In addition, the interaction effect of rs7566605 with the MC4R variant rs2229616 on BMI was observed. This effect size was three times larger than that in a previously reported single-locus main effect of rs2229616. This leads to the conclusion that SNP-age or SNP-SNP interactions can mask genetic effects for complex diseases if left unaccounted for. www.nature.com/ejhg c Longitudinal logistic regression of obesity status (BMIZ30 kg/m 2 ); model with random subject intercept and INSIG2 reference genotype GG, Bonferroni Pr0.05/4. Gene-age and gene-gene interaction effect on BMI D Malzahn et al
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1038/ejhg.2014.3">doi:10.1038/ejhg.2014.3</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/24518831">pmid:24518831</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC4169541/">pmcid:PMC4169541</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/4ibny7sd5ne4ndmqvoiodnajnm">fatcat:4ibny7sd5ne4ndmqvoiodnajnm</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20200510190911/https://www.nature.com/articles/ejhg20143.pdf?error=cookies_not_supported&amp;code=bc245b93-99e3-445b-a0ca-ba07ed3958cb" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/46/87/468701535370eec9783c233cc4c7f65f8ce38166.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1038/ejhg.2014.3"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> Publisher / doi.org </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169541" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

META-GSA: Combining Findings from Gene-Set Analyses across Several Genome-Wide Association Studies

Albert Rosenberger, Stefanie Friedrichs, Christopher I. Amos, Paul Brennan, Gordon Fehringer, Joachim Heinrich, Rayjean J. Hung, Thomas Muley, Martina Müller-Nurasyid, Angela Risch, Heike Bickeböller, Manu Sharma
<span title="2015-10-26">2015</span> <i title="Public Library of Science (PLoS)"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/s3gm7274mfe6fcs7e3jterqlri" style="color: black;">PLoS ONE</a> </i> &nbsp;
PLOS ONE |
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1371/journal.pone.0140179">doi:10.1371/journal.pone.0140179</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/26501144">pmid:26501144</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC4621033/">pmcid:PMC4621033</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/jcng5gommzcn7gnucrdbqgzqja">fatcat:jcng5gommzcn7gnucrdbqgzqja</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20171011071548/http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0140179&amp;type=printable" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/31/59/31599dd445bb4ed5039bc12d58d653ac5e37e28a.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1371/journal.pone.0140179"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> plos.org </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621033" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

pulver: an R package for parallel ultra-rapid p-value computation for linear regression interaction terms

Sophie Molnos, Clemens Baumbach, Simone Wahl, Martina Müller-Nurasyid, Konstantin Strauch, Rui Wang-Sattler, Melanie Waldenberger, Thomas Meitinger, Jerzy Adamski, Gabi Kastenmüller, Karsten Suhre, Annette Peters (+3 others)
<span title="2017-09-29">2017</span> <i title="Springer Nature"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/n5zrklrhlzhtdorf4rk4rmeo3i" style="color: black;">BMC Bioinformatics</a> </i> &nbsp;
Genome-wide association studies allow us to understand the genetics of complex diseases. Human metabolism provides information about the disease-causing mechanisms, so it is usual to investigate the associations between genetic variants and metabolite levels. However, only considering genetic variants and their effects on one trait ignores the possible interplay between different "omics" layers. Existing tools only consider single-nucleotide polymorphism (SNP)-SNP interactions, and no practical
more &raquo; ... tool is available for large-scale investigations of the interactions between pairs of arbitrary quantitative variables. Results: We developed an R package called pulver to compute p-values for the interaction term in a very large number of linear regression models. Comparisons based on simulated data showed that pulver is much faster than the existing tools. This is achieved by using the correlation coefficient to test the null-hypothesis, which avoids the costly computation of inversions. Additional tricks are a rearrangement of the order, when iterating through the different "omics" layers, and implementing this algorithm in the fast programming language C++. Furthermore, we applied our algorithm to data from the German KORA study to investigate a real-world problem involving the interplay among DNA methylation, genetic variants, and metabolite levels. Conclusions: The pulver package is a convenient and rapid tool for screening huge numbers of linear regression models for significant interaction terms in arbitrary pairs of quantitative variables. pulver is written in R and C++, and can be downloaded freely from CRAN at https://cran.r-project.org/web/packages/pulver/.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1186/s12859-017-1838-y">doi:10.1186/s12859-017-1838-y</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/28962546">pmid:28962546</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC5622569/">pmcid:PMC5622569</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/huvxmitglrbmbm6o4cguvdaale">fatcat:huvxmitglrbmbm6o4cguvdaale</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20180719132631/https://bmcbioinformatics.biomedcentral.com/track/pdf/10.1186/s12859-017-1838-y?site=bmcbioinformatics.biomedcentral.com" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/6a/bb/6abb24797db8a8def86eb90b892da010a1743cd8.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1186/s12859-017-1838-y"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> springer.com </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622569" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

Incidence of complications related to catheter ablation of atrial fibrillation and atrial flutter: a nationwide in-hospital analysis of administrative data for Germany in 2014

Gerhard Steinbeck, Moritz F Sinner, Manuel Lutz, Martina Müller-Nurasyid, Stefan Kääb, Holger Reinecke
<span title="2018-08-01">2018</span> <i title="Oxford University Press (OUP)"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/uya4vqptcrdklazphdg2nqow5u" style="color: black;">European Heart Journal</a> </i> &nbsp;
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1093/eurheartj/ehy452">doi:10.1093/eurheartj/ehy452</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/30085086">pmid:30085086</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/kqdrv7qw6vffdaquy5m5f2e6xq">fatcat:kqdrv7qw6vffdaquy5m5f2e6xq</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20190304142059/http://pdfs.semanticscholar.org/c7cb/c0b6f895be66d06d577406d8a45e2bf24cb4.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/c7/cb/c7cbc0b6f895be66d06d577406d8a45e2bf24cb4.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1093/eurheartj/ehy452"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> oup.com </button> </a>

Genetic variants including markers from the exome chip and metabolite traits of type 2 diabetes

Susanne Jäger, Simone Wahl, Janine Kröger, Sapna Sharma, Per Hoffmann, Anna Floegel, Tobias Pischon, Cornelia Prehn, Jerzy Adamski, Martina Müller-Nurasyid, Melanie Waldenberger, Konstantin Strauch (+7 others)
<span title="2017-07-20">2017</span> <i title="Springer Nature"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/tnqhc2x2aneavcd3gx5h7mswhm" style="color: black;">Scientific Reports</a> </i> &nbsp;
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1038/s41598-017-06158-3">doi:10.1038/s41598-017-06158-3</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/28729637">pmid:28729637</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC5519666/">pmcid:PMC5519666</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/d4waosb6nzh4jkxc75uvcjd2ma">fatcat:d4waosb6nzh4jkxc75uvcjd2ma</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20180719225306/http://edoc.mdc-berlin.de/16679/2/16679suppl.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/1c/bb/1cbbb7db8d434cad964aa5e8ff9e243856b0fe00.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1038/s41598-017-06158-3"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> Publisher / doi.org </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519666" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

Association of Atopic Dermatitis with Cardiovascular Risk Factors and Diseases

Marie Standl, Falko Tesch, Hansjörg Baurecht, Elke Rodríguez, Martina Müller-Nurasyid, Christian Gieger, Annette Peters, Rui Wang-Sattler, Cornelia Prehn, Jerzy Adamski, Florian Kronenberg, Holger Schulz (+8 others)
<span title="">2017</span> <i title="Elsevier BV"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/hxva2c3v7rgxffw6x5wzadfdrm" style="color: black;">Journal of Investigative Dermatology</a> </i> &nbsp;
Epidemiological studies suggested an association between atopic dermatitis (AD) and cardiovascular disease (CVD). Therefore, we investigate associations and potential underlying pathways of AD and CVD in large cohort studies: the AOK PLUS cohort (n=1.2Mio), the GINIplus/LISAplus birth cohorts (n=2286), and the KORA F4 cohort (n=2990). Additionally, metabolomics in KORA F4 and established cardiovascular risk loci in genome-wide data on 10,788 AD cases and 30,047 controls were analyzed.
more &raquo; ... al analysis of AD patients in AOK PLUS showed slightly increased risk for incident angina pectoris (AP) (adjusted risk ratio 1.17; 95%-confidence interval 1.12-1.23), hypertension (1.04 (1.02-1.06)) and peripheral arterial disease (PAD) (1.15 (1.11-1.19)) but not for myocardial infarction (MI) (1.05 (0.99-1.12) and stroke (1.02 (0.98-1.07)). In KORA F4 and GINIplus/LISAplus, AD was not associated with cardiovascular risk factors (CVRFs) and no differences in metabolite levels were detected. There was no robust evidence for shared genetic risk variants of AD and CVD. This study indicates only a marginally increased risk for AP, hypertension and PAD and no increased risk for MI or stroke in AD patients. Relevant associations of AD with CVRFs reported in US-populations could not be confirmed. Likewise, AD patients did not have increased genetic risk factors for CVD. INTRODUCTION Atopic dermatitis (AD) is a common chronic inflammatory disorder with a life time prevalence of 10-20% and represents a leading cause of illness and disability.(Weidinger and Novak, 2016) AD has a strong inherited background susceptibility and is pathophysiologically characterized by abnormalities of epidermal barrier function and T-cell driven cutaneous inflammation. (Weidinger and Novak, 2016) Genetic studies have revealed a complex polygenic architecture with striking overlaps to other 1.10), p=4.00x10 -8 ). This indicates that there is no relevant genetic overlap between CVDs and AD. Metabolomics analysis No significant associations of AD with any metabolites or metabolite ratios were observed within the KORA F4 study (Table S7 and Figure S1 ). DISCUSSION AD is one of the most common chronic diseases both among children and adults. An important implication of chronic diseases are comorbidities and sequelae, which are often key drivers of morbidity and mortality,(Global Burden of Disease Study, 2015, Prados-Torres et al., 2014) may was applied for multiple testing. The corrected significance level was determined by dividing 0.05 by the number of tests, yielding a corrected alpha level of 0.0003 (0.05/151) for the analysis of the 151 metabolites and a corrected alpha level of 4.4x10 -6 when analyzing the 151 metabolites including the ratios between all metabolites (151 metabolites + 11325 metabolite ratios). Metabolite concentrations were log-transformed with base 2 and results are presented per interquartile range increase in metabolite level. All analyses were conducted using R, version 3.3.1 (www.R-project.org). (R Core Team, 2016) and detailed power analyses are outlined in the Supplementary Material and Supplementary Table S10. Xin C, et al. Serum metabolomics study and eicosanoid analysis of childhood atopic dermatitis based on liquid chromatography-mass spectrometry. J Proteome Res 2014;13(12):5715-23. Kou K, Okawa T, Yamaguchi Y, Ono J, Inoue Y, Kohno M, et al. Periostin levels correlate with disease severity and chronicity in patients with atopic dermatitis. Br J Dermatol 2014;171(2):283-91. Kreissl S, Radon K, Dressel H, Genuneit J, Kellberger J, Nowak D, et al. Body mass index change and atopic diseases are not always associated in children and adolescents. Ann Allergy Asthma Immunol 2014;113(4):440-4 e1. Lee JH, Jung HM, Han KD, Lee SH, Lee JY, Park YG, et al. Association Between Metabolic Syndrome and Atopic Dermatitis in Korean Adults. Acta Derm Venereol 2016. Mitchell EA, Beasley R, Bjorksten B, Crane J, Garcia-Marcos L, Keil U, et al. The association between BMI, vigorous physical activity and television viewing and the risk of symptoms of asthma, rhinoconjunctivitis and eczema in children and adolescents: ISAAC Phase Three. Clin Exp Allergy 2013;43(1):73-84. Mohan GC, Silverberg JI. Association of Vitiligo and Alopecia Areata With Atopic Dermatitis: A Systematic Review and Meta-analysis. JAMA Dermatol 2015;151(5):522-8. Murray CS, Canoy D, Buchan I, Woodcock A, Simpson A, Custovic A. Body mass index in young children and allergic disease: gender differences in a longitudinal study. Clin Exp Allergy 2011;41(1):78-85. Nijsten T, Wakkee M. Complexity of the association between psoriasis and comorbidities. J Invest Dermatol 2009;129(7):1601-3. Paternoster L, Standl M, Waage J, Baurecht H, Hotze M, Strachan DP, et al. Multi-ancestry genomewide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis. Nat Genet 2015;47(12):1449-56.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1016/j.jid.2016.11.031">doi:10.1016/j.jid.2016.11.031</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/28011146">pmid:28011146</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/aa3mershizgmdex3g2hkwwmofu">fatcat:aa3mershizgmdex3g2hkwwmofu</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20190430005553/https://push-zb.helmholtz-muenchen.de/deliver.php?id=17567" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/39/87/398797177b780bdc89cc3e1675625b6057f8ed67.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1016/j.jid.2016.11.031"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> elsevier.com </button> </a>

Immunochip analysis identifies association of theRAD50/IL13region with human longevity

Friederike Flachsbart, David Ellinghaus, Liljana Gentschew, Femke-Anouska Heinsen, Amke Caliebe, Lene Christiansen, Marianne Nygaard, Kaare Christensen, Hélène Blanché, Jean-François Deleuze, Céline Derbois, Pilar Galan (+11 others)
<span title="2016-03-22">2016</span> <i title="Wiley"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/fhj726spzffznbyz5s3vyara54" style="color: black;">Aging Cell</a> </i> &nbsp;
et al.. Immunochip analysis identifies association of the RAD50/IL13 region with human longevity.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1111/acel.12471">doi:10.1111/acel.12471</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/27004735">pmid:27004735</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC4854908/">pmcid:PMC4854908</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/2qcqpzdo25abxp77iu5hccp6ja">fatcat:2qcqpzdo25abxp77iu5hccp6ja</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20201106201636/https://hal.inrae.fr/hal-02640091/file/2016_Flachsbart_AgingCell_1.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/c7/2f/c72fb3aaff4ecfd3d4f643d75327b9222b45645b.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1111/acel.12471"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> Publisher / doi.org </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854908" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

Comparison of genetic risk prediction models to improve prediction of coronary heart disease in two large cohorts of the MONICA/KORA study

Alina Bauer, Astrid Zierer, Christian Gieger, Mustafa Büyüközkan, Martina Müller‐Nurasyid, Harald Grallert, Christa Meisinger, Konstantin Strauch, Holger Prokisch, Michael Roden, Annette Peters, Jan Krumsiek (+4 others)
<span title="2021-06-03">2021</span> <i title="Wiley"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/bfe2cswpyfdjvmuvpnj65rlx7i" style="color: black;">Genetic Epidemiology</a> </i> &nbsp;
However, such approaches are rare (Antiochos et al., 2016; Müller et al., 2016) .  ...  recently, genetic risk prediction studies on complex diseases focused on variants identified as significantly associated in genome-wide association studies (GWAS) or candidate gene association studies (Müller  ... 
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1002/gepi.22389">doi:10.1002/gepi.22389</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/34082474">pmid:34082474</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/2e67yxhvn5g53gmo4d3v6dgi5e">fatcat:2e67yxhvn5g53gmo4d3v6dgi5e</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20210715203441/https://opus.bibliothek.uni-augsburg.de/opus4/frontdoor/deliver/index/docId/87319/file/gepi.22389.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/33/f2/33f267ebf2e0970bd3c4af1083f1fa07112e37fb.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1002/gepi.22389"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> wiley.com </button> </a>

Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease

Thomas W. Winkler, Felix Grassmann, Caroline Brandl, Christina Kiel, Felix Günther, Tobias Strunz, Lorraine Weidner, Martina E. Zimmermann, Christina A. Korb, Alicia Poplawski, Alexander K. Schuster, Martina Müller-Nurasyid (+13 others)
<span title="2020-08-26">2020</span> <i title="Springer Science and Business Media LLC"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/rbtzjpig4jcsfbjr5yo23sjnj4" style="color: black;">BMC Medical Genomics</a> </i> &nbsp;
Advanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the genetic architecture of early AMD. To identify genetic factors for early AMD, we conducted a genome-wide association study (GWAS) meta-analysis (14,034 cases, 91,214 controls, 11 sources of data including the International AMD Genomics Consortium, IAMDGC, and UK Biobank, UKBB). We ascertained early AMD via
more &raquo; ... or fundus photographs by manual grading for 10 sources and via an automated machine learning approach for > 170,000 photographs from UKBB. We searched for early AMD loci via GWAS and via a candidate approach based on 14 previously suggested early AMD variants. Altogether, we identified 10 independent loci with statistical significance for early AMD: (i) 8 from our GWAS with genome-wide significance (P < 5 × 10- 8), (ii) one previously suggested locus with experiment-wise significance (P < 0.05/14) in our non-overlapping data and with genome-wide significance when combining the reported and our non-overlapping data (together 17,539 cases, 105,395 controls), and (iii) one further previously suggested locus with experiment-wise significance in our non-overlapping data. Of these 10 identified loci, 8 were novel and 2 known for early AMD. Most of the 10 loci overlapped with known advanced AMD loci (near ARMS2/HTRA1, CFH, C2, C3, CETP, TNFRSF10A, VEGFA, APOE), except two that have not yet been identified with statistical significance for any AMD. Among the 17 genes within these two loci, in-silico functional annotation suggested CD46 and TYR as the most likely responsible genes. Presence or absence of an early AMD effect distinguished the known pathways of advanced AMD genetics (complement/lipid pathways versus extracellular matrix metabolism). Our GWAS on early AMD identified novel loci, highlighted shared and distinct genetics between early and advanced AMD and provides insights into AMD etiology. Our data provide a resource comparable in size to the existing IAMDGC data on advanced AMD genetics enabling a joint view. The biological relevance of this joint view is underscored by the ability of early AMD effects to differentiate the major pathways for advanced AMD.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1186/s12920-020-00760-7">doi:10.1186/s12920-020-00760-7</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/32843070">pmid:32843070</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/esg22tjnezho3blywj45bkaxfe">fatcat:esg22tjnezho3blywj45bkaxfe</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20200828224950/https://bmcmedgenomics.biomedcentral.com/track/pdf/10.1186/s12920-020-00760-7" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/ad/ca/adca8276cba86762826d7c736d1da6b98f905f09.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1186/s12920-020-00760-7"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> springer.com </button> </a>

Integrative clinical transcriptome analysis reveals TMPRSS2‐ERG dependency of prognostic biomarkers in prostate adenocarcinoma

Julia S. Gerke, Martin F. Orth, Yuri Tolkach, Laura Romero‐Pérez, Fabienne S. Wehweck, Stefanie Stein, Julian Musa, Maximilian M.L. Knott, Tilman L.B. Hölting, Jing Li, Giuseppina Sannino, Aruna Marchetto (+9 others)
<span title="2019-11-15">2019</span> <i title="Wiley"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/vm5lxrfefrc3ziqzlhk6jlqxre" style="color: black;">International Journal of Cancer</a> </i> &nbsp;
In prostate adenocarcinoma (PCa), distinction between indolent and aggressive disease is challenging. Around 50% of PCa are characterized by TMPRSS2-ERG (T2E)-fusion oncoproteins defining two molecular subtypes (T2E-positive/negative). However, current prognostic tests do not differ between both molecular subtypes, which might affect outcome prediction. To investigate gene-signatures associated with metastasis in T2E-positive and T2E-negative PCa independently, we integrated tumor
more &raquo; ... and clinicopathological data of two cohorts (total n = 783), and analyzed metastasis-associated gene-signatures regarding the T2E-status. Here, we show that the prognostic value of biomarkers in PCa critically depends on the T2E-status. Using gene-set enrichment analyses, we uncovered that metastatic T2E-positive and T2E-negative PCa are characterized by distinct gene-signatures. In addition, by testing genes shared by several functional gene-signatures for their association with event-free survival in a validation cohort (n = 272), we identified five genes (ASPN, BGN, COL1A1, RRM2 and TYMS)-three of which are included in commercially available prognostic tests-whose high expression was significantly associated with worse outcome exclusively in T2E-negative PCa. Among these genes, RRM2 and TYMS were validated by immunohistochemistry in another validation cohort (n = 135), and several of them proved to add prognostic information to current clinicopathological predictors, such as Gleason score, exclusively for T2E-negative patients. No prognostic biomarkers were identified exclusively for T2E-positive tumors. Collectively, our study discovers that the T2E-status, which is per se not a strong prognostic biomarker, crucially determines the prognostic value of other biomarkers. Our data suggest that the molecular subtype needs to be considered when applying prognostic biomarkers for outcome prediction in PCa.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1002/ijc.32792">doi:10.1002/ijc.32792</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/31732966">pmid:31732966</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/zzzaxsafofeoni6ut7nymix4cu">fatcat:zzzaxsafofeoni6ut7nymix4cu</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20210428070356/https://push-zb.helmholtz-muenchen.de/deliver.php?id=26095" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/5f/34/5f342d971ed53f0163f38b741914c3067a4b6271.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1002/ijc.32792"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> wiley.com </button> </a>

RANTES/CCL5 and Risk for Coronary Events: Results from the MONICA/KORA Augsburg Case-Cohort, Athero-Express and CARDIoGRAM Studies

Christian Herder, Wouter Peeters, Thomas Illig, Jens Baumert, Dominique P. V. de Kleijn, Frans L. Moll, Ulrike Poschen, Norman Klopp, Martina Müller-Nurasyid, Michael Roden, Michael Preuss, Mahir Karakas (+5 others)
<span title="2011-12-06">2011</span> <i title="Public Library of Science (PLoS)"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/s3gm7274mfe6fcs7e3jterqlri" style="color: black;">PLoS ONE</a> </i> &nbsp;
The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events. Methods and Findings: We conducted a case-cohort study within the population-based
more &raquo; ... CA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.264.8 years). Cox proportional hazard models adjusting for age, sex, body mass index, metabolic factors and lifestyle factors revealed no significant association between RANTES and incident coronary events (HR [95% CI] for increasing RANTES tertiles 1.0, 1.03 [0.75-1.42] and 1.11 [0.81-1.54]). None of six CCL5 single nucleotide polymorphisms and no common haplotype showed significant associations with coronary events. Also in the CARDIoGRAM study (.22,000 cases, .60,000 controls), none of these CCL5 SNPs was significantly associated with coronary artery disease. In the prospective Athero-Express biobank study, RANTES plaque levels were measured in 606 atherosclerotic lesions from patients who underwent carotid endarterectomy. RANTES content in atherosclerotic plaques was positively associated with macrophage infiltration and inversely associated with plaque calcification. However, there was no significant association between RANTES content in plaques and risk for coronary events (mean follow-up 2.860.8 years). Conclusions: High RANTES plaque levels were associated with an unstable plaque phenotype. However, the absence of associations between (i) RANTES serum levels, (ii) CCL5 genotypes and (iii) RANTES content in carotid plaques and either coronary artery disease or incident coronary events in our cohorts suggests that RANTES may not be a novel coronary risk biomarker. However, the potential relevance of RANTES levels in platelet-poor plasma needs to be investigated in further studies.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1371/journal.pone.0025734">doi:10.1371/journal.pone.0025734</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/22162987">pmid:22162987</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC3232218/">pmcid:PMC3232218</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/xgbogpi6jzhtbmbxoxxcjm4zri">fatcat:xgbogpi6jzhtbmbxoxxcjm4zri</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20170705141244/https://epub.ub.uni-muenchen.de/15680/1/fetchObject.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/50/0a/500af2e2097d2062eada8a890ec6d7487271517b.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1371/journal.pone.0025734"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> plos.org </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232218" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

Pro-arrhythmic effects of elevated branched chain amino acid levels

Vincent Portero, Thomas Nicol, Svitlana Podliesna, Gerard A Marchal, Antonius Baartscheer, Simona Casini, Rafik Tadros, Jorien L Treur, Michael W T Tanck, I Jane Cox, Fay Probert, Tertius A Hough (+13 others)
<span title="2021-06-17">2021</span> <i title="Oxford University Press (OUP)"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/kooh65zsfnakjdu6fxco3sqz6y" style="color: black;">Cardiovascular Research</a> </i> &nbsp;
Aim Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach. Methods and Results We employed a phenotype-driven
more &raquo; ... rosourea (ENU) mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6-9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4-5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs – leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to ECG indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs) and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation. Conclusions Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome and heart failure. Translational perspectives Development of efficient anti-arrhythmic strategies is hampered by incomplete knowledge of disease mechanisms. Using an unbiased approach, we here identified for the first time a pro-arrhythmic effect of increased levels of branched chain amino acids (BCAAs). This is of particular relevance for conditions associated with BCAA dysregulation and increased arrhythmia risk, including heart failure, obesity and diabetes, as well as for athletes supplementing their diet with BCAAs. Such metabolic dysregulation is potentially modifiable through dietary interventions, paving the way for novel preventive strategies. Our findings furthermore identify mTOR inhibition as a potential anti-arrhythmic strategy in patients with metabolic syndrome.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1093/cvr/cvab207">doi:10.1093/cvr/cvab207</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/34142125">pmid:34142125</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/m6ofpa2ji5gifprdtnkq5qaihm">fatcat:m6ofpa2ji5gifprdtnkq5qaihm</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20210715210457/https://epub.ub.uni-muenchen.de/76324/1/cvab207.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/b8/ff/b8ff7d3a09fbf4c5f9687ea5d96cccd2f2743193.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1093/cvr/cvab207"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> oup.com </button> </a>
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