<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Kasela, Silva</style></author><author><style face="normal" font="default" size="100%">Ortega, Victor E</style></author><author><style face="normal" font="default" size="100%">Martorella, Molly</style></author><author><style face="normal" font="default" size="100%">Garudadri, Suresh</style></author><author><style face="normal" font="default" size="100%">Nguyen, Jenna</style></author><author><style face="normal" font="default" size="100%">Ampleford, Elizabeth</style></author><author><style face="normal" font="default" size="100%">Pasanen, Anu</style></author><author><style face="normal" font="default" size="100%">Nerella, Srilaxmi</style></author><author><style face="normal" font="default" size="100%">Buschur, Kristina L</style></author><author><style face="normal" font="default" size="100%">Barjaktarevic, Igor Z</style></author><author><style face="normal" font="default" size="100%">Barr, R Graham</style></author><author><style face="normal" font="default" size="100%">Bleecker, Eugene R</style></author><author><style face="normal" font="default" size="100%">Bowler, Russell P</style></author><author><style face="normal" font="default" size="100%">Comellas, Alejandro P</style></author><author><style face="normal" font="default" size="100%">Cooper, Christopher B</style></author><author><style face="normal" font="default" size="100%">Couper, David J</style></author><author><style face="normal" font="default" size="100%">Criner, Gerard J</style></author><author><style face="normal" font="default" size="100%">Curtis, Jeffrey L</style></author><author><style face="normal" font="default" size="100%">Han, MeiLan K</style></author><author><style face="normal" font="default" size="100%">Hansel, Nadia N</style></author><author><style face="normal" font="default" size="100%">Hoffman, Eric A</style></author><author><style face="normal" font="default" size="100%">Kaner, Robert J</style></author><author><style face="normal" font="default" size="100%">Krishnan, Jerry A</style></author><author><style face="normal" font="default" size="100%">Martinez, Fernando J</style></author><author><style face="normal" font="default" size="100%">McDonald, Merry-Lynn N</style></author><author><style face="normal" font="default" size="100%">Meyers, Deborah A</style></author><author><style face="normal" font="default" size="100%">Paine, Robert</style></author><author><style face="normal" font="default" size="100%">Peters, Stephen P</style></author><author><style face="normal" font="default" size="100%">Castro, Mario</style></author><author><style face="normal" font="default" size="100%">Denlinger, Loren C</style></author><author><style face="normal" font="default" size="100%">Erzurum, Serpil C</style></author><author><style face="normal" font="default" size="100%">Fahy, John V</style></author><author><style face="normal" font="default" size="100%">Israel, Elliot</style></author><author><style face="normal" font="default" size="100%">Jarjour, Nizar N</style></author><author><style face="normal" font="default" size="100%">Levy, Bruce D</style></author><author><style face="normal" font="default" size="100%">Li, Xingnan</style></author><author><style face="normal" font="default" size="100%">Moore, Wendy C</style></author><author><style face="normal" font="default" size="100%">Wenzel, Sally E</style></author><author><style face="normal" font="default" size="100%">Zein, Joe</style></author><author><style face="normal" font="default" size="100%">Langelier, Charles</style></author><author><style face="normal" font="default" size="100%">Woodruff, Prescott G</style></author><author><style face="normal" font="default" size="100%">Lappalainen, Tuuli</style></author><author><style face="normal" font="default" size="100%">Christenson, Stephanie A</style></author></authors><translated-authors><author><style face="normal" font="default" size="100%">NHLBI SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS)</style></author><author><style face="normal" font="default" size="100%">NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium</style></author></translated-authors></contributors><titles><title><style face="normal" font="default" size="100%">Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.</style></title><secondary-title><style face="normal" font="default" size="100%">Genome Med</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Genome Med</style></alt-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Adult</style></keyword><keyword><style  face="normal" font="default" size="100%">Aged</style></keyword><keyword><style  face="normal" font="default" size="100%">Aged, 80 and over</style></keyword><keyword><style  face="normal" font="default" size="100%">Angiotensin-Converting Enzyme 2</style></keyword><keyword><style  face="normal" font="default" size="100%">Asthma</style></keyword><keyword><style  face="normal" font="default" size="100%">Bronchi</style></keyword><keyword><style  face="normal" font="default" size="100%">Cardiovascular Diseases</style></keyword><keyword><style  face="normal" font="default" size="100%">COVID-19</style></keyword><keyword><style  face="normal" font="default" size="100%">Gene Expression</style></keyword><keyword><style  face="normal" font="default" size="100%">Genetic Variation</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Middle Aged</style></keyword><keyword><style  face="normal" font="default" size="100%">Obesity</style></keyword><keyword><style  face="normal" font="default" size="100%">Pulmonary Disease, Chronic Obstructive</style></keyword><keyword><style  face="normal" font="default" size="100%">Quantitative Trait Loci</style></keyword><keyword><style  face="normal" font="default" size="100%">Respiratory Mucosa</style></keyword><keyword><style  face="normal" font="default" size="100%">Risk Factors</style></keyword><keyword><style  face="normal" font="default" size="100%">SARS-CoV-2</style></keyword><keyword><style  face="normal" font="default" size="100%">Smoking</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2021</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2021 04 21</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">13</style></volume><pages><style face="normal" font="default" size="100%">66</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;&lt;b&gt;BACKGROUND: &lt;/b&gt;The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.&lt;/p&gt;&lt;p&gt;&lt;b&gt;METHODS: &lt;/b&gt;We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants.&lt;/p&gt;&lt;p&gt;&lt;b&gt;RESULTS: &lt;/b&gt;We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections.&lt;/p&gt;&lt;p&gt;&lt;b&gt;CONCLUSIONS: &lt;/b&gt;These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.&lt;/p&gt;</style></abstract><issue><style face="normal" font="default" size="100%">1</style></issue><custom1><style face="normal" font="default" size="100%">https://www.ncbi.nlm.nih.gov/pubmed/33883027?dopt=Abstract</style></custom1></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Somineni, Hari K</style></author><author><style face="normal" font="default" size="100%">Nagpal, Sini</style></author><author><style face="normal" font="default" size="100%">Venkateswaran, Suresh</style></author><author><style face="normal" font="default" size="100%">Cutler, David J</style></author><author><style face="normal" font="default" size="100%">Okou, David T</style></author><author><style face="normal" font="default" size="100%">Haritunians, Talin</style></author><author><style face="normal" font="default" size="100%">Simpson, Claire L</style></author><author><style face="normal" font="default" size="100%">Begum, Ferdouse</style></author><author><style face="normal" font="default" size="100%">Datta, Lisa W</style></author><author><style face="normal" font="default" size="100%">Quiros, Antonio J</style></author><author><style face="normal" font="default" size="100%">Seminerio, Jenifer</style></author><author><style face="normal" font="default" size="100%">Mengesha, Emebet</style></author><author><style face="normal" font="default" size="100%">Alexander, Jonathan S</style></author><author><style face="normal" font="default" size="100%">Baldassano, Robert N</style></author><author><style face="normal" font="default" size="100%">Dudley-Brown, Sharon</style></author><author><style face="normal" font="default" size="100%">Cross, Raymond K</style></author><author><style face="normal" font="default" size="100%">Dassopoulos, Themistocles</style></author><author><style face="normal" font="default" size="100%">Denson, Lee A</style></author><author><style face="normal" font="default" size="100%">Dhere, Tanvi A</style></author><author><style face="normal" font="default" size="100%">Iskandar, Heba</style></author><author><style face="normal" font="default" size="100%">Dryden, Gerald W</style></author><author><style face="normal" font="default" size="100%">Hou, Jason K</style></author><author><style face="normal" font="default" size="100%">Hussain, Sunny Z</style></author><author><style face="normal" font="default" size="100%">Hyams, Jeffrey S</style></author><author><style face="normal" font="default" size="100%">Isaacs, Kim L</style></author><author><style face="normal" font="default" size="100%">Kader, Howard</style></author><author><style face="normal" font="default" size="100%">Kappelman, Michael D</style></author><author><style face="normal" font="default" size="100%">Katz, Jeffry</style></author><author><style face="normal" font="default" size="100%">Kellermayer, Richard</style></author><author><style face="normal" font="default" size="100%">Kuemmerle, John F</style></author><author><style face="normal" font="default" size="100%">Lazarev, Mark</style></author><author><style face="normal" font="default" size="100%">Li, Ellen</style></author><author><style face="normal" font="default" size="100%">Mannon, Peter</style></author><author><style face="normal" font="default" size="100%">Moulton, Dedrick E</style></author><author><style face="normal" font="default" size="100%">Newberry, Rodney D</style></author><author><style face="normal" font="default" size="100%">Patel, Ashish S</style></author><author><style face="normal" font="default" size="100%">Pekow, Joel</style></author><author><style face="normal" font="default" size="100%">Saeed, Shehzad A</style></author><author><style face="normal" font="default" size="100%">Valentine, John F</style></author><author><style face="normal" font="default" size="100%">Wang, Ming-Hsi</style></author><author><style face="normal" font="default" size="100%">McCauley, Jacob L</style></author><author><style face="normal" font="default" size="100%">Abreu, Maria T</style></author><author><style face="normal" font="default" size="100%">Jester, Traci</style></author><author><style face="normal" font="default" size="100%">Molle-Rios, Zarela</style></author><author><style face="normal" font="default" size="100%">Palle, Sirish</style></author><author><style face="normal" font="default" size="100%">Scherl, Ellen J</style></author><author><style face="normal" font="default" size="100%">Kwon, John</style></author><author><style face="normal" font="default" size="100%">Rioux, John D</style></author><author><style face="normal" font="default" size="100%">Duerr, Richard H</style></author><author><style face="normal" font="default" size="100%">Silverberg, Mark S</style></author><author><style face="normal" font="default" size="100%">Zwick, Michael E</style></author><author><style face="normal" font="default" size="100%">Stevens, Christine</style></author><author><style face="normal" font="default" size="100%">Daly, Mark J</style></author><author><style face="normal" font="default" size="100%">Cho, Judy H</style></author><author><style face="normal" font="default" size="100%">Gibson, Greg</style></author><author><style face="normal" font="default" size="100%">McGovern, Dermot P B</style></author><author><style face="normal" font="default" size="100%">Brant, Steven R</style></author><author><style face="normal" font="default" size="100%">Kugathasan, Subra</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.</style></title><secondary-title><style face="normal" font="default" size="100%">Am J Hum Genet</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Am J Hum Genet</style></alt-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">African Americans</style></keyword><keyword><style  face="normal" font="default" size="100%">Aged</style></keyword><keyword><style  face="normal" font="default" size="100%">Aged, 80 and over</style></keyword><keyword><style  face="normal" font="default" size="100%">Calbindin 2</style></keyword><keyword><style  face="normal" font="default" size="100%">Colitis, Ulcerative</style></keyword><keyword><style  face="normal" font="default" size="100%">Crohn Disease</style></keyword><keyword><style  face="normal" font="default" size="100%">European Continental Ancestry Group</style></keyword><keyword><style  face="normal" font="default" size="100%">Female</style></keyword><keyword><style  face="normal" font="default" size="100%">Gene Frequency</style></keyword><keyword><style  face="normal" font="default" size="100%">Genetic Predisposition to Disease</style></keyword><keyword><style  face="normal" font="default" size="100%">Genome-Wide Association Study</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Inflammatory Bowel Diseases</style></keyword><keyword><style  face="normal" font="default" size="100%">Male</style></keyword><keyword><style  face="normal" font="default" size="100%">Multifactorial Inheritance</style></keyword><keyword><style  face="normal" font="default" size="100%">Polymorphism, Single Nucleotide</style></keyword><keyword><style  face="normal" font="default" size="100%">Receptors, Prostaglandin E, EP4 Subtype</style></keyword><keyword><style  face="normal" font="default" size="100%">Whole Genome Sequencing</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2021</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2021 03 04</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">108</style></volume><pages><style face="normal" font="default" size="100%">431-445</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.&lt;/p&gt;</style></abstract><issue><style face="normal" font="default" size="100%">3</style></issue><custom1><style face="normal" font="default" size="100%">https://www.ncbi.nlm.nih.gov/pubmed/33600772?dopt=Abstract</style></custom1></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Bick, Alexander G</style></author><author><style face="normal" font="default" size="100%">Weinstock, Joshua S</style></author><author><style face="normal" font="default" size="100%">Nandakumar, Satish K</style></author><author><style face="normal" font="default" size="100%">Fulco, Charles P</style></author><author><style face="normal" font="default" size="100%">Bao, Erik L</style></author><author><style face="normal" font="default" size="100%">Zekavat, Seyedeh M</style></author><author><style face="normal" font="default" size="100%">Szeto, Mindy D</style></author><author><style face="normal" font="default" size="100%">Liao, Xiaotian</style></author><author><style face="normal" font="default" size="100%">Leventhal, Matthew J</style></author><author><style face="normal" font="default" size="100%">Nasser, Joseph</style></author><author><style face="normal" font="default" size="100%">Chang, Kyle</style></author><author><style face="normal" font="default" size="100%">Laurie, Cecelia</style></author><author><style face="normal" font="default" size="100%">Burugula, Bala Bharathi</style></author><author><style face="normal" font="default" size="100%">Gibson, Christopher J</style></author><author><style face="normal" font="default" size="100%">Lin, Amy E</style></author><author><style face="normal" font="default" size="100%">Taub, Margaret A</style></author><author><style face="normal" font="default" size="100%">Aguet, François</style></author><author><style face="normal" font="default" size="100%">Ardlie, Kristin</style></author><author><style face="normal" font="default" size="100%">Mitchell, Braxton D</style></author><author><style face="normal" font="default" size="100%">Barnes, Kathleen C</style></author><author><style face="normal" font="default" size="100%">Moscati, Arden</style></author><author><style face="normal" font="default" size="100%">Fornage, Myriam</style></author><author><style face="normal" font="default" size="100%">Redline, Susan</style></author><author><style face="normal" font="default" size="100%">Psaty, Bruce M</style></author><author><style face="normal" font="default" size="100%">Silverman, Edwin K</style></author><author><style face="normal" font="default" size="100%">Weiss, Scott T</style></author><author><style face="normal" font="default" size="100%">Palmer, Nicholette D</style></author><author><style face="normal" font="default" size="100%">Vasan, Ramachandran S</style></author><author><style face="normal" font="default" size="100%">Burchard, Esteban G</style></author><author><style face="normal" font="default" size="100%">Kardia, Sharon L R</style></author><author><style face="normal" font="default" size="100%">He, Jiang</style></author><author><style face="normal" font="default" size="100%">Kaplan, Robert C</style></author><author><style face="normal" font="default" size="100%">Smith, Nicholas L</style></author><author><style face="normal" font="default" size="100%">Arnett, Donna K</style></author><author><style face="normal" font="default" size="100%">Schwartz, David A</style></author><author><style face="normal" font="default" size="100%">Correa, Adolfo</style></author><author><style face="normal" font="default" size="100%">de Andrade, Mariza</style></author><author><style face="normal" font="default" size="100%">Guo, Xiuqing</style></author><author><style face="normal" font="default" size="100%">Konkle, Barbara A</style></author><author><style face="normal" font="default" size="100%">Custer, Brian</style></author><author><style face="normal" font="default" size="100%">Peralta, Juan M</style></author><author><style face="normal" font="default" size="100%">Gui, Hongsheng</style></author><author><style face="normal" font="default" size="100%">Meyers, Deborah A</style></author><author><style face="normal" font="default" size="100%">McGarvey, Stephen T</style></author><author><style face="normal" font="default" size="100%">Chen, Ida Yii-Der</style></author><author><style face="normal" font="default" size="100%">Shoemaker, M Benjamin</style></author><author><style face="normal" font="default" size="100%">Peyser, Patricia A</style></author><author><style face="normal" font="default" size="100%">Broome, Jai G</style></author><author><style face="normal" font="default" size="100%">Gogarten, Stephanie M</style></author><author><style face="normal" font="default" size="100%">Wang, Fei Fei</style></author><author><style face="normal" font="default" size="100%">Wong, Quenna</style></author><author><style face="normal" font="default" size="100%">Montasser, May E</style></author><author><style face="normal" font="default" size="100%">Daya, Michelle</style></author><author><style face="normal" font="default" size="100%">Kenny, Eimear E</style></author><author><style face="normal" font="default" size="100%">North, Kari E</style></author><author><style face="normal" font="default" size="100%">Launer, Lenore J</style></author><author><style face="normal" font="default" size="100%">Cade, Brian E</style></author><author><style face="normal" font="default" size="100%">Bis, Joshua C</style></author><author><style face="normal" font="default" size="100%">Cho, Michael H</style></author><author><style face="normal" font="default" size="100%">Lasky-Su, Jessica</style></author><author><style face="normal" font="default" size="100%">Bowden, Donald W</style></author><author><style face="normal" font="default" size="100%">Cupples, L Adrienne</style></author><author><style face="normal" font="default" size="100%">Mak, Angel C Y</style></author><author><style face="normal" font="default" size="100%">Becker, Lewis C</style></author><author><style face="normal" font="default" size="100%">Smith, Jennifer A</style></author><author><style face="normal" font="default" size="100%">Kelly, Tanika N</style></author><author><style face="normal" font="default" size="100%">Aslibekyan, Stella</style></author><author><style face="normal" font="default" size="100%">Heckbert, Susan R</style></author><author><style face="normal" font="default" size="100%">Tiwari, Hemant K</style></author><author><style face="normal" font="default" size="100%">Yang, Ivana V</style></author><author><style face="normal" font="default" size="100%">Heit, John A</style></author><author><style face="normal" font="default" size="100%">Lubitz, Steven A</style></author><author><style face="normal" font="default" size="100%">Johnsen, Jill M</style></author><author><style face="normal" font="default" size="100%">Curran, Joanne E</style></author><author><style face="normal" font="default" size="100%">Wenzel, Sally E</style></author><author><style face="normal" font="default" size="100%">Weeks, Daniel E</style></author><author><style face="normal" font="default" size="100%">Rao, Dabeeru C</style></author><author><style face="normal" font="default" size="100%">Darbar, Dawood</style></author><author><style face="normal" font="default" size="100%">Moon, Jee-Young</style></author><author><style face="normal" font="default" size="100%">Tracy, Russell P</style></author><author><style face="normal" font="default" size="100%">Buth, Erin J</style></author><author><style face="normal" font="default" size="100%">Rafaels, Nicholas</style></author><author><style face="normal" font="default" size="100%">Loos, Ruth J F</style></author><author><style face="normal" font="default" size="100%">Durda, Peter</style></author><author><style face="normal" font="default" size="100%">Liu, Yongmei</style></author><author><style face="normal" font="default" size="100%">Hou, Lifang</style></author><author><style face="normal" font="default" size="100%">Lee, Jiwon</style></author><author><style face="normal" font="default" size="100%">Kachroo, Priyadarshini</style></author><author><style face="normal" font="default" size="100%">Freedman, Barry I</style></author><author><style face="normal" font="default" size="100%">Levy, Daniel</style></author><author><style face="normal" font="default" size="100%">Bielak, Lawrence F</style></author><author><style face="normal" font="default" size="100%">Hixson, James E</style></author><author><style face="normal" font="default" size="100%">Floyd, James S</style></author><author><style face="normal" font="default" size="100%">Whitsel, Eric A</style></author><author><style face="normal" font="default" size="100%">Ellinor, Patrick T</style></author><author><style face="normal" font="default" size="100%">Irvin, Marguerite R</style></author><author><style face="normal" font="default" size="100%">Fingerlin, Tasha E</style></author><author><style face="normal" font="default" size="100%">Raffield, Laura M</style></author><author><style face="normal" font="default" size="100%">Armasu, Sebastian M</style></author><author><style face="normal" font="default" size="100%">Wheeler, Marsha M</style></author><author><style face="normal" font="default" size="100%">Sabino, Ester C</style></author><author><style face="normal" font="default" size="100%">Blangero, John</style></author><author><style face="normal" font="default" size="100%">Williams, L Keoki</style></author><author><style face="normal" font="default" size="100%">Levy, Bruce D</style></author><author><style face="normal" font="default" size="100%">Sheu, Wayne Huey-Herng</style></author><author><style face="normal" font="default" size="100%">Roden, Dan M</style></author><author><style face="normal" font="default" size="100%">Boerwinkle, Eric</style></author><author><style face="normal" font="default" size="100%">Manson, JoAnn E</style></author><author><style face="normal" font="default" size="100%">Mathias, Rasika A</style></author><author><style face="normal" font="default" size="100%">Desai, Pinkal</style></author><author><style face="normal" font="default" size="100%">Taylor, Kent D</style></author><author><style face="normal" font="default" size="100%">Johnson, Andrew D</style></author><author><style face="normal" font="default" size="100%">Auer, Paul L</style></author><author><style face="normal" font="default" size="100%">Kooperberg, Charles</style></author><author><style face="normal" font="default" size="100%">Laurie, Cathy C</style></author><author><style face="normal" font="default" size="100%">Blackwell, Thomas W</style></author><author><style face="normal" font="default" size="100%">Smith, Albert V</style></author><author><style face="normal" font="default" size="100%">Zhao, Hongyu</style></author><author><style face="normal" font="default" size="100%">Lange, Ethan</style></author><author><style face="normal" font="default" size="100%">Lange, Leslie</style></author><author><style face="normal" font="default" size="100%">Rich, Stephen S</style></author><author><style face="normal" font="default" size="100%">Rotter, Jerome I</style></author><author><style face="normal" font="default" size="100%">Wilson, James G</style></author><author><style face="normal" font="default" size="100%">Scheet, Paul</style></author><author><style face="normal" font="default" size="100%">Kitzman, Jacob O</style></author><author><style face="normal" font="default" size="100%">Lander, Eric S</style></author><author><style face="normal" font="default" size="100%">Engreitz, Jesse M</style></author><author><style face="normal" font="default" size="100%">Ebert, Benjamin L</style></author><author><style face="normal" font="default" size="100%">Reiner, Alexander P</style></author><author><style face="normal" font="default" size="100%">Jaiswal, Siddhartha</style></author><author><style face="normal" font="default" size="100%">Abecasis, Gonçalo</style></author><author><style face="normal" font="default" size="100%">Sankaran, Vijay G</style></author><author><style face="normal" font="default" size="100%">Kathiresan, Sekar</style></author><author><style face="normal" font="default" size="100%">Natarajan, Pradeep</style></author></authors><translated-authors><author><style face="normal" font="default" size="100%">NHLBI Trans-Omics for Precision Medicine Consortium</style></author></translated-authors></contributors><titles><title><style face="normal" font="default" size="100%">Inherited causes of clonal haematopoiesis in 97,691 whole genomes.</style></title><secondary-title><style face="normal" font="default" size="100%">Nature</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Nature</style></alt-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Adult</style></keyword><keyword><style  face="normal" font="default" size="100%">Africa</style></keyword><keyword><style  face="normal" font="default" size="100%">African Continental Ancestry Group</style></keyword><keyword><style  face="normal" font="default" size="100%">Aged</style></keyword><keyword><style  face="normal" font="default" size="100%">Aged, 80 and over</style></keyword><keyword><style  face="normal" font="default" size="100%">alpha Karyopherins</style></keyword><keyword><style  face="normal" font="default" size="100%">Cell Self Renewal</style></keyword><keyword><style  face="normal" font="default" size="100%">Clonal Hematopoiesis</style></keyword><keyword><style  face="normal" font="default" size="100%">DNA-Binding Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">Female</style></keyword><keyword><style  face="normal" font="default" size="100%">Genetic Predisposition to Disease</style></keyword><keyword><style  face="normal" font="default" size="100%">Genome, Human</style></keyword><keyword><style  face="normal" font="default" size="100%">Germ-Line Mutation</style></keyword><keyword><style  face="normal" font="default" size="100%">Hematopoietic Stem Cells</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Intracellular Signaling Peptides and Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">Male</style></keyword><keyword><style  face="normal" font="default" size="100%">Middle Aged</style></keyword><keyword><style  face="normal" font="default" size="100%">National Heart, Lung, and Blood Institute (U.S.)</style></keyword><keyword><style  face="normal" font="default" size="100%">Phenotype</style></keyword><keyword><style  face="normal" font="default" size="100%">Precision Medicine</style></keyword><keyword><style  face="normal" font="default" size="100%">Proto-Oncogene Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">Tripartite Motif Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">United States</style></keyword><keyword><style  face="normal" font="default" size="100%">Whole Genome Sequencing</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2020</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2020 10</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">586</style></volume><pages><style face="normal" font="default" size="100%">763-768</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.&lt;/p&gt;</style></abstract><issue><style face="normal" font="default" size="100%">7831</style></issue><custom1><style face="normal" font="default" size="100%">https://www.ncbi.nlm.nih.gov/pubmed/33057201?dopt=Abstract</style></custom1></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Natarajan, Pradeep</style></author><author><style face="normal" font="default" size="100%">Young, Robin</style></author><author><style face="normal" font="default" size="100%">Stitziel, Nathan O</style></author><author><style face="normal" font="default" size="100%">Padmanabhan, Sandosh</style></author><author><style face="normal" font="default" size="100%">Baber, Usman</style></author><author><style face="normal" font="default" size="100%">Mehran, Roxana</style></author><author><style face="normal" font="default" size="100%">Sartori, Samantha</style></author><author><style face="normal" font="default" size="100%">Fuster, Valentin</style></author><author><style face="normal" font="default" size="100%">Reilly, Dermot F</style></author><author><style face="normal" font="default" size="100%">Butterworth, Adam</style></author><author><style face="normal" font="default" size="100%">Rader, Daniel J</style></author><author><style face="normal" font="default" size="100%">Ford, Ian</style></author><author><style face="normal" font="default" size="100%">Sattar, Naveed</style></author><author><style face="normal" font="default" size="100%">Kathiresan, Sekar</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Polygenic Risk Score Identifies Subgroup With Higher Burden of Atherosclerosis and Greater Relative Benefit From Statin Therapy in the Primary Prevention Setting.</style></title><secondary-title><style face="normal" font="default" size="100%">Circulation</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Circulation</style></alt-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Adolescent</style></keyword><keyword><style  face="normal" font="default" size="100%">Adult</style></keyword><keyword><style  face="normal" font="default" size="100%">Aged</style></keyword><keyword><style  face="normal" font="default" size="100%">Aged, 80 and over</style></keyword><keyword><style  face="normal" font="default" size="100%">Atherosclerosis</style></keyword><keyword><style  face="normal" font="default" size="100%">Cohort Studies</style></keyword><keyword><style  face="normal" font="default" size="100%">Cost of Illness</style></keyword><keyword><style  face="normal" font="default" size="100%">Female</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Hydroxymethylglutaryl-CoA Reductase Inhibitors</style></keyword><keyword><style  face="normal" font="default" size="100%">Male</style></keyword><keyword><style  face="normal" font="default" size="100%">Middle Aged</style></keyword><keyword><style  face="normal" font="default" size="100%">Multifactorial Inheritance</style></keyword><keyword><style  face="normal" font="default" size="100%">Primary Prevention</style></keyword><keyword><style  face="normal" font="default" size="100%">Risk Factors</style></keyword><keyword><style  face="normal" font="default" size="100%">Young Adult</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2017</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2017 May 30</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">135</style></volume><pages><style face="normal" font="default" size="100%">2091-2101</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;&lt;b&gt;BACKGROUND: &lt;/b&gt;Relative risk reduction with statin therapy has been consistent across nearly all subgroups studied to date. However, in analyses of 2 randomized controlled primary prevention trials (ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm] and JUPITER [Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin]), statin therapy led to a greater relative risk reduction among a subgroup at high genetic risk. Here, we aimed to confirm this observation in a third primary prevention randomized controlled trial. In addition, we assessed whether those at high genetic risk had a greater burden of subclinical coronary atherosclerosis.&lt;/p&gt;&lt;p&gt;&lt;b&gt;METHODS: &lt;/b&gt;We studied participants from a randomized controlled trial of primary prevention with statin therapy (WOSCOPS [West of Scotland Coronary Prevention Study]; n=4910) and 2 observational cohort studies (CARDIA [Coronary Artery Risk Development in Young Adults] and BioImage; n=1154 and 4392, respectively). For each participant, we calculated a polygenic risk score derived from up to 57 common DNA sequence variants previously associated with coronary heart disease. We compared the relative efficacy of statin therapy in those at high genetic risk (top quintile of polygenic risk score) versus all others (WOSCOPS), as well as the association between the polygenic risk score and coronary artery calcification (CARDIA) and carotid artery plaque burden (BioImage).&lt;/p&gt;&lt;p&gt;&lt;b&gt;RESULTS: &lt;/b&gt;Among WOSCOPS trial participants at high genetic risk, statin therapy was associated with a relative risk reduction of 44% (95% confidence interval [CI], 22-60; &lt;0.001), whereas in all others, the relative risk reduction was 24% (95% CI, 8-37; =0.004) despite similar low-density lipoprotein cholesterol lowering. In a study-level meta-analysis across the WOSCOPS, ASCOT, and JUPITER primary prevention, relative risk reduction in those at high genetic risk was 46% versus 26% in all others ( for heterogeneity=0.05). Across all 3 studies, the absolute risk reduction with statin therapy was 3.6% (95% CI, 2.0-5.1) among those in the high genetic risk group and 1.3% (95% CI, 0.6-1.9) in all others. Each 1-SD increase in the polygenic risk score was associated with 1.32-fold (95% CI, 1.04-1.68) greater likelihood of having coronary artery calcification and 9.7% higher (95% CI, 2.2-17.8) burden of carotid plaque.&lt;/p&gt;&lt;p&gt;&lt;b&gt;CONCLUSIONS: &lt;/b&gt;Those at high genetic risk have a greater burden of subclinical atherosclerosis and derive greater relative and absolute benefit from statin therapy to prevent a first coronary heart disease event.&lt;/p&gt;&lt;p&gt;&lt;b&gt;CLINICAL TRIAL REGISTRATION: &lt;/b&gt;URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00738725 (BioImage) and NCT00005130 (CARDIA). WOSCOPS was carried out and completed before the requirement for clinical trial registration.&lt;/p&gt;</style></abstract><issue><style face="normal" font="default" size="100%">22</style></issue><custom1><style face="normal" font="default" size="100%">https://www.ncbi.nlm.nih.gov/pubmed/28223407?dopt=Abstract</style></custom1></record></records></xml>