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2. Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthmaResearch in context

Author

Kathryn Recto, Priyadarshini Kachroo, Tianxiao Huan, David Van Den Berg, Gha Young Lee, Helena Bui, Dong Heon Lee, Jessica Gereige, Chen Yao, Shih-Jen Hwang, Roby Joehanes, Scott T. Weiss, George T. O’Connor, Daniel Levy, Dawn L. DeMeo, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Nathan Blue, Eric Boerwinkle, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, April P. Carson, Cara Carty, Richard Casaburi, Juan P. Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Yii-Der Ida Chen, Michael Cho, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Yan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Xiuqing Guo, Namrata Gupta, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Jianhong Hu, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Sandra Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yongmei Liu, Yu Liu, Ruth J.F. Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Ani Manichaikul, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Rasika Mathias, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James Meigs, Vipin Menon, Luisa Mestroni, Ginger Metcalf, Deborah A. Meyers, Emmanuel Mignot, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton D. Mitchell, Matt Moll, Zeineen Momin, May E. Montasser, Courtney Montgomery, Donna Muzny, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Pradeep Natarajan, Sergei Nekhai, Sarah C. Nelson, Bonnie Neltner, Caitlin Nessner, Deborah Nickerson, Osuji Nkechinyere, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, Geoffrey Okwuonu, Allan Pack, David T. Paik, Nicholette Palmer, James Pankow, George Papanicolaou, Cora Parker, Gina Peloso, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Jacob Pleiness, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Mahitha Rajendran, Vasan S. Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Muagututi‘a Sefuiva Reupena, Ken Rice, Stephen Rich, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven Salzberg, Kevin Sandow, Vijay G. Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L. Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Robert Skomro, Albert Vernon Smith, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Daniel Taliun, Hua Tang, Margaret Taub, Kent Taylor, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Russell Tracy, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E. Weeks, Joshua Weinstock, Bruce Weir, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, L. Keoki Williams, Scott Williams, Carla Wilson, James Wilson, Lara Winterkorn, Quenna Wong, Baojun Wu, Joseph Wu, Huichun Xu, Lisa Yanek, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Elad Ziv, Michael Zody, and Sebastian Zoellner

Subjects
EWAS, DNA methylation, IgE, Asthma, RNA-Sequencing, Mendelian randomization, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. Methods: We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables. Findings: We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P

Published
2023
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3. Proceedings from the 9th annual conference on the science of dissemination and implementation

Author

David Chambers, Lisa Simpson, Gila Neta, Ulrica von Thiele Schwarz, Antoinette Percy-Laurry, Gregory A. Aarons, Ross Brownson, Amanda Vogel, Shannon Wiltsey Stirman, Kenneth Sherr, Rachel Sturke, Wynne E. Norton, Allyson Varley, Cynthia Vinson, Lisa Klesges, Suzanne Heurtin-Roberts, M. Rashad Massoud, Leighann Kimble, Arne Beck, Claire Neely, Jennifer Boggs, Carmel Nichols, Wen Wan, Erin Staab, Neda Laiteerapong, Nathalie Moise, Ravi Shah, Susan Essock, Margaret Handley, Amy Jones, Jay Carruthers, Karina Davidson, Lauren Peccoralo, Lloyd Sederer, Todd Molfenter, Ashley Scudder, Sarah Taber-Thomas, Kristen Schaffner, Amy Herschell, Eva Woodward, Jeffery Pitcock, Mona Ritchie, JoAnn Kirchner, Julia E. Moore, Sobia Khan, Shusmita Rashid, Jamie Park, Melissa Courvoisier, Sharon Straus, Daniel Blonigen, Allison Rodriguez, Luisa Manfredi, Andrea Nevedal, Joel Rosenthal, David Smelson, Christine Timko, Nicole Stadnick, Jennifer Regan, Miya Barnett, Anna Lau, Lauren Brookman-Frazee, Erick Guerrero, Karissa Fenwick, Yinfei Kong, Gregory Aarons, Rebecca Lengnick-Hall, Benjamin Henwood, Nina Sayer, Craig Rosen, Robert Orazem, Brandy Smith, Lindsey Zimmerman, David Lounsbury, Rachel Kimerling, Jodie A. Trafton, Steven Lindley, Rahul Bhargava, Hal Roberts, Laura Gibson, Gabriel J. Escobar, Vincent Liu, Benjamin Turk, Arona Ragins, Patricia Kipnis, Ashley Ketterer Gruszkowski, Michael W. Kennedy, Emily Rentschler Drobek, Lior Turgeman, Aleksandra Sasha Milicevic, Terrence L. Hubert, Larissa Myaskovsky, Youxu C. Tjader, Robert J. Monte, Kathryn G. Sapnas, Edmond Ramly, Diane R Lauver, Christie M Bartels, Shereef Elnahal, Andrea Ippolito, Hillary Peabody, Carolyn Clancy, Randall Cebul, Thomas Love, Douglas Einstadter, Shari Bolen, Brook Watts, Vera Yakovchenko, Angela Park, William Lukesh, Donald R. Miller, David Thornton, Mari-Lynn Drainoni, Allen L. Gifford, Shawna Smith, Julia Kyle, Mark S Bauer, Daniel Eisenberg, Celeste Liebrecht, Michelle Barbaresso, Amy Kilbourne, Elyse Park, Giselle Perez, Jamie Ostroff, Sarah Greene, Michael Parchman, Brian Austin, Eric Larson, Stefanie Ferreri, Chris Shea, Megan Smith, Kea Turner, Jennifer Bacci, Kyle Bigham, Geoffrey Curran, Caity Frail, Cory Hamata, Terry Jankowski, Wendy Lantaff, Melissa Somma McGivney, Margie Snyder, Megan McCullough, Chris Gillespie, Beth Ann Petrakis, Ellen Jones, Carol VanDeusen Lukas, Adam Rose, Sarah J. Shoemaker, Jeremy Thomas, Benjamin Teeter, Holly Swan, Appathurai Balamurugan, Meghan Lane-Fall, Rinad Beidas, Laura Di Taranti, Sruthi Buddai, Enrique Torres Hernandez, Jerome Watts, Lee Fleisher, Frances Barg, Isomi Miake-Lye, Tanya Olmos, Emmeline Chuang, Hector Rodriguez, Gerald Kominski, Becky Yano, Stephen Shortell, Mary Hook, Linda Fleisher, Alexander Fiks, Katie Halkyard, Rachel Gruver, Emily Sykes, Kimberly Vesco, Kate Beadle, Joanna Bulkley, Ashley Stoneburner, Michael Leo, Amanda Clark, Joan Smith, Christopher Smyser, Maggie Wolf, Shamik Trivedi, Brian Hackett, Rakesh Rao, F. Sessions Cole, Rose McGonigle, Ann Donze, Enola Proctor, Amit Mathur, Emmanuela Gakidou, Stephen Gloyd, Carolyn Audet, Jose Salato, Sten Vermund, Rivet Amico, Stephanie Smith, Beatha Nyirandagijimana, Hildegarde Mukasakindi, Christian Rusangwa, Molly Franke, Giuseppe Raviola, Matthew Cummings, Elijah Goldberg, Savio Mwaka, Olive Kabajaasi, Adithya Cattamanchi, Achilles Katamba, Shevin Jacob, Nathan Kenya-Mugisha, J. Lucian Davis, Julie Reed, Rohit Ramaswamy, Gareth Parry, Sylvia Sax, Heather Kaplan, Keng-yen Huang, Sabrina Cheng, Susan Yee, Kimberly Hoagwood, Mary McKay, Donna Shelley, Gbenga Ogedegbe, Laurie Miller Brotman, Roman Kislov, John Humphreys, Gill Harvey, Paul Wilson, Robert Lieberthal, Colleen Payton, Mona Sarfaty, George Valko, Rendelle Bolton, Christine Hartmann, Nora Mueller, Sally K. Holmes, Barbara Bokhour, Sarah Ono, Benjamin Crabtree, Leah Gordon, William Miller, Bijal Balasubramanian, Leif Solberg, Deborah Cohen, Kate McGraw, Andrew Blatt, Demietrice Pittman, Helen Kales, Dan Berlowitz, Teresa Hudson, Christian Helfrich, Erin Finley, Ashley Garcia, Kristen Rosen, Claudina Tami, Don McGeary, Mary Jo Pugh, Jennifer Sharpe Potter, Krysttel Stryczek, David Au, Steven Zeliadt, George Sayre, Jennifer Leeman, Allison Myers, Jennifer Grant, Mary Wangen, Tara Queen, Alexandra Morshed, Elizabeth Dodson, Rachel Tabak, Ross C. Brownson, R. Chris Sheldrick, Thomas Mackie, Justeen Hyde, Laurel Leslie, Itzhak Yanovitzky, Matthew Weber, Nicole Gesualdo, Teis Kristensen, Cameo Stanick, Heather Halko, Caitlin Dorsey, Byron Powell, Bryan Weiner, Cara Lewis, Patricia Carreno, Kera Mallard, Tasoula Masina, Candice Monson, Taren Swindle, Zachary Patterson, Leanne Whiteside-Mansell, Rochelle Hanson, Benjamin Saunders, Sonja Schoenwald, Angela Moreland, Sarah Birken, Justin Presseau, David Ganz, Brian Mittman, Deborah Delevan, Jennifer N. Hill, Sara Locatelli, Gemmae Fix, Jeffrey Solomon, Sherri L. Lavela, Victoria Scott, Jonathan Scaccia, Kassy Alia, Brittany Skiles, Abraham Wandersman, Anne Sales, Megan Roberts, Amy Kennedy, Muin J. Khoury, Nina Sperber, Lori Orlando, Janet Carpenter, Larisa Cavallari, Joshua Denny, Amanda Elsey, Fern Fitzhenry, Yue Guan, Carol Horowitz, Julie Johnson, Ebony Madden, Toni Pollin, Victoria Pratt, Tejinder Rakhra-Burris, Marc Rosenman, Corrine Voils, Kristin Weitzel, Ryanne Wu, Laura Damschroder, Christine Lu, Rachel Ceccarelli, Kathleen M. Mazor, Ann Wu, Alanna Kulchak Rahm, Adam H. Buchanan, Marci Schwartz, Cara McCormick, Kandamurugu Manickam, Marc S. Williams, Michael F. Murray, Ngoc-Cam Escoffery, Erin Lebow-Skelley, Hallie Udelson, Elaine Böing, Maria E. Fernandez, Richard J. Wood, Patricia Dolan Mullen, Jenita Parekh, Valerie Caldas, Elizabeth A. Stuart, Shalynn Howard, Gilo Thomas, Jacky M. Jennings, Jennifer Torres, Christine Markham, Ross Shegog, Melissa Peskin, Stephanie Craig Rushing, Amanda Gaston, Gwenda Gorman, Cornelia Jessen, Jennifer Williamson, Dianne Ward, Amber Vaughn, Ellie Morris, Stephanie Mazzucca, Regan Burney, Shoba Ramanadhan, Sara Minsky, Vilma Martinez-Dominguez, Kasisomayajula Viswanath, Megan Barker, Myra Fahim, Arezoo Ebnahmady, Rosa Dragonetti, Peter Selby, Margaret Farrell, Jordan Tompkins, Wynne Norton, Kaelin Rapport, Margaret Hargreaves, Rebekka Lee, Gina Kruse, Charles Deutsch, Emily Lanier, Ashley Gray, Aaron Leppin, Lori Christiansen, Karen Schaepe, Jason Egginton, Megan Branda, Charlene Gaw, Sara Dick, Victor Montori, Nilay Shah, Ariella Korn, Peter Hovmand, Karen Fullerton, Nancy Zoellner, Erin Hennessy, Alison Tovar, Ross Hammond, Christina Economos, Christi Kay, Julie Gazmararian, Emily Vall, Patricia Cheung, Padra Franks, Shannon Barrett-Williams, Paul Weiss, Erica Hamilton, Luana Marques, Louise Dixon, Emily Ahles, Sarah Valentine, Derri Shtasel, Ruben Parra-Cardona, Mary Northridge, Rucha Kavathe, Jennifer Zanowiak, Laura Wyatt, Hardayal Singh, Nadia Islam, Madalena Monteban, Darcy Freedman, Kimberly Bess, Colleen Walsh, Kristen Matlack, Susan Flocke, Heather Baily, Samantha Harden, NithyaPriya Ramalingam, VCE Physical Activity Leadership Team, Rachel Gold, Erika Cottrell, Celine Hollombe, Katie Dambrun, Arwen Bunce, Mary Middendorf, Marla Dearing, Stuart Cowburn, Ned Mossman, Gerry Melgar, Suellen Hopfer, Michael Hecht, Anne Ray, Michelle Miller-Day, Rhonda BeLue, Greg Zimet, Eve-Lynn Nelson, Sandy Kuhlman, Gary Doolittle, Hope Krebill, Ashley Spaulding, Theodore Levin, Michael Sanchez, Molly Landau, Patricia Escobar, Nadia Minian, Aliya Noormohamed, Laurie Zawertailo, Dolly Baliunas, Norman Giesbrecht, Bernard Le Foll, Andriy Samokhvalov, Zachary Meisel, Daniel Polsky, Bruce Schackman, Julia Mitchell, Kaitlyn Sevarino, Sarah Gimbel, Moses Mwanza, Marie Paul Nisingizwe, Catherine Michel, Lisa Hirschhorn, Mahrukh Choudhary, Della Thonduparambil, Paul Meissner, Hilary Pinnock, Melanie Barwick, Christopher Carpenter, Sandra Eldridge, Gonzalo Grandes-Odriozola, Chris Griffiths, Jo Rycroft-Malone, Elizabeth Murray, Anita Patel, Aziz Sheikh, Stephanie J. C. Taylor, Martin Guilliford, Gemma Pearce, Diane Korngiebel, Kathleen West, Wylie Burke, Peggy Hannon, Jeffrey Harris, Kristen Hammerback, Marlana Kohn, Gary K. C. Chan, Riki Mafune, Amanda Parrish, Shirley Beresford, K. Joanne Pike, Rachel Shelton, Lina Jandorf, Deborah Erwin, Thana-Ashley Charles, Laura-Mae Baldwin, Brooke Ike, Jacqueline Fickel, Jason Lind, Diane Cowper, Marguerite Fleming, Amy Sadler, Melinda Dye, Judith Katzburg, Michael Ong, Sarah Tubbesing, Molly Simmons, Autumn Harnish, Sonya Gabrielian, Keith McInnes, Jeffrey Smith, John Ferrand, Elisa Torres, Amy Green, Angela R. Bradbury, Linda J. Patrick-Miller, Brian L. Egleston, Susan M. Domchek, Olufunmilayo I. Olopade, Michael J. Hall, Mary B. Daly, Generosa Grana, Pamela Ganschow, Dominique Fetzer, Amanda Brandt, Rachelle Chambers, Dana F. Clark, Andrea Forman, Rikki S. Gaber, Cassandra Gulden, Janice Horte, Jessica Long, Terra Lucas, Shreshtha Madaan, Kristin Mattie, Danielle McKenna, Susan Montgomery, Sarah Nielsen, Jacquelyn Powers, Kim Rainey, Christina Rybak, Christina Seelaus, Jessica Stoll, Jill Stopfer, Xinxin Shirley Yao, Michelle Savage, Edward Miech, Teresa Damush, Nicholas Rattray, Jennifer Myers, Barbara Homoya, Kate Winseck, Carrie Klabunde, Deb Langer, Avi Aggarwal, Elizabeth Neilson, Lara Gunderson, Marla Gardner, Liam O’Sulleabhain, and Candyce Kroenke

Subjects
Medicine (General), R5-920
Published
2017
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4. Insights from rare variants into the genetic architecture and biology of youth-onset type 2 diabetes

Author

Soo Heon Kwak, Shylaja Sriniva, Ling Chen, Jennifer Todd, Josep Mercader, Elizabeth Jensen, Jasmin Divers, Amy Mottl, Catherine Pihoker, Rachelle Gandica, Lori Laffel, Elvira Isganaitis, Morey Haymond, Lynne Levitsky, Toni Pollin, Jose Florez, and Jason Flannick

Abstract

Youth-onset type 2 diabetes (T2D) is a growing public health concern. Its genetic basis and relationship to other forms of diabetes are largely unknown. To gain insight into the genetic architecture and biology of youth-onset T2D, we analyzed exome sequences of 3,005 youth-onset T2D cases and 9,777 ancestry matched adult controls. We identified (a) monogenic diabetes variants in 2.1% of individuals; (b) two exome-wide significant (P < 4.3×10-7) common coding variant associations (in WFS1 and SLC30A8); (c) three exome-wide significant (P < 2.5×10-6) rare variant gene-level associations (HNF1A, MC4R, ATX2NL); and (d) rare variant association enrichments within 25 gene sets broadly related to obesity, monogenic diabetes, and β-cell function. Many association signals were shared between youth-onset and adult-onset T2D but had larger effects for youth-onset T2D risk (1.18-fold increase for common variants and 2.86-fold increase for rare variants). Both common and rare variant associations contributed more to youth-onset T2D liability variance than they did to adult-onset T2D, but the relative increase was larger for rare variant associations (5.0-fold) than for common variant associations (3.4-fold). Youth-onset T2D cases showed phenotypic differences depending on whether their genetic risk was driven by common variants (primarily related to insulin resistance) or rare variants (primarily related to β-cell dysfunction). These data paint a picture of youth-onset T2D as a disease genetically similar to both monogenic diabetes and adult-onset T2D, in which genetic heterogeneity might be used to sub-classify patients for different treatment strategies.

Published
2023
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5. Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease

Author

Daniel H. Katz, Usman A. Tahir, Alexander G. Bick, Akhil Pampana, Debby Ngo, Mark D. Benson, Zhi Yu, Jeremy M. Robbins, Zsu-Zsu Chen, Daniel E. Cruz, Shuliang Deng, Laurie Farrell, Sumita Sinha, Alec A. Schmaier, Dongxiao Shen, Yan Gao, Michael E. Hall, Adolfo Correa, Russell P. Tracy, Peter Durda, Kent D. Taylor, Yongmei Liu, W. Craig Johnson, Xiuqing Guo, Jie Yao, Yii-Der Ida Chen, Ani W. Manichaikul, Deepti Jain, Claude Bouchard, Mark A. Sarzynski, Stephen S. Rich, Jerome I. Rotter, Thomas J. Wang, James G. Wilson, Pradeep Natarajan, Robert E. Gerszten, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, April Carson, Cara Carty, Richard Casaburi, Juan P. Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Michael Cho, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Namrata Gupta, David M. Haas, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Jianhong Hu, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Sandra Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yu Liu, Ruth J.F. Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Ani Manichaikul, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Rasika Mathias, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James Meigs, Vipin Menon, Luisa Mestroni, Ginger Metcalf, Deborah A. Meyers, Emmanuel Mignot, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton D. Mitchell, Matt Moll, Zeineen Momin, May E. Montasser, Courtney Montgomery, Donna Muzny, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Sergei Nekhai, Sarah C. Nelson, Bonnie Neltner, Caitlin Nessner, Deborah Nickerson, Osuji Nkechinyere, Kari North, Jeff O’Connell, Tim O’Connor, Heather Ochs-Balcom, Geoffrey Okwuonu, Allan Pack, David T. Paik, Nicholette Palmer, James Pankow, George Papanicolaou, Cora Parker, Gina Peloso, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Jacob Pleiness, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Mahitha Rajendran, Vasan S. Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Muagututi’a Sefuiva Reupena, Ken Rice, Stephen Rich, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven Salzberg, Kevin Sandow, Vijay G. Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L. Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Robert Skomro, Albert Vernon Smith, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Daniel Taliun, Hua Tang, Margaret Taub, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Russell Tracy, Michael Tsai, Dhananjay Vaidya, David Van Den Berg, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E. Weeks, Joshua Weinstock, Bruce Weir, Scott T. Weiss, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, L. Keoki Williams, Carla Wilson, James Wilson, Lara Winterkorn, Quenna Wong, Joseph Wu, Huichun Xu, Lisa Yanek, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Michael Zody, and Sebastian Zoellner

Subjects
Adult, Male, Proteomics, Aging, Whole genome sequence analysis, Proteome, Clinical Sciences, Black People, Disease, Computational biology, race and ethnicity, Cardiorespiratory Medicine and Haematology, Cardiovascular, Article, proteomics, cardiovascular disease, Physiology (medical), Genetics, 2.1 Biological and endogenous factors, Humans, Medicine, Aetiology, Lung, Heart Disease - Coronary Heart Disease, and Blood Institute TOPMed (Trans-Omics for Precision Medicine) Consortium†, business.industry, Prevention, Human Genome, National Heart, Genomics, Blood proteins, Genetic architecture, Heart Disease, Good Health and Well Being, Cardiovascular System & Hematology, Cardiovascular Diseases, Public Health and Health Services, Female, Cardiology and Cardiovascular Medicine, business, Biotechnology, Genome-Wide Association Study
Abstract

Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

Published
2022
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8. Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma

Author

Priyadarshini Kachroo, Julian Hecker, Bo L. Chawes, Tarunveer S. Ahluwalia, Michael H. Cho, Dandi Qiao, Rachel S. Kelly, Su H. Chu, Yamini V. Virkud, Mengna Huang, Kathleen C. Barnes, Esteban G. Burchard, Celeste Eng, Donglei Hu, Juan C. Celedón, Michelle Daya, Albert M. Levin, Hongsheng Gui, L. Keoki Williams, Erick Forno, Angel C.Y. Mak, Lydiana Avila, Manuel E. Soto-Quiros, Michelle M. Cloutier, Edna Acosta-Pérez, Glorisa Canino, Klaus Bønnelykke, Hans Bisgaard, Benjamin A. Raby, Christoph Lange, Scott T. Weiss, Jessica A. Lasky-Su, Namiko Abe, Goncalo Abecasis, Christine Albert, Nicholette (Nichole) Palmer Allred, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Terri Beaty, Diane Becker, Lewis Becker, Rebecca Beer, Ferdouse Begum, Amber Beitelshees, Emelia Benjamin, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Ingrid Borecki, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Karen Bunting, Esteban Burchard, Jonathan Cardwell, Cara Carty, Richard Casaburi, James Casella, Mark Chaffin, Christy Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Yii-Der Ida Chen, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sayantan Das, Sean David, Colleen Davis, Mariza de Andrade, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Ron Do, Qing Duan, Ravi Duggirala, Peter Durda, Susan Dutcher, Charles Eaton, Lynette Ekunwe, Patrick Ellinor, Leslie Emery, Charles Farber, Leanna Farnam, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Yan Gao, Margery Gass, Bruce Gelb, Xiaoqi (Priscilla) Geng, Soren Germer, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, C. Charles Gu, Yue Guan, Xiuqing Guo, Jeff Haessler, Michael Hall, Daniel Harris, Nicola Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, John Hokanson, Kramer Holly, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Min A. Jhun, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Sekar Kathiresan, Laura Kaufman, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Greg Kinney, Barbara Konkle, Charles Kooperberg, Stephanie Krauter, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Seunggeun Shawn Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Yun Li, Honghuang Lin, Keng Han Lin, Simin Liu, Yongmei Liu, Ruth Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Michael Mahaney, Barry Make, Ani Manichaikul, JoAnn Manson, Lauren Margolin, Lisa Martin, Susan Mathai, Rasika Mathias, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Hao Mei, Deborah A. Meyers, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton Mitchell, May E. Montasser, Solomon Musani, Stanford Mwasongwe, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Pradeep Natarajan, Sergei Nekhai, Deborah Nickerson, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, James Pankow, George Papanicolaou, Margaret Parker, Afshin Parsa, Sara Penchev, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Sam Phillips, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Dmitry Prokopenko, Bruce Psaty, Pankaj Qasba, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Vasan Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Elizabeth Regan, Alex Reiner, Ken Rice, Stephen Rich, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Phuwanat Sakornsakolpat, Shabnam Salimi, Steven Salzberg, Kevin Sandow, Vijay Sankaran, Christopher Scheller, Ellen Schmidt, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Vivien Sheehan, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Tamar Sofer, Nona Sotoodehnia, Adrienne Stilp, Elizabeth Streeten, Yun Ju Sung, Jessica Su-Lasky, Jody Sylvia, Adam Szpiro, Carole Sztalryd, Daniel Taliun, Hua Tang, Margaret Taub, Kent Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Lesley Tinker, David Tirschwell, Hemant Tiwari, Russell Tracy, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Emily Wan, Fei Fei Wang, Karol Watson, Daniel E. Weeks, Bruce Weir, Scott Weiss, Lu-Chen Weng, Cristen Willer, Kayleen Williams, Carla Wilson, James Wilson, Quenna Wong, Huichun Xu, Lisa Yanek, Ivana Yang, Rongze Yang, Norann Zaghloul, Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiuwen Zheng, Degui Zhi, Xiang Zhou, Michael Zody, and Sebastian Zoellner

Subjects
Adult, Costa Rica, Male, Pulmonary and Respiratory Medicine, Adolescent, Vital Capacity, Single-nucleotide polymorphism, Pedigree chart, Critical Care and Intensive Care Medicine, Young Adult, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Polymorphism (computer science), Forced Expiratory Volume, Humans, Medicine, SNP, 030212 general & internal medicine, Child, Asthma, Whole Genome Sequencing, business.industry, Middle Aged, respiratory system, medicine.disease, respiratory tract diseases, Minor allele frequency, 030228 respiratory system, Genetic epidemiology, Child, Preschool, Interferon Regulatory Factors, Immunology, Respiratory Physiological Phenomena, Female, Cardiology and Cardiovascular Medicine, business, Cell Adhesion Molecules
Abstract

BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.

Published
2019
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9. Abstract 21310: ApoCIII RX19 Mutation Lowers the Production of ApoCIII and Increases the Clearance of VLDL-TG

Author

Gissette Reyes-Soffer, Anstasiya Matveyenko, Maryam Khavandi, Wahida Karmally, Rajasekhar Ramakrishnan, Stephen Holleran, Henry Ginsberg, and Toni Pollin

Subjects
Physiology (medical), lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine
Abstract

The APOCIII R19X mutation (rs76353203), has been found in ~5% of the Lancaster Old Order Amish. It is a C ->T substitution at the 55th nucleotide in human aolipoprotein C-III mRNA that prevents translation of mature apoC-III protein. The mutation decreases apoC-III levels by ~50% and confers favorable lipid profiles and less coronary artery calcification, providing evidence that ApoC-III deficiency is cardioprotective. This conclusion is supported by recent data in Danish and U.S. cohorts showing a 40% reduction in myocardial infarction rates in people with this mutation. The mechanisms whereby apoc-III deficiency exerts its effects are not fully understood. The aim of this study was to describe the fractional clearance rates (FCR) and production rates (PR) of apoB containing lipoproteins, apoCIII, and very low density lipoprotein (VLDL) tryglyceride (TG) in five Amish sibling pairs (CT vs. CC) discordant for the APOC3 R19X mutation and matched for age and sex. Methods: Sib pairs completed a 24-hr stable isotope kinetic study using leucine and glycerol. Blood samples were collected over 24-hr period. We measured plasma lipids and apoCIII by Elisa. We determined the FCR and PR of VLDL apoB, apoCIII, and VLDL-TG. Results: The CT subjects had a 38% decrease in baseline TG levels compared to CC. ApoCIII levels were reduced by 42% in the CT vs. CC. We observed reductions in VLDL-Chol (49%), IDL-Chol (52%), VLDL-TG(44%), and IDL-TG(39%) in the CT when compared to CC. The changes in plasma levels were due to an increase in the VLDL apoB FCR (p = 0.001) without significant changes in production. VLDL-TG FCR increased by 76% in the CT when compared to CC (p=0.03). We observed no differences in post-heparin plasma levels of hepatic and lipoprotein lipase activity in the CT vs. CC. The plasma changes in apoCIII were due to and increased FCR in the CT compared to CC. Conclusions: Reductions in plasma TG levels in heterozygous apoC-III deficient individuals is due to enhanced FCRs of VLDL-apoB and VLDL-TG.

Published
2017
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10. Proceedings of the 8th Annual Conference on the Science of Dissemination and Implementation

Author

Lina Jandorf, Janice Horte, Claire Neely, Christine Hartmann, Jennifer Regan, Lior Turgeman, Laura Wyatt, Avi Aggarwal, Elizabeth Murray, Susan Montgomery, Anne Ray, William Lukesh, Susan Yee, Keng-yen Huang, William L. Miller, Terry Jankowski, Anne E. Sales, Samantha M. Harden, Alexandra B. Morshed, George Valko, Julie Gazmararian, Kristen Schaffner, Marie Paul Nisingizwe, Amy Sadler, Heather Kaplan, Celeste Liebrecht, Jennifer Sharpe Potter, Helen Kales, M. Rashad Massoud, Caity Frail, Christian Rusangwa, Candice Monson, Bernard Le Foll, Gemmae Fix, Justin Presseau, George Sayre, Nicholas A. Rattray, Rebekka Lee, Arne Beck, Vincent Liu, Chris Griffiths, Megan Barker, Thomas Love, Leanne Whiteside-Mansell, Ross Shegog, Susan A. Flocke, Laurie Miller Brotman, Jeffery Pitcock, Moses Mwanza, Kera Mallard, Don McGeary, Rinad S. Beidas, Tara Queen, Thana-Ashley Charles, Toni Pollin, Jennifer Zanowiak, Julie Johnson, Carrie Klabunde, Wendy Lantaff, Martin Guilliford, Sabrina Cheng, Elyse Park, Mary McKay, Patricia Cheung, Marla Gardner, Suellen Hopfer, Julie E Reed, Jamie Park, Sarah M. Nielsen, Andrea Forman, Paul Meissner, Brittany Skiles, Steven B. Zeliadt, Shannon Wiltsey Stirman, Christina D. Economos, Amanda Clark, Rachel Kimerling, Katie Dambrun, Leah Gordon, Wen Wan, Krysttel Stryczek, Shari Bolen, Marc Rosenman, Kimberly K Vesco, Joel Rosenthal, Mona Sarfaty, Lara Gunderson, Hardayal Singh, Ann Donze, Ross A. Hammond, Catherine Michel, Stephanie Taylor, David Au, Rakesh Rao, Chris Shea, Christine Markham, David Smelson, Mary Northridge, K. Joanne Pike, Terra Lucas, Sherri L. Lavela, Mary Wangen, Appathurai Balamurugan, Hope Krebill, Daniel Blonigen, Roman Kislov, Edward J. Miech, Peggy A. Hannon, Myra Fahim, Mary Jo Pugh, Ross C. Brownson, Erika Cottrell, Emmanuela Gakidou, Paul Weiss, Kathryn G. Sapnas, Padra Franks, Shereef Elnahal, Margaret Hargreaves, Candyce Kroenke, Sandra Eldridge, Charles Deutsch, Elizabeth A. Dodson, Mona J. Ritchie, Jennifer Leeman, Barbara Bokhour, Paul Wilson, Christina Seelaus, Gina Kruse, Margaret Handley, Rachelle Chambers, Emily Vall, Norman Giesbrecht, Brian L. Egleston, Ariella R. Korn, Melissa Somma McGivney, Della Thonduparambil, Valerie Caldas, Maggie Wolf, Ashley Stoneburner, David A. Ganz, Patricia Dolan Mullen, Kaelin Rapport, Stephen M. Shortell, Teresa Hudson, John Ferrand, Sarah Ono, Jerome Watts, Allison Rodriguez, Ngoc-Cam Escoffery, Rose McGonigle, Ebony Madden, Donna Shelley, Rachel Sturke, Hillary Peabody, Ned Mossman, Giuseppe Raviola, J. Lucian Davis, Ashley Gray, Antoinette Percy-Laurry, Keith McInnes, Ashley Garcia, Nicole Gesualdo, Benjamin Saunders, Jacqueline J. Fickel, Nilay Shah, Barbara Homoya, Olive Kabajaasi, Amy Kilbourne, Aliya Noormohamed, John Humphreys, Sonya Gabrielian, Jennifer Williamson, Frances K. Barg, Thomas Mackie, Jessica Stoll, Ruben Parra-Cardona, Douglas Einstadter, Neda Laiteerapong, Gary Doolittle, Muin J. Khoury, Nadia Minian, Andrew N Blatt, Sylvia Sax, Edmond Ramly, Arezoo Ebnahmady, Achilles Katamba, Amit Mathur, Celine Hollombe, Christopher Smyser, Brook Watts, Nina Sperber, Sarah Birken, Karina Davidson, Jeffrey Solomon, Rosa Dragonetti, Fern Fitzhenry, Leif Solberg, Megan McCullough, Nina Sayer, Michelle Savage, Ashley Ketterer Gruszkowski, Linda Patrick-Miller, Molly Franke, Nora Mueller, Rachel G. Tabak, Elizabeth Neilson, Tejinder Rakhra-Burris, Laura-Mae Baldwin, Peter Selby, Hal Roberts, F. Sessions Cole, Gerry Melgar, Dianne Ward, Ellie Morris, Jamie Ostroff, Kimberly Hoagwood, Stephanie Mazzucca, Victoria Scott, Katie Halkyard, Jason Egginton, Amy Herschell, Nadia Islam, Danielle McKenna, Erin Lebow-Skelley, Richard J. Wood, Michael F. Murray, Jordan Tompkins, Aleksandra Sasha Milicevic, Lisa R. Hirschhorn, Jo Rycroft-Malone, David W. Lounsbury, Kathleen West, Tanya Olmos, Cassandra Gulden, Shalynn Howard, Stephanie Craig Rushing, Sten Vermund, Margaret M. Farrell, Dominique Fetzer, Linda Fleisher, Lisa Simpson, Michael J. Hall, Lisa M Klesges, Marc S. Williams, Karen Schaepe, Allyson Varley, Wynne E. Norton, Julia Kyle, Rivet Amico, Emily Ahles, Bruce R. Schackman, Erin P. Finley, Kristin Weitzel, Shevin Jacob, Rikki S. Gaber, Pamela Ganschow, Joshua Denny, Victor Montori, JoAnn Kirchner, Lauren Brookman-Frazee, Rhonda BeLue, Zachary Patterson, Jennifer Boggs, Riki Mafune, Sarah J. Shoemaker, Kate Winseck, Joan Smith, Marci Schwartz, Gabriel J. Escobar, Shannon Barrett-Williams, Gary K. C. Chan, Arona Ragins, Beth Ann Petrakis, Liam O’Sulleabhain, David Thornton, Cynthia Vinson, Jacky M. Jennings, Rucha Kavathe, Enrique Torres Hernandez, Elijah Goldberg, Patricia Carreno, Gill Harvey, Nathan Kenya-Mugisha, Brandy Smith, Demietrice Pittman, Enola K. Proctor, Angela Moreland, Kasisomayajula Viswanath, Adam Rose, Jennifer Bacci, Sarah Tubbesing, Kenneth Sherr, Emily Sykes, Shoba Ramanadhan, Nicole A. Stadnick, Amanda Brandt, Abraham Wandersman, Chris Gillespie, R. Chris Sheldrick, Amy Kennedy, Sara Dick, Carolyn M. Clancy, Savio Mwaka, Adithya Cattamanchi, Mahrukh Choudhary, Sruthi Buddai, Mark S Bauer, Generosa Grana, Shamik Trivedi, Gwenda Gorman, Deb Langer, Karissa Fenwick, Darcy A. Freedman, Jason Lind, Cara C. Lewis, Steven Lindley, Deborah O. Erwin, Melissa Peskin, Kristen D. Rosen, Terrence L. Hubert, Michael Ong, Aziz Sheikh, Justeen Hyde, Zachary F. Meisel, Claudina Tami, Greg Zimet, Jennifer Grant, Gerald F. Kominski, Jessica M. Long, Allison Myers, Chris Carpenter, Rachel Ceccarelli, Marla Dearing, Sharon Straus, Stephanie Smith, Michael A. Sanchez, Angela Park, Ellen Jones, Luisa Manfredi, Ravi Shah, Jacquelyn Powers, Cara McCormick, Shusmita Rashid, Victoria Pratt, Miya L. Barnett, Michael Parchman, Elaine Böing, Suzanne Heurtin-Roberts, Anita Patel, Christine Lu, Christi Kay, Jeremy Thomas, Craig Rosen, Gbenga Ogedegbe, Amanda T. Parrish, Diane R Lauver, Lori Orlando, Brian S. Mittman, Hallie Udelson, Rachel Gold, Erica Hamilton, José Salato, Youxu C. Tjader, Benjamin Turk, Giselle Perez, Amber Vaughn, Jeffrey R. Smith, Eric R. Larson, Rohit Ramaswamy, Colleen Payton, Jodie A. Trafton, Elisa M. Torres, Cameo Stanick, Bryan J. Weiner, Beatha Nyirandagijimana, Rachel C. Shelton, Rebecca Lengnick-Hall, Michael W. Kennedy, Madalena Monteban, Megan Roberts, Laurel Leslie, Autumn Harnish, Ann Wu, Janet Carpenter, Alexander Fiks, Carol R. Horowitz, Michael Hecht, Andriy V. Samokhvalov, Amanda Gaston, Olufunmilayo I. Olopade, Elizabeth A. Stuart, Dan Berlowitz, Matthew Weber, Amanda Vogel, Yinfei Kong, Rochelle Hanson, Lee Fleisher, Stephen Gloyd, Jay Carruthers, Melissa Courvoisier, Kim Rainey, Carmel Nichols, Christie M Bartels, Gregory A. Aarons, Kristin Mattie, Jonathan Scaccia, Vilma Martinez-Dominguez, Charlene Gaw, Christina Rybak, Nancy Zoellner, Leighann Kimble, Xinxin Shirley Yao, Kandamurugu Manickam, Caitlin Dorsey, Nathalie Moise, Marguerite Fleming, Meghan Lane-Fall, Michael Leo, Carolyn Audet, Stefanie Ferreri, Laura J. Damschroder, Kate McGraw, Colleen Walsh, Ross Brownson, Lindsey Zimmerman, Teresa M. Damush, Lori Christiansen, Hildegarde Mukasakindi, Mary B. Daly, Itzhak Yanovitzky, Laura Di Taranti, Mary Middendorf, Ashley Scudder, Diane Korngiebel, Kimberly Bess, Sarah Valentine, Erick G. Guerrero, Jennifer N. Hill, Sally K. Holmes, Hector P. Rodriguez, Sarah Greene, Joanna Bulkley, Theodore Levin, Cory Hamata, Michelle Barbaresso, Melanie Barwick, Margie Snyder, Sonja K. Schoenwald, Sara Locatelli, Jeffrey R. Harris, Laurie Zawertailo, Adam H. Buchanan, Erin Staab, Isomi Miake-Lye, Emily Lanier, Eva Woodward, David A. Chambers, Dolly Baliunas, Rachel Gruver, Amanda Elsey, Rahul Bhargava, Amy E. Green, Emmeline Chuang, Larissa Myaskovsky, Gemma Pearce, Megan Smith, Melinda Dye, Emily Rentschler Drobek, Lauren Peccoralo, Louise Dixon, Kassy Alia, Daniel Polsky, NithyaPriya Ramalingam, Byron J. Powell, Taren Swindle, Molly M. Simmons, Derri Shtasel, Brian Hackett, Lloyd Sederer, Michelle Miller-Day, Tasoula Masina, Kathleen M. Mazor, Gilo Thomas, Andrea Nevedal, Kaitlyn Sevarino, Julia E. Moore, Susan Essock, Patricia Kipnis, Gila Neta, Kyle Bigham, Christian Helfrich, Peter Hovmand, Sarah Gimbel, Luana Marques, Rendelle Bolton, Yue Guan, Benjamin Teeter, Angela R. Bradbury, Kristen Hammerback, Susan M. Domchek, Heather Baily, Dana F. Clark, Geoffrey M. Curran, Randall Cebul, Anna S. Lau, Shirley Beresford, Larisa Cavallari, Gonzalo Grandes-Odriozola, Eve-Lynn Nelson, Matthew Cummings, Ashley Spaulding, Bijal Balasubramanian, Brooke Ike, Arwen Bunce, Deborah J. Cohen, Jennifer Torres, Heather Halko, Karen Fullerton, Erin Hennessy, Benjamin Crabtree, Carol VanDeusen Lukas, Shawna Smith, Todd Molfenter, Gareth Parry, Kea Turner, Laura Gibson, Patricia Escobar, Becky Yano, Sobia Khan, Shreshtha Madaan, Teis Kristensen, Stuart Cowburn, Allen L. Gifford, Judith Katzburg, Kate Beadle, Maria E. Fernandez, Hilary Pinnock, Alanna Kulchak Rahm, Robert Lieberthal, Sarah Taber-Thomas, Daniel Eisenberg, Regan Burney, Amy Jones, Andrea Ippolito, Donald R. Miller, Christine Timko, Deborah Delevan, Marlana Kohn, Sara Minsky, Wylie Burke, Ulrica von Thiele Schwarz, Megan E. Branda, Alison Tovar, Corrine Voils, Kristen Matlack, Holly Swan, Vera Yakovchenko, Brian Austin, Benjamin Henwood, Mari-Lynn Drainoni, R. Ryanne Wu, Sandy Kuhlman, Jenita Parekh, Jennifer Myers, Aaron Leppin, Julia Mitchell, Robert J. Monte, Cornelia Jessen, Robert Orazem, Diane Cowper, Mary Hook, Jill Stopfer, and Molly Landau

Subjects
medicine.medical_specialty, education.field_of_study, business.industry, Health Policy, Public health, Population, Public Health, Environmental and Occupational Health, Health services research, Library science, Health Informatics, General Medicine, Population health, Health equity, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Community health, Health care, medicine, 030212 general & internal medicine, business, education, 030217 neurology & neurosurgery, Health policy
Abstract

A1 Introduction to the 8th Annual Conference on the Science of Dissemination and Implementation: Optimizing Personal and Population Health David Chambers1, Lisa Simpson2 1Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Rockville, MD, 20850, USA; 2AcademyHealth, Washington, DC, 20036, USA For the second year in a row, we are pleased to be able to share the proceedings of the Annual Conference on the Science of Dissemination and Implementation in Health, a large meeting reflecting the expanding and evolving research field that seeks to optimize the use of evidence, interventions, and tools from health research within the myriad of settings where people receive health care, make health-related decisions, and increase knowledge of influences on the health of the population. We once again benefitted from a strong partnership, co-led by AcademyHealth and the National Institutes of Health (NIH), with co-sponsorship from the Agency for Healthcare Research and Quality (AHRQ), the Patient Centered Outcomes Research Institute (PCORI), the Robert Wood Johnson Foundation (RWJF), the US Department of Veterans Affairs (VA), and the WT Grant Foundation. In addition, we benefitted from the collaboration of staff from the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO). NIH and AcademyHealth again co-led the program planning committee, which focused on the development of the plenary sessions, and convened a scientific advisory panel to suggest speakers and advise on the overall conference development. The planning committee identified four key areas around which to focus the plenary panels and keynote address. Dr. America Bracho, M.D., M.P.H., Executive Director of Latino Health Access in Orange County, California, spoke about the opportunities for implementation science to inform efforts to improve community health and engage underserved populations. The three plenary panels each focused on a significant future direction for dissemination and implementation (D & I) research: the interface between D&I science and population health, emerging opportunities for global implementation science, and the challenges around implementation of precision medicine. The plenary sessions were complemented by facilitated lunchtime discussions on the same three topics, which offered participants an opportunity to identify key research questions for each and brainstorm next steps. Synopses of the lunchtime discussions are included in this supplement. Given the overwhelming success of the 2014 conference and the large number of abstracts received in 2014 (660), the program planning committee identified eight program tracks for abstract submitters to respond to, and through which the concurrent sessions of the conference would be organized. These tracks—Behavioral Health, Big Data and Technology for Dissemination and Implementation Research, Clinical Care Settings, Global Dissemination and Implementation, Promoting Health Equity and Eliminating Disparities, Health Policy Dissemination and Implementation, Prevention and Public Health, and Models, Measures and Methods— were designed to enable conference participants to follow a consistent theme across the multiple sessions of the conference and form the structure of this supplement. The call for abstracts, including individual paper presentations, individual posters and panel presentations, resulted in 515 submissions, spread across the eight thematic tracks. Over one hundred reviewers devoted their time to ensuring a comprehensive and expert review, and reviews were conducted within each track and coordinated by the track leads. For the final program, 64 oral presentations, 12 panels, and 263 posters were presented over the two-day meeting. Slides for the oral presentations and panels (with the agreement of the authors) were posted on the conference website (http://diconference.academyhealth.org/archives/2015archives) and all abstracts were included on the conference webapp (https://academyhealth.confex.com/academyhealth/2015di/meetingapp.cgi). This supplement has compiled the abstracts for presented papers, panel sessions, and lunchtime discussions from the 8th Annual Meeting on the Science of Dissemination and Implementation in Health: Optimizing Personal and Population Health. We are pleased to have the abstracts from the conference together in one volume once again, and look forward to the 9th Annual meeting, scheduled for December in Washington, D.C.

Published
2016
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11. Using Workflow Modeling to Identify Areas to Improve Genetic Test Processes in the University of Maryland Translational Pharmacogenomics Project

Author

Elizabeth M, Cutting, Casey L, Overby, Meghan, Banchero, Toni, Pollin, Mark, Kelemen, Alan R, Shuldiner, and Amber L, Beitelshees

Subjects
Academic Medical Centers, Pharmacogenetics, Models, Organizational, Humans, Genetic Testing, Articles, Precision Medicine, Quality Improvement, Workflow
Abstract

Delivering genetic test results to clinicians is a complex process. It involves many actors and multiple steps, requiring all of these to work together in order to create an optimal course of treatment for the patient. We used information gained from focus groups in order to illustrate the current process of delivering genetic test results to clinicians. We propose a business process model and notation (BPMN) representation of this process for a Translational Pharmacogenomics Project being implemented at the University of Maryland Medical Center, so that personalized medicine program implementers can identify areas to improve genetic testing processes. We found that the current process could be improved to reduce input errors, better inform and notify clinicians about the implications of certain genetic tests, and make results more easily understood. We demonstrate our use of BPMN to improve this important clinical process for CYP2C19 genetic testing in patients undergoing invasive treatment of coronary heart disease.

Published
2016

12. Abstract 1096: Predictors Of Carotid Intimal-medial Thickness In Subjects With Hyperalphalipoproteinemia

Author

Michael West, Bela Asztalos, Toni Pollin, Wendy Post, and Annabelle Rodriguez

Subjects
Physiology (medical), Cardiology and Cardiovascular Medicine
Abstract

HDL cholesterol (HDL-C) is inversely associated with risk for CVD in the general population. However, the metabolic pathways leading to high HDL (hyperalphalipoproteinemia) are complex, and some patients with high HDL-C are not protected against atherosclerotic disease. The purpose of this study was to determine the associations between CVD risk factors, especially HDL subpopulations, and subclinical vascular disease in patients with high HDL-C. Community-dwelling adult subjects with and without CAD between the ages of 18 – 80 years with HDL-C levels above 60 mg/dl were recruited for this study (n=46, 34 women and 12 men, mean age 58.7 ± 9.7 years). After an overnight fast, blood was obtained for measurement of lipids, inflammatory markers and lipoproteins by NMR spectroscopy (Liposcience, NC) and 2D-gel analysis. Far wall common carotid artery intimal-medial thickness (IMT) was measured using carotid ultrasonography. None of the subjects were taking statins. The lipid levels (mean ± SD) were total cholesterol 225.6 ± 37.9 mg/dl, triglycerides 77.9 ± 29.4 mg/dl, HDL 90.4 ± 22.5 mg/dl and LDL 119.6 ± 33.4 mg/dl. Carotid IMT values were normally distributed, with a range of 0.46 –1.1 mm. Unadjusted pairwise-correlations showed that carotid IMT was significantly associated with LDL particle number ( p< 0.03), HDL subpopulations by 2D-gel analysis [α-3: p< 0.005; α-4: p< 0.04; and preα-1: p< 0.03], C-reactive protein ( p< 0.03), sVCAM-1 ( p< 0.02), age ( p< 0.0008), systolic blood pressure ( p< 0.02), heart rate ( p< 0.02) and corneal arcus ( p< 0.04). Carotid IMT was not associated with any traditional lipid level, gender or history of CAD. In a multiple regression model, age ( p =0.0007), α-3 ( p< 0.008) and CRP ( p< 0.03) were significant independent predictors of carotid IMT in this population. Thus, in subjects with hyperalphalipoproteinemia, increased small, dense HDL (α-3) and CRP levels were associated with increasing carotid IMT, suggesting heterogeneity in the role of HDL particles on subclinical atherosclerosis.

Published
2007
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