16 results on '"Weinstock, Joshua"'
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2. Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis
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Weinstock, Joshua S., Gopakumar, Jayakrishnan, Burugula, Bala Bharathi, Uddin, Md Mesbah, Jahn, Nikolaus, Belk, Julia A., Bouzid, Hind, Daniel, Bence, Miao, Zhuang, Ly, Nghi, Mack, Taralynn M., Luna, Sofia E., Prothro, Katherine P., Mitchell, Shaneice R., Laurie, Cecelia A., Broome, Jai G., Taylor, Kent D., Guo, Xiuqing, Sinner, Moritz F., von Falkenhausen, Aenne S., Kääb, Stefan, Shuldiner, Alan R., O’Connell, Jeffrey R., Lewis, Joshua P., Boerwinkle, Eric, Barnes, Kathleen C., Chami, Nathalie, Kenny, Eimear E., Loos, Ruth J. F., Fornage, Myriam, Hou, Lifang, Lloyd-Jones, Donald M., Redline, Susan, Cade, Brian E., Psaty, Bruce M., Bis, Joshua C., Brody, Jennifer A., Silverman, Edwin K., Yun, Jeong H., Qiao, Dandi, Palmer, Nicholette D., Freedman, Barry I., Bowden, Donald W., Cho, Michael H., DeMeo, Dawn L., Vasan, Ramachandran S., Yanek, Lisa R., Becker, Lewis C., Kardia, Sharon L. R., Peyser, Patricia A., He, Jiang, Rienstra, Michiel, Van der Harst, Pim, Kaplan, Robert, Heckbert, Susan R., Smith, Nicholas L., Wiggins, Kerri L., Arnett, Donna K., Irvin, Marguerite R., Tiwari, Hemant, Cutler, Michael J., Knight, Stacey, Muhlestein, J. Brent, Correa, Adolfo, Raffield, Laura M., Gao, Yan, de Andrade, Mariza, Rotter, Jerome I., Rich, Stephen S., Tracy, Russell P., Konkle, Barbara A., Johnsen, Jill M., Wheeler, Marsha M., Smith, J. Gustav, Melander, Olle, Nilsson, Peter M., Custer, Brian S., Duggirala, Ravindranath, Curran, Joanne E., Blangero, John, McGarvey, Stephen, Williams, L. Keoki, Xiao, Shujie, Yang, Mao, Gu, C. Charles, Chen, Yii-Der Ida, Lee, Wen-Jane, Marcus, Gregory M., Kane, John P., Pullinger, Clive R., Shoemaker, M. Benjamin, Darbar, Dawood, Roden, Dan M., Albert, Christine, Kooperberg, Charles, Zhou, Ying, Manson, JoAnn E., Desai, Pinkal, Johnson, Andrew D., Mathias, Rasika A., Blackwell, Thomas W., Abecasis, Goncalo R., Smith, Albert V., Kang, Hyun M., Satpathy, Ansuman T., Natarajan, Pradeep, Kitzman, Jacob O., Whitsel, Eric A., Reiner, Alexander P., Bick, Alexander G., and Jaiswal, Siddhartha
- Abstract
Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2–6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1Apromoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1Awas not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2or ASXL1led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1Aexpression. Forced expression of TCL1Apromoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1Aactivation.
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- 2023
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3. Clonal haematopoiesis and risk of chronic liver disease
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Wong, Waihay J., Emdin, Connor, Bick, Alexander G., Zekavat, Seyedeh M., Niroula, Abhishek, Pirruccello, James P., Dichtel, Laura, Griffin, Gabriel, Uddin, Md Mesbah, Gibson, Christopher J., Kovalcik, Veronica, Lin, Amy E., McConkey, Marie E., Vromman, Amelie, Sellar, Rob S., Kim, Peter G., Agrawal, Mridul, Weinstock, Joshua, Long, Michelle T., Yu, Bing, Banerjee, Rajarshi, Nicholls, Rowan C., Dennis, Andrea, Kelly, Matt, Loh, Po-Ru, McCarroll, Steve, Boerwinkle, Eric, Vasan, Ramachandran S., Jaiswal, Siddhartha, Johnson, Andrew D., Chung, Raymond T., Corey, Kathleen, Levy, Daniel, Ballantyne, Christie, Ebert, Benjamin L., and Natarajan, Pradeep
- Abstract
Chronic liver disease is a major public health burden worldwide1. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis2. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent and incident chronic liver disease (odds ratio = 2.01, 95% confidence interval (95% CI) [1.46, 2.79]; P< 0.001). Individuals with CHIP were more likely to demonstrate liver inflammation and fibrosis detectable by magnetic resonance imaging compared to those without CHIP (odds ratio = 1.74, 95% CI [1.16, 2.60]; P= 0.007). To assess potential causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (odds ratio = 2.37, 95% CI [1.57, 3.6]; P< 0.001). In a dietary model of non-alcoholic steatohepatitis, mice transplanted with Tet2-deficient haematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated by the NLRP3 inflammasome and increased levels of expression of downstream inflammatory cytokines in Tet2-deficient macrophages. In summary, clonal haematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression through an aberrant inflammatory response.
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- 2023
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4. Clonal hematopoiesis is associated with protection from Alzheimer’s disease
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Bouzid, Hind, Belk, Julia A., Jan, Max, Qi, Yanyan, Sarnowski, Chloé, Wirth, Sara, Ma, Lisa, Chrostek, Matthew R., Ahmad, Herra, Nachun, Daniel, Yao, Winnie, Beiser, Alexa, Bick, Alexander G., Bis, Joshua C., Fornage, Myriam, Longstreth, William T., Lopez, Oscar L., Natarajan, Pradeep, Psaty, Bruce M., Satizabal, Claudia L., Weinstock, Joshua, Larson, Eric B., Crane, Paul K., Keene, C. Dirk, Seshadri, Sudha, Satpathy, Ansuman T., Montine, Thomas J., and Jaiswal, Siddhartha
- Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer’s disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P= 3.8 × 10−5), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD.
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- 2023
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5. Inherited causes of clonal haematopoiesis in 97,691 whole genomes
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Bick, Alexander G., Weinstock, Joshua S., Nandakumar, Satish K., Fulco, Charles P., Bao, Erik L., Zekavat, Seyedeh M., Szeto, Mindy D., Liao, Xiaotian, Leventhal, Matthew J., Nasser, Joseph, Chang, Kyle, Laurie, Cecelia, Burugula, Bala Bharathi, Gibson, Christopher J., Lin, Amy E., Taub, Margaret A., Aguet, Francois, Ardlie, Kristin, Mitchell, Braxton D., Barnes, Kathleen C., Moscati, Arden, Fornage, Myriam, Redline, Susan, Psaty, Bruce M., Silverman, Edwin K., Weiss, Scott T., Palmer, Nicholette D., Vasan, Ramachandran S., Burchard, Esteban G., Kardia, Sharon L. R., He, Jiang, Kaplan, Robert C., Smith, Nicholas L., Arnett, Donna K., Schwartz, David A., Correa, Adolfo, de Andrade, Mariza, Guo, Xiuqing, Konkle, Barbara A., Custer, Brian, Peralta, Juan M., Gui, Hongsheng, Meyers, Deborah A., McGarvey, Stephen T., Chen, Ida Yii-Der, Shoemaker, M. Benjamin, Peyser, Patricia A., Broome, Jai G., Gogarten, Stephanie M., Wang, Fei Fei, Wong, Quenna, Montasser, May E., Daya, Michelle, Kenny, Eimear E., North, Kari E., Launer, Lenore J., Cade, Brian E., Bis, Joshua C., Cho, Michael H., Lasky-Su, Jessica, Bowden, Donald W., Cupples, L. Adrienne, Mak, Angel C. Y., Becker, Lewis C., Smith, Jennifer A., Kelly, Tanika N., Aslibekyan, Stella, Heckbert, Susan R., Tiwari, Hemant K., Yang, Ivana V., Heit, John A., Lubitz, Steven A., Johnsen, Jill M., Curran, Joanne E., Wenzel, Sally E., Weeks, Daniel E., Rao, Dabeeru C., Darbar, Dawood, Moon, Jee-Young, Tracy, Russell P., Buth, Erin J., Rafaels, Nicholas, Loos, Ruth J. F., Durda, Peter, Liu, Yongmei, Hou, Lifang, Lee, Jiwon, Kachroo, Priyadarshini, Freedman, Barry I., Levy, Daniel, Bielak, Lawrence F., Hixson, James E., Floyd, James S., Whitsel, Eric A., Ellinor, Patrick T., Irvin, Marguerite R., Fingerlin, Tasha E., Raffield, Laura M., Armasu, Sebastian M., Wheeler, Marsha M., Sabino, Ester C., Blangero, John, Williams, L. Keoki, Levy, Bruce D., Sheu, Wayne Huey-Herng, Roden, Dan M., Boerwinkle, Eric, Manson, JoAnn E., Mathias, Rasika A., Desai, Pinkal, Taylor, Kent D., Johnson, Andrew D., Auer, Paul L., Kooperberg, Charles, Laurie, Cathy C., Blackwell, Thomas W., Smith, Albert V., Zhao, Hongyu, Lange, Ethan, Lange, Leslie, Rich, Stephen S., Rotter, Jerome I., Wilson, James G., Scheet, Paul, Kitzman, Jacob O., Lander, Eric S., Engreitz, Jesse M., Ebert, Benjamin L., Reiner, Alexander P., Jaiswal, Siddhartha, Abecasis, Gonçalo, Sankaran, Vijay G., Kathiresan, Sekar, and Natarajan, Pradeep
- Abstract
Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. 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 cancer2–4and coronary heart disease5—this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. 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 TET2that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2germline locus enabled the identification of a causal variant that disrupts a TET2distal 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.
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- 2020
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6. A genetic-association study of circulating coagulation factor VIII and von Willebrand factor levels
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de Vries, Paul S., Reventun, Paula, Brown, Michael R., Heath, Adam S., Huffman, Jennifer E., Le, Ngoc-Quynh, Bebo, Allison, Brody, Jennifer A., Temprano-Sagrera, Gerard, Raffield, Laura M., Ozel, Ayse Bilge, Thibord, Florian, Jain, Deepti, Lewis, Joshua P., Rodriguez, Benjmain A. T., Pankratz, Nathan, Taylor, Kent D., Polasek, Ozren, Chen, Ming-Huei, Yanek, Lisa R., Carrasquilla, German D., Marioni, Riccardo E., Kleber, Marcus E., Trégouët, David-Alexandre, Yao, Jie, Li-Gao, Ruifang, Joshi, Peter K., Trompet, Stella, Martinez-Perez, Angel, Ghanbari, Mohsen, Howard, Tom E., Reiner, Alex P., Arvanitis, Marios, Ryan, Kathleen A., Bartz, Traci M., Rudan, Igor, Faraday, Nauder, Linneberg, Allan, Ekunwe, Lynette, Davies, Gail, Delgado, Graciela E., Suchon, Pierre, Guo, Xiuqing, Rosendaal, Frits R., Klaric, Lucija, Noordam, Raymond, van Rooij, Frank, Curran, Joanne E., Wheeler, Marsha M., Osburn, William O., O'Connell, Jeffrey R., Boerwinkle, Eric, Beswick, Andrew, Psaty, Bruce M., Kolcic, Ivana, Souto, Juan Carlos, Becker, Lewis C., Hansen, Torben, Doyle, Margaret F., Harris, Sarah E., Moissl, Angela P., Deleuze, Jean-François, Rich, Stephen S., van Hylckama Vlieg, Astrid, Campbell, Harry, Stott, David J., Soria, Jose Manuel, de Maat, Moniek P. M., Almasy, Laura, Brody, Lawrence C., Auer, Paul L., Abe, Namiko, Abecasis, Gonçalo, Aguet, Francois, Albert, Christine, Almasy, Laura, Alonso, Alvaro, Ament, Seth, Anderson, Peter, Anugu, Pramod, Applebaum-Bowden, Deborah, Ardlie, Kristin, Arking, Dan, Arnett, Donna K, Ashley-Koch, Allison, Aslibekyan, Stella, Assimes, Tim, Auer, Paul, Avramopoulos, Dimitrios, Ayas, Najib, Balasubramanian, Adithya, Barnard, John, Barnes, Kathleen, Barr, R. Graham, Barron-Casella, Emily, Barwick, Lucas, Beaty, Terri, Beck, Gerald, Becker, Diane, Becker, Lewis, Beer, Rebecca, Beitelshees, Amber, Benjamin, Emelia, Benos, Takis, Bezerra, Marcos, Bielak, Larry, Bis, Joshua, Blackwell, Thomas, Blangero, John, Blue, Nathan, Boerwinkle, Eric, Bowden, Donald W., Bowler, Russell, Brody, Jennifer, Broeckel, Ulrich, Broome, Jai, Brown, Deborah, Bunting, Karen, Burchard, Esteban, Bustamante, Carlos, Buth, Erin, Cade, Brian, Cardwell, Jonathan, Carey, Vincent, Carrier, Julie, Carson, April P., Carty, Cara, Casaburi, Richard, Casas Romero, Juan P, Casella, James, Castaldi, Peter, Chaffin, Mark, Chang, Christy, Chang, Yi-Cheng, Chasman, Daniel, Chavan, Sameer, Chen, Bo-Juen, Chen, Wei-Min, Ida Chen, Yii-Der, Cho, Michael, Choi, Seung Hoan, Chuang, Lee-Ming, Chung, Mina, Chung, Ren-Hua, Clish, Clary, Comhair, Suzy, Conomos, Matthew, Cornell, Elaine, Correa, Adolfo, Crandall, Carolyn, Crapo, James, Cupples, L. Adrienne, Curran, Joanne, Curtis, Jeffrey, Custer, Brian, Damcott, Coleen, Darbar, Dawood, David, Sean, Davis, Colleen, Daya, Michelle, de Andrade, Mariza, de las Fuentes, Lisa, de Vries, Paul, DeBaun, Michael, Deka, Ranjan, DeMeo, Dawn, Devine, Scott, Dinh, Huyen, Doddapaneni, Harsha, Duan, Qing, Dugan-Perez, Shannon, Duggirala, Ravi, Durda, Jon Peter, Dutcher, Susan K., Eaton, Charles, Ekunwe, Lynette, El Boueiz, Adel, Ellinor, Patrick, Emery, Leslie, Erzurum, Serpil, Farber, Charles, Farek, Jesse, Fingerlin, Tasha, Flickinger, Matthew, Fornage, Myriam, Franceschini, Nora, Frazar, Chris, Fu, Mao, Fullerton, Stephanie M., Fulton, Lucinda, Gabriel, Stacey, Gan, Weiniu, Gao, Shanshan, Gao, Yan, Gass, Margery, Geiger, Heather, Gelb, Bruce, Geraci, Mark, Germer, Soren, Gerszten, Robert, Ghosh, Auyon, Gibbs, Richard, Gignoux, Chris, Gladwin, Mark, Glahn, David, Gogarten, Stephanie, Gong, Da-Wei, Goring, Harald, Graw, Sharon, Gray, Kathryn J., Grine, Daniel, Gross, Colin, Gu, C. Charles, Guan, Yue, Guo, Xiuqing, Gupta, Namrata, Haessler, Jeff, Hall, Michael, Han, Yi, Hanly, Patrick, Harris, Daniel, Hawley, Nicola L., He, Jiang, Heavner, Ben, Heckbert, Susan, Hernandez, Ryan, Herrington, David, Hersh, Craig, Hidalgo, Bertha, Hixson, James, Hobbs, Brian, Hokanson, John, Hong, Elliott, Hoth, Karin, Hsiung, Chao (Agnes), Hu, Jianhong, Hung, Yi-Jen, Huston, Haley, Hwu, Chii Min, Irvin, Marguerite Ryan, Jackson, Rebecca, Jain, Deepti, Jaquish, Cashell, Johnsen, Jill, Johnson, Andrew, Johnson, Craig, Johnston, Rich, Jones, Kimberly, Kang, Hyun Min, Kaplan, Robert, Kardia, Sharon, Kelly, Shannon, Kenny, Eimear, Kessler, Michael, Khan, Alyna, Khan, Ziad, Kim, Wonji, Kimoff, John, Kinney, Greg, Konkle, Barbara, Kooperberg, Charles, Kramer, Holly, Lange, Christoph, Lange, Ethan, Lange, Leslie, Laurie, Cathy, Laurie, Cecelia, LeBoff, Meryl, Lee, Jiwon, Lee, Sandra, Lee, Wen-Jane, LeFaive, Jonathon, Levine, David, Levy, Dan, Lewis, Joshua, Li, Xiaohui, Li, Yun, Lin, Henry, Lin, Honghuang, Lin, Xihong, Liu, Simin, Liu, Yongmei, Liu, Yu, Loos, Ruth J. F., Lubitz, Steven, Lunetta, Kathryn, Luo, James, Magalang, Ulysses, Mahaney, Michael, Make, Barry, Manichaikul, Ani, Manning, Alisa, Manson, JoAnn, Martin, Lisa, Marton, Melissa, Mathai, Susan, Mathias, Rasika, May, Susanne, McArdle, Patrick, McDonald, Merry-Lynn, McFarland, Sean, McGarvey, Stephen, McGoldrick, Daniel, McHugh, Caitlin, McNeil, Becky, Mei, Hao, Meigs, James, Menon, Vipin, Mestroni, Luisa, Metcalf, Ginger, Meyers, Deborah A, Mignot, Emmanuel, Mikulla, Julie, Min, Nancy, Minear, Mollie, Minster, Ryan L, Mitchell, Braxton D., Moll, Matt, Momin, Zeineen, Montasser, May E., Montgomery, Courtney, Muzny, Donna, Mychaleckyj, Josyf C, Nadkarni, Girish, Naik, Rakhi, Naseri, Take, Natarajan, Pradeep, Nekhai, Sergei, Nelson, Sarah C., Neltner, Bonnie, Nessner, Caitlin, Nickerson, Deborah, Nkechinyere, Osuji, North, Kari, O'Connell, Jeff, O'Connor, Tim, Ochs-Balcom, Heather, Okwuonu, Geoffrey, Pack, Allan, Paik, David T., Palmer, Nicholette, Pankow, James, Papanicolaou, George, Parker, Cora, Peloso, Gina, Peralta, Juan Manuel, Perez, Marco, Perry, James, Peters, Ulrike, Peyser, Patricia, Phillips, Lawrence S, Pleiness, Jacob, Pollin, Toni, Post, Wendy, Becker, Julia Powers, Boorgula, Meher Preethi, Preuss, Michael, Psaty, Bruce, Qasba, Pankaj, Qiao, Dandi, Qin, Zhaohui, Rafaels, Nicholas, Raffield, Laura, Rajendran, Mahitha, Ramachandran, Vasan S., Rao, D. C., Rasmussen-Torvik, Laura, Ratan, Aakrosh, Redline, Susan, Reed, Robert, Reeves, Catherine, Regan, Elizabeth, Reiner, Alex, Reupena, Muagututi‘a Sefuiva, Rice, Ken, Rich, Stephen, Robillard, Rebecca, Robine, Nicolas, Roden, Dan, Roselli, Carolina, Rotter, Jerome, Ruczinski, Ingo, Runnels, Alexi, Russell, Pamela, Ruuska, Sarah, Ryan, Kathleen, Sabino, Ester Cerdeira, Saleheen, Danish, Salimi, Shabnam, Salvi, Sejal, Salzberg, Steven, Sandow, Kevin, Sankaran, Vijay G., Santibanez, Jireh, Schwander, Karen, Schwartz, David, Sciurba, Frank, Seidman, Christine, Seidman, Jonathan, Sériès, Frédéric, Sheehan, Vivien, Sherman, Stephanie L., Shetty, Amol, Shetty, Aniket, Hui-Heng Sheu, Wayne, Shoemaker, M. Benjamin, Silver, Brian, Silverman, Edwin, Skomro, Robert, Smith, Albert Vernon, Smith, Jennifer, Smith, Josh, Smith, Nicholas, Smith, Tanja, Smoller, Sylvia, Snively, Beverly, Snyder, Michael, Sofer, Tamar, Sotoodehnia, Nona, Stilp, Adrienne M., Storm, Garrett, Streeten, Elizabeth, Su, Jessica Lasky, Sung, Yun Ju, Sylvia, Jody, Szpiro, Adam, Taliun, Daniel, Tang, Hua, Taub, Margaret, Taylor, Kent D., Taylor, Matthew, Taylor, Simeon, Telen, Marilyn, Thornton, Timothy A., Threlkeld, Machiko, Tinker, Lesley, Tirschwell, David, Tishkoff, Sarah, Tiwari, Hemant, Tong, Catherine, Tracy, Russell, Tsai, Michael, Vaidya, Dhananjay, Van Den Berg, David, VandeHaar, Peter, Vrieze, Scott, Walker, Tarik, Wallace, Robert, Walts, Avram, Wang, Fei Fei, Wang, Heming, Wang, Jiongming, Watson, Karol, Watt, Jennifer, Weeks, Daniel E., Weinstock, Joshua, Weir, Bruce, Weiss, Scott T, Weng, Lu-Chen, Wessel, Jennifer, Willer, Cristen, Williams, Kayleen, Williams, L. Keoki, Wilson, Carla, Wilson, James, Winterkorn, Lara, Wong, Quenna, Wu, Joseph, Xu, Huichun, Yanek, Lisa, Yang, Ivana, Yu, Ketian, Zekavat, Seyedeh Maryam, Zhang, Yingze, Zhao, Snow Xueyan, Zhao, Wei, Zhu, Xiaofeng, Ziv, Elad, Zody, Michael, Zoellner, Sebastian, Lindstrom, Sara, Wang, Lu, Smith, Erin N., Gordon, William, van Hylckama Vlieg, Astrid, de Andrade, Mariza, Brody, Jennifer A., Pattee, Jack W., Haessler, Jeffrey, Brumpton, Ben M., Chasman, Daniel I., Suchon, Pierre, Chen, Ming-Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L., MacDonald, James, Braekkan, Sigrid K., Armasu, Sebastian M., Pankratz, Nathan, Jackson, Rabecca D., Nielsen, Jonas B., Giulianini, Franco, Puurunen, Marja K., Ibrahim, Manal, Heckbert, Susan R., Bammler, Theo K., Frazer, Kelly A., McCauley, Bryan M., Taylor, Kent, Pankow, James S., Reiner, Alexander P., Gabrielsen, Maiken E., Deleuze, Jean-François, O'Donnell, Chris J., Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits R., Heit, John A., Psaty, Bruce M., Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M., Morange, Pierre-Emmanuel, Johnson, Andrew D., Kabrhel, Christopher, AlexandreTrégouët, David, Smith, Nicholas L., Mitchell, Braxton D., Ben-Shlomo, Yoav, Fornage, Myriam, Hayward, Caroline, Mathias, Rasika A., Kilpeläinen, Tuomas O., Lange, Leslie A., Cox, Simon R., März, Winfried, Morange, Pierre-Emmanuel, Rotter, Jerome I., Mook-Kanamori, Dennis O., Wilson, James F., van der Harst, Pim, Jukema, J. Wouter, Ikram, M. Arfan, Blangero, John, Kooperberg, Charles, Desch, Karl C., Johnson, Andrew D., Sabater-Lleal, Maria, Lowenstein, Charles J., Smith, Nicholas L., and Morrison, Alanna C.
- Abstract
•We identified 7 new genetic regions for factor VIII levels, 1 for von Willebrand factor levels, and 3 in a combined analysis.•Silencing B3GNT2and CD36reduced factor VIII release in vitro.Silencing B3GNT2, CD36, and PDIA3reduced von Willebrand factor release.
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- 2024
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7. Exome-wide association study of plasma lipids in >300,000 individuals
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Liu, Dajiang J, Peloso, Gina M, Yu, Haojie, Butterworth, Adam S, Wang, Xiao, Mahajan, Anubha, Saleheen, Danish, Emdin, Connor, Alam, Dewan, Alves, Alexessander Couto, Amouyel, Philippe, Di Angelantonio, Emanuele, Arveiler, Dominique, Assimes, Themistocles L, Auer, Paul L, Baber, Usman, Ballantyne, Christie M, Bang, Lia E, Benn, Marianne, Bis, Joshua C, Boehnke, Michael, Boerwinkle, Eric, Bork-Jensen, Jette, Bottinger, Erwin P, Brandslund, Ivan, Brown, Morris, Busonero, Fabio, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Chen, Y Eugene, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Connell, John M, Cucca, Francesco, Cupples, L Adrienne, Damrauer, Scott M, Davies, Gail, Deary, Ian J, Dedoussis, George, Denny, Joshua C, Dominiczak, Anna, Dubé, Marie-Pierre, Ebeling, Tapani, Eiriksdottir, Gudny, Esko, Tõnu, Farmaki, Aliki-Eleni, Feitosa, Mary F, Ferrario, Marco, Ferrieres, Jean, Ford, Ian, Fornage, Myriam, Franks, Paul W, Frayling, Timothy M, Frikke-Schmidt, Ruth, Fritsche, Lars G, Frossard, Philippe, Fuster, Valentin, Ganesh, Santhi K, Gao, Wei, Garcia, Melissa E, Gieger, Christian, Giulianini, Franco, Goodarzi, Mark O, Grallert, Harald, Grarup, Niels, Groop, Leif, Grove, Megan L, Gudnason, Vilmundur, Hansen, Torben, Harris, Tamara B, Hayward, Caroline, Hirschhorn, Joel N, Holmen, Oddgeir L, Huffman, Jennifer, Huo, Yong, Hveem, Kristian, Jabeen, Sehrish, Jackson, Anne U, Jakobsdottir, Johanna, Jarvelin, Marjo-Riitta, Jensen, Gorm B, Jørgensen, Marit E, Jukema, J Wouter, Justesen, Johanne M, Kamstrup, Pia R, Kanoni, Stavroula, Karpe, Fredrik, Kee, Frank, Khera, Amit V, Klarin, Derek, Koistinen, Heikki A, Kooner, Jaspal S, Kooperberg, Charles, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo, Langenberg, Claudia, Langsted, Anne, Launer, Lenore J, Lauritzen, Torsten, Liewald, David C M, Lin, Li An, Linneberg, Allan, Loos, Ruth J F, Lu, Yingchang, Lu, Xiangfeng, Mägi, Reedik, Malarstig, Anders, Manichaikul, Ani, Manning, Alisa K, Mäntyselkä, Pekka, Marouli, Eirini, Masca, Nicholas G D, Maschio, Andrea, Meigs, James B, Melander, Olle, Metspalu, Andres, Morris, Andrew P, Morrison, Alanna C, Mulas, Antonella, Müller-Nurasyid, Martina, Munroe, Patricia B, Neville, Matt J, Nielsen, Jonas B, Nielsen, Sune F, Nordestgaard, Børge G, Ordovas, Jose M, Mehran, Roxana, O'Donnell, Christoper J, Orho-Melander, Marju, Molony, Cliona M, Muntendam, Pieter, Padmanabhan, Sandosh, Palmer, Colin N A, Pasko, Dorota, Patel, Aniruddh P, Pedersen, Oluf, Perola, Markus, Peters, Annette, Pisinger, Charlotta, Pistis, Giorgio, Polasek, Ozren, Poulter, Neil, Psaty, Bruce M, Rader, Daniel J, Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F, Reiner, Alex P, Renström, Frida, Rich, Stephen S, Ridker, Paul M, Rioux, John D, Robertson, Neil R, Roden, Dan M, Rotter, Jerome I, Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J, Sanna, Serena, Sattar, Naveed, Schmidt, Ellen M, Scott, Robert A, Sever, Peter, Sevilla, Raquel S, Shaffer, Christian M, Sim, Xueling, Sivapalaratnam, Suthesh, Small, Kerrin S, Smith, Albert V, Smith, Blair H, Somayajula, Sangeetha, Southam, Lorraine, Spector, Timothy D, Speliotes, Elizabeth K, Starr, John M, Stirrups, Kathleen E, Stitziel, Nathan, Strauch, Konstantin, Stringham, Heather M, Surendran, Praveen, Tada, Hayato, Tall, Alan R, Tang, Hua, Tardif, Jean-Claude, Taylor, Kent D, Trompet, Stella, Tsao, Philip S, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, van Zuydam, Natalie R, Varbo, Anette, Varga, Tibor V, Virtamo, Jarmo, Waldenberger, Melanie, Wang, Nan, Wareham, Nick J, Warren, Helen R, Weeke, Peter E, Weinstock, Joshua, Wessel, Jennifer, Wilson, James G, Wilson, Peter W F, Xu, Ming, Yaghootkar, Hanieh, Young, Robin, Zeggini, Eleftheria, Zhang, He, Zheng, Neil S, Zhang, Weihua, Zhang, Yan, Zhou, Wei, Zhou, Yanhua, Zoledziewska, Magdalena, Howson, Joanna M M, Danesh, John, McCarthy, Mark I, Cowan, Chad A, Abecasis, Goncalo, Deloukas, Panos, Musunuru, Kiran, Willer, Cristen J, and Kathiresan, Sekar
- Abstract
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
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- 2017
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8. Author Correction: Clonal haematopoiesis and risk of chronic liver disease
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Wong, Waihay J., Emdin, Connor, Bick, Alexander G., Zekavat, Seyedeh M., Niroula, Abhishek, Pirruccello, James P., Dichtel, Laura, Griffin, Gabriel, Uddin, Md Mesbah, Gibson, Christopher J., Kovalcik, Veronica, Lin, Amy E., McConkey, Marie E., Vromman, Amelie, Sellar, Rob S., Kim, Peter G., Agrawal, Mridul, Weinstock, Joshua, Long, Michelle T., Yu, Bing, Banerjee, Rajarshi, Nicholls, Rowan C., Dennis, Andrea, Kelly, Matt, Loh, Po-Ru, McCarroll, Steve, Boerwinkle, Eric, Vasan, Ramachandran S., Jaiswal, Siddhartha, Johnson, Andrew D., Chung, Raymond T., Corey, Kathleen, Levy, Daniel, Ballantyne, Christie, Ebert, Benjamin L., and Natarajan, Pradeep
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- 2023
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9. Abstract 15719: Proteomic Analyses Reveal Mechanistic Links Between Clonal Hematopoiesis of Indeterminate Potential and Coronary Artery Disease
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Yu, Zhi, Yu, Bing, Vromman, Amelie, Nguyen, Quynh H, Khetarpal, Sumeet, Honigberg, Michael, Lin, Amy E, Katz, Daniel H, Tahir, Usman A, Weinstock, Joshua S, Jaiswal, Siddhartha, Austin, Thomas, Ramachandran, Vasan S, Peloso, Gina, Manson, Joann E, Haring, Bernhard, Kooperberg, Charles, Reiner, Alex P, Bis, Joshua, Psaty, Bruce M, Correa, Adolfo, Lange, Leslie, Post, Wendy S, Rotter, Jerome I, Rich, Stephen S, Wilson, James, Ballantyne, Christie M, Coresh, Josef, Sankaran, Vijay, Libby, Peter, Bick, Alexander G, Ebert, Benjamin L, Gerszten, Robert E, and Natarajan, Pradeep
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Introduction:Clonal hematopoiesis of indeterminate potential (CHIP) is a phenomenon where hematopoietic stem cells acquire leukemogenic mutations without blood cancer. CHIP is a causal risk factor for coronary artery disease (CAD), yet underlying mechanisms remain unclear. The plasma proteome may provide novel mechanistic insights into the links between CHIP and CAD.Methods:We studied the associations of CHIP with the plasma proteins and CAD risk in four Trans-Omics for Precision Medicine (TOPMed) longitudinal cohorts: ARIC (N=9,084), CHS (N=1,727), JHS (N=1,858), and MESA (N=978). CHIP (variant allele fraction >2%) was identified from whole genome sequences of blood DNA and modeled both as a composite of the most common drivers (DNMT3A, TET2, ASXL1, and JAK2) and separately. Levels of ~1,300 serum proteins measured by SomaScan were log-transformed and residualized on study-specific covariates. The association between CHIP and protein levels was estimated across all participants within each study, as well as by sex, and meta-analyzed. For proteins significantly (FDR<0.05) associated with CHIP, pathway analysis and functional validation in Tet2-/-mice were conducted.Results:Across all studies (mean age: 59.8 y; 43.6% male), 720 (5.6%) individuals were identified with CHIP. There were 143 significant CHIP-protein pairs, with carbonic anhydrase 1, lysozyme C, and properdin being the most associated proteins. TET2had the largest number of, and strongest, associations among examined driver genes. In sex-stratified analysis, follicle-stimulating hormone was inversely associated in females. Pathway analysis implicated the inflammation-related STAT3 and IL-17 signaling pathways. We observed significantly greater expression of Cfpand Lyz(encoding properdin and lysosome C, respectively) in the monocytes of Tet2-/- female mice compared to wild-type female mice and Tet2-/- male mice. A number of proteins (including PCSK9) were significantly associated with both CHIP and CAD, suggesting both shared and nonshared mechanisms.Conclusions:CHIP, particularly TET2, is broadly associated with plasma proteins, as validated by evidence in Tet2-/- mice. Further studies are needed to understand the biological mechanisms linking CHIP to CAD.
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- 2022
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10. Clonal Hematopoiesis Is Driven By Aberrant Activation of TCL1A
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Gopakumar, Jk, Weinstock, Joshua, Burugula, Bala B, Jahn, Nikolaus, Kooperberg, Charles, Desai, Pinkal, Natarajan, Pradeep, Kitzman, Jacob O, Reiner, Alexander, Bick, Alexander G., and Jaiswal, Siddhartha
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Introduction:Clonal hematopoiesis of indeterminate potential (CHIP) may occur when a hematopoietic stem cell (HSC) acquires a fitness-increasing mutation resulting in its clonal expansion. A diverse set of driver genes, such as regulators of DNA methylation, splicing, and chromatin remodeling, have been associated with CHIP, but it remains largely unknown why HSCs bearing these mutations are positively selected. It has been challenging to identify the genetic and environmental factors mediating clonal expansion in humans, partially due to a lack of large cohorts with longitudinal blood sampling of participants. To circumvent this limitation, we developed a method to infer clonal expansion rate from single timepoint data called PACER (passenger-approximated clonal expansion rate).
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- 2021
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11. Clonal Hematopoiesis is Associated with Reduced Risk of Alzheimer's Disease
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Bouzid, Hind, Belk, Julia, Jan, Max, Qi, Yanyan, Sarnowski, Chloé, Wirth, Sara, Ma, Lisa, Chrostek, Matthew, Ahmad, Herra, Nachun, Daniel, Yao, Winnie, Beiser, Alexa, Bick, Alexander G., Bis, Joshua, Fornage, Myriam, Longstreth, W.T., Lopez, Oscar, Nataranjan, Pradeep, Psaty, Bruce, Satizabal, Claudia, Weinstock, Joshua, Larson, Eric, Crane, Paul, Keene, C. Dirk, Seshadri, Sudha, Satpathy, Ansuman T., Montine, Thomas, and Jaiswal, Siddhartha
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- 2021
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12. Abstract 14309: Clinical Outcomes of Acute Myocardial Infarction in Hematological Cancers
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KHAN, MUHAMMAD ZUBAIR, Weinstock, Joshua, Patel, Kirtenkumar, Franklin, Sona, Naftulin, Jason, Jamil, Ayesha, Abraham, Aida, and Kutalek, Steven
- Abstract
The purpose of our study is to determine hospital outcomes of acute myocardial infarction (MI) with hematological cancers and their subtypes.Method:Patient data was obtained from the Nationwide Inpatient Sample (NIS) database between years 2009-2015. Patients with a diagnosis of acute MI [non-ST segment elevation myocardial infarction and ST segment elevation myocardial infarction (NSTEMI/STEMI)] and hematological cancer subtypes were identified using validated International Classification of Diseases, 9th revision, and Clinical Modification (ICD-9-CM) codes. Statistical analysis using Pearson chi-squared test was performed to determine hospital outcomes between acute MI and hematological cancer subtypes.Results:The prevalence of NSTEMI was 1.2%, and STEMI was 0.2% in hematological cancers, n=3,027,800. Among hematological cancer subtypes, the highest prevalence of NSTEMI and STEMI was seen in lymphocytic leukemia (2.4% and 0.25%, respectively). Mortality (16.8% vs. 8.8%), hospitalization cost (25469$ ± 36763$ vs. 20534$ ± 24767$) and length of stay (8.3 days ± 10 days vs. 6.3 ± 7.8 days) were higher in the acute MI patients with hematological cancers compared to acute MI patients without cancer. Among hematological cancer patients with acute MI, the highest mortality was found in patients with myeloid leukemia (23%) followed by multiple myeloma (MM) (17.9%), lymphocytic leukemia (15.9%) and lymphoma (14.4%). The length of stay and hospitalization cost was highest in those with myeloid leukemia followed by MM, lymphocytic leukemia and lymphoma.Conclusion:This study showed that hematological cancer patients with acute MI had a higher mortality, hospitalization cost and length of stay. Among the hematological cancer subtypes, the highest mortality, length of stay and hospitalization cost was found in myeloid leukemia.
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- 2021
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13. Clonal Hematopoiesis is Associated with Reduced Risk of Alzheimer's Disease
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Bouzid, Hind, Belk, Julia, Jan, Max, Qi, Yanyan, Sarnowski, Chloé, Wirth, Sara, Ma, Lisa, Chrostek, Matthew, Ahmad, Herra, Nachun, Daniel, Yao, Winnie, Beiser, Alexa, Bick, Alexander G., Bis, Joshua, Fornage, Myriam, Longstreth, W. T., Lopez, Oscar, Nataranjan, Pradeep, Psaty, Bruce, Satizabal, Claudia, Weinstock, Joshua, Larson, Eric, Crane, Paul, Keene, C. Dirk, Seshadri, Sudha, Satpathy, Ansuman T., Montine, Thomas, and Jaiswal, Siddhartha
- Abstract
Jaiswal: Novartis: Consultancy, Honoraria; Foresite Labs: Consultancy; Genentech: Consultancy, Honoraria; AVRO Bio: Consultancy, Honoraria; Caylo: Current holder of stock options in a privately-held company.
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- 2021
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14. Clonal Hematopoiesis Is Driven By Aberrant Activation of TCL1A
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Gopakumar, Jk, Weinstock, Joshua, Burugula, Bala B, Jahn, Nikolaus, Kooperberg, Charles, Desai, Pinkal, Natarajan, Pradeep, Kitzman, Jacob O, Reiner, Alexander, Bick, Alexander G., and Jaiswal, Siddhartha
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Desai: Bristol Myers Squibb: Consultancy; Kura Oncology: Consultancy; Agios: Consultancy; Astex: Research Funding; Takeda: Consultancy; Janssen R&D: Research Funding. Natarajan: Blackstone Life Sciences: Consultancy; Boston Scientific: Research Funding; Novartis: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Apple: Consultancy, Research Funding; Amgen: Research Funding; Genentech: Consultancy; Foresite Labs: Consultancy. Jaiswal: Novartis: Consultancy, Honoraria; AVRO Bio: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Foresite Labs: Consultancy; Caylo: Current holder of stock options in a privately-held company.
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- 2021
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15. Author Correction: Inherited causes of clonal haematopoiesis in 97,691 whole genomes
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Bick, Alexander G., Weinstock, Joshua S., Nandakumar, Satish K., Fulco, Charles P., Bao, Erik L., Zekavat, Seyedeh M., Szeto, Mindy D., Liao, Xiaotian, Leventhal, Matthew J., Nasser, Joseph, Chang, Kyle, Laurie, Cecelia, Burugula, Bala Bharathi, Gibson, Christopher J., Niroula, Abhishek, Lin, Amy E., Taub, Margaret A., Aguet, Francois, Ardlie, Kristin, Mitchell, Braxton D., Barnes, Kathleen C., Moscati, Arden, Fornage, Myriam, Redline, Susan, Psaty, Bruce M., Silverman, Edwin K., Weiss, Scott T., Palmer, Nicholette D., Vasan, Ramachandran S., Burchard, Esteban G., Kardia, Sharon L. R., He, Jiang, Kaplan, Robert C., Smith, Nicholas L., Arnett, Donna K., Schwartz, David A., Correa, Adolfo, de Andrade, Mariza, Guo, Xiuqing, Konkle, Barbara A., Custer, Brian, Peralta, Juan M., Gui, Hongsheng, Meyers, Deborah A., McGarvey, Stephen T., Chen, Ida Yii-Der, Shoemaker, M. Benjamin, Peyser, Patricia A., Broome, Jai G., Gogarten, Stephanie M., Wang, Fei Fei, Wong, Quenna, Montasser, May E., Daya, Michelle, Kenny, Eimear E., North, Kari E., Launer, Lenore J., Cade, Brian E., Bis, Joshua C., Cho, Michael H., Lasky-Su, Jessica, Bowden, Donald W., Cupples, L. Adrienne, Mak, Angel C. Y., Becker, Lewis C., Smith, Jennifer A., Kelly, Tanika N., Aslibekyan, Stella, Heckbert, Susan R., Tiwari, Hemant K., Yang, Ivana V., Heit, John A., Lubitz, Steven A., Johnsen, Jill M., Curran, Joanne E., Wenzel, Sally E., Weeks, Daniel E., Rao, Dabeeru C., Darbar, Dawood, Moon, Jee-Young, Tracy, Russell P., Buth, Erin J., Rafaels, Nicholas, Loos, Ruth J. F., Durda, Peter, Liu, Yongmei, Hou, Lifang, Lee, Jiwon, Kachroo, Priyadarshini, Freedman, Barry I., Levy, Daniel, Bielak, Lawrence F., Hixson, James E., Floyd, James S., Whitsel, Eric A., Ellinor, Patrick T., Irvin, Marguerite R., Fingerlin, Tasha E., Raffield, Laura M., Armasu, Sebastian M., Wheeler, Marsha M., Sabino, Ester C., Blangero, John, Williams, L. Keoki, Levy, Bruce D., Sheu, Wayne Huey-Herng, Roden, Dan M., Boerwinkle, Eric, Manson, JoAnn E., Mathias, Rasika A., Desai, Pinkal, Taylor, Kent D., Johnson, Andrew D., Auer, Paul L., Kooperberg, Charles, Laurie, Cathy C., Blackwell, Thomas W., Smith, Albert V., Zhao, Hongyu, Lange, Ethan, Lange, Leslie, Rich, Stephen S., Rotter, Jerome I., Wilson, James G., Scheet, Paul, Kitzman, Jacob O., Lander, Eric S., Engreitz, Jesse M., Ebert, Benjamin L., Reiner, Alexander P., Jaiswal, Siddhartha, Abecasis, Gonçalo, Sankaran, Vijay G., Kathiresan, Sekar, and Natarajan, Pradeep
- Abstract
A Correction to this paper has been published: https://doi.org/10.1038/s41586-021-03280-1.
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- 2021
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16. Abstract 17142: A Real-world Experience For Implantable Loop Recorder Monitoring To Detect Subclinical Atrial Fibrillation In Patients With Cryptogenic Stroke
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Marks, Daniel, Ho, Rady, Nathan, Karim, Weinstock, Joshua, Hunter, Krystal, Ortman, Matthew, and Russo, Andrea M
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Introduction:Cryptogenic stroke represents approximately 30% of all ischemic strokes. Clinical studies have shown that implantable loop recorders (ILRs) may identify subclinical AF in up to 1/3 of these patients. However, there is variation in the literature of the yield of these devices.Hypothesis:Those implanted with ILR for cryptogenic stroke will show an AF detection rate comparable to that of prior clinical studies. Analysis of electrocardiograms may help identify those at higher risk of AF detection.Methods:A retrospective chart review was conducted of all patients who presented with cryptogenic stroke and received an ILR at an academic medical center from 2015-2017. There were no exclusion criteria among such patients. The electronic health record and remote monitoring were used to identify occurrence of AF and timing to first event. Baseline demographics, co-morbidities, electrocardiogram (ECG) and echocardiogram characteristics were analyzed for predictors of AF detection.Results:A total of 178 patients who received ILRs for cryptogenic stroke were included. Overall, 35 (19.6%) were found to have AF detected on ILR (figure 1). Mean follow-up duration was 365 days with a median time to detection of 131 days. The median duration of AF detected was 120 minutes. The only demographic variable predictive of AF detection was advanced age (p = 0.001). ECG findings of premature atrial contractions (PACs), and p wave dispersion (PWD) > 40 ms were also found to be predictive (p = 0.04, p < 0.001, respectively).Conclusions:Approximately 20% of patients presenting to our facility with cryptogenic stroke were found to have AF with ILR surveillance. Advanced age, as well as ECG findings of PACs and increased PWD may help to predict those at higher risk of AF detection. Given the high yield and relatively prolonged median time to detection (131 d) in this population, earlier ILR implantation may be warranted in certain high risk groups.
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- 2019
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