Citations 2
Abstract 15706: Common- and Rare-Variant Genetic Architecture of Heart Failure Across the Allele Frequency Spectrum
Depaolo, John, Aragam, Krishna G. , Biddinger, Kiran J., Khan, Atlas , Day, Sharlene M. , McNally, Elizabeth M., Owens, Anjali , Levin, Michael G. , Lee, David S. , DePaolo, John S. , Conery, Mitchell , Dikilitas, Ozan , Puckelwartz, Megan J. , Reza, Nosheen , Satterfield, Benjamin A. , Arany, Zoltan Pierre , Cappola, Thomas P. , Joseph, Jacob , Voight, Benjamin F. , Damrauer, Scott M
Circulation | December 19, 2023 | Volume: 148 | Issue: Suppl_1 | Pages: No page available
10.1161/circ.148.suppl_1.15706
Background: Heart failure (HF) is a complex trait influenced by environmental and genetic factors. Genome-wide association studies (GWAS) have found common genetic variants associated with HF risk, but the extent that common and rare variants explain risk and implicate similar genes and pathways in HF remains less understood. Methods: For common variants, we meta-analyze existing GWAS of all-cause HF with data from the Million Veteran Program, including 207,346 individuals with HF and 2,151,210 without in diverse populations. We examine rare coding variants in the Penn Medicine BioBank (PMBB) using gene-collapsing association studies and burden heritability regression. We test for an interaction between a polygenic risk score (PRS) based on our GWAS meta-analysis and truncating variants in TTN (TTNtv). Results: GWAS meta-analysis identified 176 risk loci (146 previously unreported), implicating known risk factors for HF and genes involved in cardiac development. New signals at GIPR/ GLP1R highlight potential contributions of dysregulated glucose homeostasis and metabolism in HF. Gene collapsing studies identified associations between HF and rare loss-of-function variants in TTN (OR 2.94, 95% CI 2.43-3.56) and MYBPC3 (OR 7.71, 95% CI 3.97-14.97) at exome-wide significance. HF heritability mediated through common variants (4.5%) was significantly higher than for rare variants (1.8%), but rare variant heritability was further enriched in cardiomyopathy genes compared to common variants (27-fold vs. 3.4-fold). We found a significant interaction between a new multi-ancestry HF-associated PRS (AUC 0.72, 95% CI 0.72-0.73) and TTNtv carrier status (interaction OR 1.32, 95% CI 1.06-1.64). Conclusions: Common and rare variants contribute to HF heritability. Common variant HF heritability is highly polygenic, while rare variant burden heritability appears more concentrated in core cardiomyopathy genes. HF risk conferred by TTNtv carrier status is further increased by an individual’s polygenic contribution. Our results support the continued inclusion of cardiomyopathy genes in rare-variant genetic testing panels for HF but suggest a meaningful polygenic component to HF exists that is not currently captured by clinical genetic testing.
Factors Associated With Large Improvements in Health-Related Quality of Life in Patients With Atrial Fibrillation
Holmes, DaJuanicia N. , Pieper, Karen S. , Ezekowitz, Michael D. , Fonarow, Gregg C. , Gersh, Bernard J. , Kowey, Peter R. , Mahaffey, Kenneth W. , Reiffel, James A. , Singer, Daniel E. , Piccini, Jonathan P. , Mendelson, R. A., NEUTEL, J, Pan, Dengji, Poock, James J., Raffetto, J.D., Greengold, R., Roan, P G, Saba, F., Sackett, Melanie K., Schneider, R., Seymour, Zachary , Shanes, Jeffrey G., Smiley, Nasser, Smith, David H. , Snipes, C., Sotolongo, Rodolfo, Staniloae, Cezar , Stoltz, S., Suresh, D.P. , Tak, Tahir , Tannenbaum, A., Turk, Samir, Vora, Kishor, Randhawa, P., Zebrack, James S., Silva, Eduardo , Riley, Edward T., Weinstein, D., Vasiliauskas, Tomas, Goldbarg, Seth , Yarlagadda, Chakri, Laurion, D., Osunkoya, A., Burns, Richéal , Castor, Tatsiana , Luttman, C., Anton, Stephen D. , McGarvey, Jeremy R., Guthrie, Robert D., Deriso, George T., Flood, Raymond, Fleischer, L H, Fierstein, J.S., Jacobs, George B., Adjei, Nasser, Akyea-Djamson, Ayim, Bacon, Jenny , Bedwell, Noel W., Berger, PB, Berry, Joni I., Bhagwat, Ravi, Boccalandro, Fernando , Capó, Jaïr Dilmé, Kapadia, Sumit, Casanova, Rene, Morriss, J.E., Elsen, J., Farsad, Ramin, Fox, David J. , Frandsen, Brad, Gelernt, M., Hall, Cassandra L. , Hotchkiss, David R. , Ip, J., Jaffrani, Naseem, Kazmierski, John F., Waxman, F., Kneller, G. Larsen, Labroo, Ajay, Jaffe, Bernard M., Lebenthal, Mark, Lillestol, Michael, Leclerc, Kenneth M. , Maccaro, Paul, Mayer, Nolan, Kozłowski, J , Benjamin, Sanford P., Detweiler, Robert, Igic, Petar, Jackson, Tatum, Pappas, Janine, Littlefield, Ryan , Frey, Anna , Vranian, Robert B., Long, W., Grena, Paul, Arouni, Amy , Quinn, John , Blonder, Ronald, Snyder, H., Slabic, S., Cohen, Kenneth D., Walthall, W. W., Snoddy, Brian, Alvarado, Olga Franco, Leach, Corinne L., Rothman, Steven A., Olatidoye, Abiodun G, Almahameed, Soufian , Rosenthal, Shelly, Reiter, William M., Thompson, T., Thew, Stephen, Kobayashi, Junji , Williams, M., Kramer, Joel H. , Latif, Sidrah , Rhee, B., Ruiz-Serrano, D., Stringam, Stanley, Wolok, K., Focil, Augusto, Butman, Samuel, Ingersoll, Henry, Borge, R. P., Al-Saghir, Y., Farris, Neil, Shore, Karen, Gornick, C., Eilat, P., Paliwal, Y., Mitra, Rito , Jingo, Ahmad, Aslam, Asma , Watson, Robert, Voyce, Stephen , Turakhia, Mintu P. , Goytia-Leos, D., Lurie, Miriam, Mallis, G., Strobel, John, Fisher, D M, Atieh, Mutaz I., Drabick, Andrew, Harman, Ece, Ashcraft, B., Krista, M., Videlefsky, A., Zayas, E. Rivera, Tan, A.E., Gersh, Bernard J , Turakhia, Mintu P , Steinberg, Benjamin A. , Allen, Larry A. , Chan, Paul S. , Freeman, James V. , Hylek, Elaine M. , Naccarelli, Gerald V. , Peterson, Eric D. , Mendelson, R., AL-NAHHAS, ADIL M. , Padanilam, B., Pan, D., Raffetto, J., Roan, P., Sackett, M., Seymour, Z., Shoemaker, J. Kevin , Simms, V., Tak, T., Riley, E., Weinstein, D., Hayward, D., Burns, R., Spiller, D., McGarvey, J., Guthrie, R., Flood, R., Aggarwal, R., Jacobs, G., Alfieri, A., Bacon, J., Berger, P., Berry, J., Bloom, S., Kapadia, S., Casanova, R., Christensen, T., Fox, D., Gill, S., Grubb, Søren , Hall, C., Harris, H., Hotchkiss, D., Jones, A., Lee, David S. , Kozlowski, J., Benjamin, S., Detweiler, R., Jackson, T., Littlefield, R., Long, W., Quinn, J., Browne, Kevin D. , Forman, Steven L. , Ebinger, Martin , Williams, David Michael , Stein, R., Kirkland, S., Cohen, K., Walthall, W., Davis, Keith L. , Alvarado, O., Leach, C., Sharma, Anand , Sutter, G., Reiter, W., Kobayashi, J., Kramer, J., Latif, S.A., Adler, Alma J , Butman, Samuel M. , Coats, Paul , Shore, K., Schwartz, M.B., Quinlan, E., Mitra, R., Aslam, A.A., Lurie, M., Atwater, Brett D. , Murray, John M. , Fisher, D., Landes, Reid D. , Harman, E., Zayas, E. Rivera
Circulation: Arrhythmia and Electrophysiology | April 16, 2020 | Volume: 13 | Issue: 5 | Pages: No page available
Background: Atrial fibrillation (AF) adversely impacts health-related quality of life (hrQoL). While some patients demonstrate improvements in hrQoL, the factors associated with large improvements in hrQoL are not well described. Methods: We assessed factors associated with a 1-year increase in the Atrial Fibrillation Effect on Quality-of-Life score of 1 SD (≥18 points; 3× clinically important difference), among outpatients in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation I registry. Results: Overall, 28% (181/636) of patients had such a hrQoL improvement. Compared with patients not showing large hrQoL improvement, they were of similar age (median 73 versus 74, P =0.3), equally likely to be female (44% versus 48%, P =0.3), but more likely to have newly diagnosed AF at baseline (18% versus 8%; P =0.0004), prior antiarrhythmic drug use (52% versus 40%, P =0.005), baseline antiarrhythmic drug use (34.8% versus 26.8%, P =0.045), and more likely to undergo AF-related procedures during follow-up (AF ablation: 6.6% versus 2.0%, P =0.003; cardioversion: 12.2% versus 5.9%, P =0.008). In multivariable analysis, a history of alcohol abuse (adjusted OR, 2.41; P =0.01) and increased baseline diastolic blood pressure (adjusted OR, 1.23 per 10-point increase and >65 mm Hg; P =0.04) were associated with large improvements in hrQoL at 1 year, whereas patients with prior stroke/transient ischemic attack, chronic obstructive pulmonary disease, and peripheral arterial disease were less likely to improve ( P <0.05 for each). Conclusions: In this national registry of patients with AF, potentially treatable AF risk factors are associated with large hrQoL improvement, whereas less reversible conditions appeared negatively associated with hrQoL improvement. Understanding which patients are most likely to have large hrQoL improvement may facilitate targeting interventions for high-value care that optimizes patient-reported outcomes in AF. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01165710.