Scott M Damrauer1,2, Kumardeep Chaudhary3,4,5, Judy H Cho3,4,5,6, Lusha W Liang7, Edgar Argulian8, Lili Chan3,4,6, Amanda Dobbyn3,4,5, Marie A Guerraty9, Renae Judy1, Jenna Kay9, Rachel L Kember10,11, Michael G Levin9, Aparna Saha3,4, Tielman Van Vleck3,4, Shefali S Verma10, JoEllen Weaver12, Noura S Abul-Husn3,5,6,13, Aris Baras14, Julio A Chirinos9, Brian Drachman9, Eimear E Kenny3,5,13, Ruth J F Loos3,15,16, Jagat Narula8, John Overton14, Jeffrey Reid14, Marylyn Ritchie10, Giorgio Sirugo17, Girish Nadkarni3,4,6, Daniel J Rader7,10,17, Ron Do3,4,5. 1. Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia. 2. Department of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, Pennsylvania. 3. The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. 4. Bio Phenomics Center, Icahn School of Medicine at Mount Sinai, New York, New York. 5. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. 6. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. 7. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia. 8. Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, New York. 9. Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia. 10. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia. 11. MIRECC, Corporal Michael Crescenz VA Medical Center, Philadelphia, Pennsylvania. 12. Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia. 13. The Center for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York. 14. Regeneron Genetics Center, Tarrytown, New York. 15. Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York. 16. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 17. Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Pennsylvania.
Abstract
Importance: Hereditary transthyretin (TTR) amyloid cardiomyopathy (hATTR-CM) due to the TTR V122I variant is an autosomal-dominant disorder that causes heart failure in elderly individuals of African ancestry. The clinical associations of carrying the variant, its effect in other African ancestry populations including Hispanic/Latino individuals, and the rates of achieving a clinical diagnosis in carriers are unknown. Objective: To assess the association between the TTR V122I variant and heart failure and identify rates of hATTR-CM diagnosis among carriers with heart failure. Design, Setting, and Participants: Cross-sectional analysis of carriers and noncarriers of TTR V122I of African ancestry aged 50 years or older enrolled in the Penn Medicine Biobank between 2008 and 2017 using electronic health record data from 1996 to 2017. Case-control study in participants of African and Hispanic/Latino ancestry with and without heart failure in the Mount Sinai BioMe Biobank enrolled between 2007 and 2015 using electronic health record data from 2007 to 2018. Exposures: TTR V122I carrier status. Main Outcomes and Measures: The primary outcome was prevalent heart failure. The rate of diagnosis with hATTR-CM among TTR V122I carriers with heart failure was measured. Results: The cross-sectional cohort included 3724 individuals of African ancestry with a median age of 64 years (interquartile range, 57-71); 1755 (47%) were male, 2896 (78%) had a diagnosis of hypertension, and 753 (20%) had a history of myocardial infarction or coronary revascularization. There were 116 TTR V122I carriers (3.1%); 1121 participants (30%) had heart failure. The case-control study consisted of 2307 individuals of African ancestry and 3663 Hispanic/Latino individuals; the median age was 73 years (interquartile range, 68-80), 2271 (38%) were male, 4709 (79%) had a diagnosis of hypertension, and 1008 (17%) had a history of myocardial infarction or coronary revascularization. There were 1376 cases of heart failure. TTR V122I was associated with higher rates of heart failure (cross-sectional cohort: n = 51/116 TTR V122I carriers [44%], n = 1070/3608 noncarriers [30%], adjusted odds ratio, 1.7 [95% CI, 1.2-2.4], P = .006; case-control study: n = 36/1376 heart failure cases [2.6%], n = 82/4594 controls [1.8%], adjusted odds ratio, 1.8 [95% CI, 1.2-2.7], P = .008). Ten of 92 TTR V122I carriers with heart failure (11%) were diagnosed as having hATTR-CM; the median time from onset of symptoms to clinical diagnosis was 3 years. Conclusions and Relevance: Among individuals of African or Hispanic/Latino ancestry enrolled in 2 academic medical center-based biobanks, the TTR V122I genetic variant was significantly associated with heart failure.
Importance: Hereditary transthyretin (TTR) amyloid cardiomyopathy (hATTR-CM) due to the TTRV122I variant is an autosomal-dominant disorder that causes heart failure in elderly individuals of African ancestry. The clinical associations of carrying the variant, its effect in other African ancestry populations including Hispanic/Latino individuals, and the rates of achieving a clinical diagnosis in carriers are unknown. Objective: To assess the association between the TTRV122I variant and heart failure and identify rates of hATTR-CM diagnosis among carriers with heart failure. Design, Setting, and Participants: Cross-sectional analysis of carriers and noncarriers of TTRV122I of African ancestry aged 50 years or older enrolled in the Penn Medicine Biobank between 2008 and 2017 using electronic health record data from 1996 to 2017. Case-control study in participants of African and Hispanic/Latino ancestry with and without heart failure in the Mount Sinai BioMe Biobank enrolled between 2007 and 2015 using electronic health record data from 2007 to 2018. Exposures: TTRV122I carrier status. Main Outcomes and Measures: The primary outcome was prevalent heart failure. The rate of diagnosis with hATTR-CM among TTRV122I carriers with heart failure was measured. Results: The cross-sectional cohort included 3724 individuals of African ancestry with a median age of 64 years (interquartile range, 57-71); 1755 (47%) were male, 2896 (78%) had a diagnosis of hypertension, and 753 (20%) had a history of myocardial infarction or coronary revascularization. There were 116 TTRV122I carriers (3.1%); 1121 participants (30%) had heart failure. The case-control study consisted of 2307 individuals of African ancestry and 3663 Hispanic/Latino individuals; the median age was 73 years (interquartile range, 68-80), 2271 (38%) were male, 4709 (79%) had a diagnosis of hypertension, and 1008 (17%) had a history of myocardial infarction or coronary revascularization. There were 1376 cases of heart failure. TTRV122I was associated with higher rates of heart failure (cross-sectional cohort: n = 51/116 TTRV122I carriers [44%], n = 1070/3608 noncarriers [30%], adjusted odds ratio, 1.7 [95% CI, 1.2-2.4], P = .006; case-control study: n = 36/1376 heart failure cases [2.6%], n = 82/4594 controls [1.8%], adjusted odds ratio, 1.8 [95% CI, 1.2-2.7], P = .008). Ten of 92 TTRV122I carriers with heart failure (11%) were diagnosed as having hATTR-CM; the median time from onset of symptoms to clinical diagnosis was 3 years. Conclusions and Relevance: Among individuals of African or Hispanic/Latino ancestry enrolled in 2 academic medical center-based biobanks, the TTRV122I genetic variant was significantly associated with heart failure.
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