Cardiovascular Risk Factors and Genetic Risk in Transthyretin V142I Carriers

Naman S Shetty; Mokshad Gaonkar; Akhil Pampana; Nirav Patel; Alanna C Morrison; Alexander P Reiner; April P Carson; Bing Yu; Bruce M Psaty; Charles Kooperberg; Diane Fatkin; Eric Boerwinkle; Jerome I Rotter; Kent D Taylor; Lifang Hou; Marguerite R Irvin; Michael E Hall; Mathew Maurer; Myriam Fornage; Nicole D Armstrong; Nicole Bart; Parag Goyal; Stephen S Rich; Ramachandran S Vasan; Peng Li; Garima Arora; Pankaj Arora

doi:10.1016/j.jchf.2024.08.019

Cardiovascular Risk Factors and Genetic Risk in Transthyretin V142I Carriers

JACC Heart Fail. 2024 Oct 23:S2213-1779(24)00625-5. doi: 10.1016/j.jchf.2024.08.019. Online ahead of print.

Authors

Naman S Shetty¹, Mokshad Gaonkar², Akhil Pampana², Nirav Patel², Alanna C Morrison³, Alexander P Reiner⁴, April P Carson⁵, Bing Yu³, Bruce M Psaty⁶, Charles Kooperberg⁷, Diane Fatkin⁸, Eric Boerwinkle³, Jerome I Rotter⁹, Kent D Taylor⁹, Lifang Hou¹⁰, Marguerite R Irvin¹¹, Michael E Hall⁵, Mathew Maurer¹², Myriam Fornage¹³, Nicole D Armstrong¹¹, Nicole Bart⁸, Parag Goyal¹⁴, Stephen S Rich¹⁵, Ramachandran S Vasan¹⁶, Peng Li¹⁷, Garima Arora², Pankaj Arora¹⁸

Affiliations

¹ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
² Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama, USA.
³ Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA.
⁴ Department of Epidemiology, University of Washington, Seattle, Washington, USA; Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
⁵ Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.
⁶ Department of Epidemiology, University of Washington, Seattle, Washington, USA; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA; Department of Health Systems and Population Health, University of Washington, Seattle, Washington, USA.
⁷ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
⁸ Cardiology Department, St. Vincent's Hospital, Sydney, New South Wales, Australia; Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
⁹ Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at the Harbor-UCLA Medical Center, Torrance, California, USA.
¹⁰ Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
¹¹ Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA.
¹² Cardiac Amyloidosis Program, Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.
¹³ University of Texas Health Science Center, Houston, Texas, USA.
¹⁴ Weill Cornell Medicine Division of Cardiology, New York, New York, USA.
¹⁵ Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
¹⁶ University of Texas School of Public Health San Antonio, San Antonio, Texas, USA.
¹⁷ School of Nursing, University of Alabama at Birmingham, Birmingham, Alabama, USA.
¹⁸ Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama, USA; Section of Cardiology, Birmingham Veterans Affairs Medical Center, Birmingham, Alabama, USA. Electronic address: parora@uabmc.edu.

PMID: 39520444
DOI: 10.1016/j.jchf.2024.08.019

Abstract

Background: Nearly 3% to 4% of Black individuals in the United States carry the transthyretin V142I variant, which increases their risk of heart failure. However, the role of cardiovascular (CV) risk factors (RFs) in influencing the risk of clinical outcomes among V142I variant carriers is unknown.

Objectives: This study aimed to assess the impact of CV RFs on the risk of heart failure in V142I carriers.

Methods: This study included self-identified Black individuals without prevalent heart failure from 6 TOPMed (Trans-Omics for Precision Medicine) cohorts, the REGARDS (Reasons for Geographic And Racial Differences in Stroke) study, and the All of Us Research Program. The cohort was stratified based on the V142I genotype and the number of CV RFs (hypertension, diabetes, obesity, and hypercholesterolemia). Adjusted Cox models were used to assess the association of heart failure with the V142I genotype and CV RF profile, taking noncarriers with a favorable CV RF profile as reference.

Results: The cross-sectional analysis, including 1,625 V142I carriers among 48,365 Black individuals, found that the prevalence of CV RFs did not vary by V142I carrier status. In the longitudinal analysis, there were 587 (3.2%) V142I carriers among 18,407 Black individuals (median age: 60 years [Q1-Q3: 52-68 years], 63.0% female). Among carriers, the heart failure risk was attenuated with a favorable (0 or 1 RF) CV RF profile (adjusted HR: 2.26; 95% CI: 1.58-3.23) compared with an unfavorable (3 or 4 RFs) CV RF profile (adjusted HR: 4.14; 95% CI: 2.79-6.14).

Conclusions: A favorable CV RF profile lowers but does not abrogate V142I variant-associated heart failure risk. This study highlights the importance of having a favorable CV RF profile among V142I carriers for risk reduction of heart failure.

Keywords: Black individuals; V142I; amyloidosis; cardiovascular risk factors; heart failure; mortality.