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Observational Study
. 2024 Jun 4;331(21):1824-1833.
doi: 10.1001/jama.2024.4467.

Cardiovascular Burden of the V142I Transthyretin Variant

Senthil Selvaraj  1   2 , Brian Claggett  3 , Svati H Shah  1   2 , Robert J Mentz  1 , Michel G Khouri  1 , Ani W Manichaikul  4 , Sadiya S Khan  5 , Stephen S Rich  4 , Thomas H Mosley  6 , Emily B Levitan  7 , Pankaj Arora  8 , Parag Goyal  9 , Bernhard Haring  10   11 , Charles B Eaton  12 , Richard K Cheng  13 , Gretchen L Wells  8 , JoAnn E Manson  14 , Marianna Fontana  15 , Scott D Solomon  3
Affiliations
Observational Study

Cardiovascular Burden of the V142I Transthyretin Variant

Senthil Selvaraj et al. JAMA. .

Abstract

Importance: Individual cohort studies concur that the amyloidogenic V142I variant of the transthyretin (TTR) gene, present in 3% to 4% of US Black individuals, increases heart failure (HF) and mortality risk. Precisely defining carrier risk across relevant clinical outcomes and estimating population burden of disease are important given established and emerging targeted treatments.

Objectives: To better define the natural history of disease in carriers across mid to late life, assess variant modifiers, and estimate cardiovascular burden to the US population.

Design, setting, and participants: A total of 23 338 self-reported Black participants initially free from HF were included in 4 large observational studies across the US (mean [SD], 15.5 [8.2] years of follow-up). Data analysis was performed between May 2023 and February 2024.

Exposure: V142I carrier status (n = 754, 3.2%).

Main outcomes and measures: Hospitalizations for HF (including subtypes of reduced and preserved ejection fraction) and all-cause mortality. Outcomes were analyzed by generating 10-year hazard ratios for each age between 50 and 90 years. Using actuarial methods, mean survival by carrier status was estimated and applied to the 2022 US population using US Census data.

Results: Among the 23 338 participants, the mean (SD) age at baseline was 62 (9) years and 76.7% were women. Ten-year carrier risk increased for HF hospitalization by age 63 years, predominantly driven by HF with reduced ejection fraction, and 10-year all-cause mortality risk increased by age 72 years. Only age (but not sex or other select variables) modified risk with the variant, with estimated reductions in longevity ranging from 1.9 years (95% CI, 0.6-3.1) at age 50 to 2.8 years (95% CI, 2.0-3.6) at age 81. Based on these data, 435 851 estimated US Black carriers between ages 50 and 95 years are projected to cumulatively lose 957 505 years of life (95% CI, 534 475-1 380 535) due to the variant.

Conclusions and relevance: Among self-reported Black individuals, male and female V142I carriers faced similar and substantial risk for HF hospitalization, predominantly with reduced ejection fraction, and death, with steep age-dependent penetrance. Delineating the individual contributions of, and complex interplay among, the V142I variant, ancestry, the social construct of race, and biological or social determinants of health to cardiovascular disease merits further investigation.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Selvaraj reported receiving grants from the National Heart, Lung, and Blood Institute (NHLBI), American Heart Association, Doris Duke Foundation, Institute for Translational Medicine and Therapeutics, American Society of Nuclear Cardiology, Mandel Foundation, Duke Heart Center Leadership Council, and Foundation for Sarcoidosis Research and personal fees from AstraZeneca outside the submitted work. Dr Claggett reported receiving personal fees from Alnylam Pharmaceuticals, Cardurion, Corvia, Cytokinetics, Intellia, Rocket, and CVRx outside the submitted work. Dr Mentz reported receiving personal fees from Novartis and AstraZeneca during the conduct of the study; personal fees from Merck, Boehringer Ingelheim/Lilly, Bayer, Medtronic, Novo Nordisk, Pharmacosmos, and Rocket and grants from American Regent outside the submitted work. Dr Khouri reported receiving personal fees from Alnylam Pharmaceuticals, BridgeBio Pharma, and PRIME Education and grants from Alnylam Pharmaceuticals, BridgeBio Pharma, Ionis Pharmaceuticals, and Pfizer outside the submitted work. Dr Khan reported receiving grants from the NHLBI (U01HL160279 and R01HL159250) during the conduct of the study and grants from NHLBI (HL161514) outside the submitted work. Dr Levitan reported receiving grants from the NHLBI during the conduct of the study and grants from Amgen Inc and personal fees from the University of Pittsburgh outside the submitted work. Dr Arora reported receiving grants from Bristol Myers Squibb, Merck Sharp & Dohme LLC, and National Institutes of Health (NIH) and personal fees from Bristol Myers Squibb outside the submitted work. Dr Eaton reported receiving grants from the NIH during the conduct of the study. Dr Manson reported receiving grants from the NIH during the conduct of the study. Dr Fontana reported receiving grants from the British Heart Foundation, Pfizer, AstraZeneca, and BridgeBio and personal fees from Alnylam, AstraZeneca, Attralus, BridgeBio, Ionis, Intellia, Pfizer, Lexeo, Prothena, Janssen, and Akcea outside the submitted work. Dr Solomon reported receiving grants from Alexion, Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Boston Scientific, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, Us2.AI, and Edgewise and personal fees from Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProthera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Analysis of Black Participants From 4 Large Cohort Studies
The process for inclusion and exclusion of participants is delineated for each study. A total of 23 338 participants were ultimately analyzed, including 754 carriers of the V142I variant. ARIC indicates Atherosclerosis Risk in Communities; HF, heart failure; MESA, Multi-Ethnic Study of Atherosclerosis; REGARDS, Reasons for Geographic and Racial Differences in Stroke; and WHI, Women’s Health Initiative.
Figure 2.
Figure 2.. V142I Hazard Ratios for Adverse Cardiovascular Events by Age
Ten-year hazard ratios and 95% CIs (shaded areas) are estimated at each age between 50 and 90 years for carriers vs noncarriers. Analyses are adjusted for interactions between study genotyping platform and the first 10 principal components, while stratified by sex and study genotyping platform. HF indicates heart failure.
Figure 3.
Figure 3.. Effect of V142I on Overall Survival of Carriers Compared With Noncarriers
A, Estimated mean overall survival in carriers and noncarriers for every year between ages 50 and 95 years. B, The difference in mean years lost among carriers compared with noncarriers shown with the smoothed estimate (blue line), and 95% CI of the smoothed estimate (shaded area) after application of a locally weighted scatterplot smoothing procedure.
See this image and copyright information in PMC

Comment in

References

    1. Quarta CC, Buxbaum JN, Shah AM, et al. . The amyloidogenic V122I transthyretin variant in elderly Black Americans. N Engl J Med. 2015;372(1):21-29. doi:10.1056/NEJMoa1404852 - DOI - PMC - PubMed
    1. Chandrashekar P, Alhuneafat L, Mannello M, et al. . Prevalence and outcomes of p.Val142Ile TTR amyloidosis cardiomyopathy: a systematic review. Circ Genom Precis Med. 2021;14(5):e003356. doi:10.1161/CIRCGEN.121.003356 - DOI - PMC - PubMed
    1. Maurer MS, Hanna M, Grogan M, et al. ; THAOS Investigators . Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol. 2016;68(2):161-172. doi:10.1016/j.jacc.2016.03.596 - DOI - PMC - PubMed
    1. Jacobson DR, Pastore RD, Yaghoubian R, et al. . Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in Black Americans. N Engl J Med. 1997;336(7):466-473. doi:10.1056/NEJM199702133360703 - DOI - PubMed
    1. Miller DT, Lee K, Abul-Husn NS, et al. ; ACMG Secondary Findings Working Group . ACMG SF v3.2 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2023;25(8):100866. doi:10.1016/j.gim.2023.100866 - DOI - PMC - PubMed

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