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Comment
. 2024 Nov 1;9(11):964-972.
doi: 10.1001/jamacardio.2024.2190.

Prevalence, Cardiac Phenotype, and Outcomes of Transthyretin Variants in the UK Biobank Population

Nay Aung  1   2 , Hannah L Nicholls  1 , C Anwar A Chahal  1   2   3   4 , Mohammed Y Khanji  1   2 , Elisa Rauseo  1   2 , Sucharitha Chadalavada  1   2 , Steffen E Petersen  1   2   5 , Patricia B Munroe  1 , Perry M Elliott  2   6 , Luis R Lopes  2   6
Affiliations
Comment

Prevalence, Cardiac Phenotype, and Outcomes of Transthyretin Variants in the UK Biobank Population

Nay Aung et al. JAMA Cardiol. .

Abstract

Importance: The population prevalence of cardiac transthyretin amyloidosis (ATTR) caused by pathogenic variation in the TTR gene (vATTR) is unknown.

Objective: To estimate the population prevalence of disease-causing TTR variants and evaluate associated phenotypes and outcomes.

Design, setting, and participants: This population-based cohort study analyzed UK Biobank (UKB) participants with whole-exome sequencing, electrocardiogram, and cardiovascular magnetic resonance data. Participants were enrolled from 2006 to 2010, with a median follow-up of 12 (IQR, 11-13) years (cutoff date for the analysis, March 12, 2024). Sixty-two candidate TTR variants were extracted based on rarity (minor allele frequency ≤0.0001) and/or previously described associations with amyloidosis if more frequent.

Exposure: Carrier status for TTR variants.

Main outcomes and measures: Associations of TTR carrier status with vATTR prevalence and cardiovascular imaging and electrocardiogram traits were explored using descriptive statistics. Associations between TTR carrier status and atrial fibrillation, conduction disease, heart failure, and all-cause mortality were evaluated using adjusted Cox proportional hazards models. Genotypic and diagnostic concordance was examined using International Statistical Classification of Diseases, Tenth Revision codes from the hospital record.

Results: The overall cohort included 469 789 UKB participants (mean [SD] age, 56.5 [8.1] years; 54.2% female and 45.8% male). A likely pathogenic/pathogenic (LP/P) TTR variant was detected in 473 (0.1%) participants, with Val142Ile being the most prevalent (367 [77.6%]); 91 individuals (0.02%) were carriers of a variant of unknown significance . The overall prevalence of LP/P variants was 0.02% (105 of 444 243) in participants with European ancestry and 4.3% (321 of 7533) in participants with African ancestry. The LP/P variants were associated with higher left ventricular mass indexed to body surface area (β = 4.66; 95% CI, 1.87-7.44), and Val142Ile was associated with a longer PR interval (β = 18.34; 95% CI, 5.41-31.27). The LP/P carrier status was associated with a higher risk of heart failure (hazard ratio [HR], 2.68; 95% CI, 1.75-4.12) and conduction disease (HR, 1.88; 95% CI, 1.25-2.83). Higher all-cause mortality risk was observed for non-Val142Ile LP/P variants (HR, 1.98; 95% CI, 1.06-3.67). Thirteen participants (2.8%) with LP/P variants had diagnostic codes compatible with cardiac or neurologic amyloidosis. Variants of unknown significance were not associated with outcomes.

Conclusions and relevance: This study found that approximately 1 in 1000 UKB participants were LP/P TTR variant carriers, exceeding previously reported prevalence. The findings emphasize the need for clinical vigilance in identifying individuals at risk of developing vATTR and associated poor outcomes.

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Conflict of interest statement

Conflict of Interest Disclosures: Prof Petersen reported receiving personal fees from Circle Cardiovascular Imaging Inc outside the submitted work. Prof Elliott reported receiving consultant and speaker fees from Pfizer during the conduct of the study, consultant fees from Bristol-Myers Squibb and Biomarin, speaker fees from Bristol-Myers Squibb, and advisory board fees from Cytokinetics outside the submitted work. Prof Lopes reported receiving consulting fees from Bristol-Myers Squibb and Novo Nordisk; speaker fees from Bristol-Myers Squibb, Sanofi, and Alnylam; and grants from Bristol-Myers Squibb outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Prevalence of TTR Gene Variants in the UK Biobank
VUS indicates variant of uncertain significance.
Figure 2.
Figure 2.. Association Between TTR Variants and Left Ventricular Imaging Measurements and Electrocardiogram Parameters
GLS indicates global longitudinal strain; LP/P, likely pathogenic/pathogenic; LVEDVi, left ventricular end-diastolic volume indexed to body surface area; LVEF, left ventricular ejection fraction; LVMCF, left ventricular myocardial contraction fraction; LVMi, left ventricular mass indexed to body surface area; LVSVi, left ventricular stroke volume indexed to body surface area; MWT, maximum wall thickness; native T1, myocardial noncontrast T1 values; Vol/LVMi, ratio of total QRS voltage to left ventricular mass indexed to body surface area; VUS, variant of uncertain significance.
Figure 3.
Figure 3.. Kaplan-Meier Survival Curves for Heart Failure
Individuals with prevalent heart failure were removed from the survival analyses. LP/P indicates likely pathogenic/pathogenic; VUS, variant of uncertain significance.
Figure 4.
Figure 4.. Prognostic Associations Between TTR Variants and Adverse Outcomes in Cox Models
HR indicates hazard ratio; LP/P, likely pathogenic/pathogenic; VUS, variant of uncertain significance.
See this image and copyright information in PMC

Comment on

References

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