Key result
Transthyretin V142I variant is linked to higher mortality risk and systemic amyloidosis manifestations.
Why the study?
The systemic manifestations and mortality risk associated with the TTR V142I variant in individuals of African ancestry were not fully characterized.
Does TTR V142I variant carrier status increase the risk of heart failure, systemic manifestations, and mortality in individuals of African ancestry?
Cohort (n=16,117)
Does TTR V142I variant carrier status increase the risk of heart failure, systemic manifestations, and mortality in individuals of African ancestry?
TTR V142I variant carriers of African ancestry have a significantly increased risk of heart failure, systemic manifestations such as carpal tunnel syndrome and neuropathy, and cardiovascular mortality compared to matched controls.
BACKGROUND: The most common pathogenic transthyretin variant underlying variant transthyretin amyloidosis in the United States is c.424G>A, p.Val142Ile (V142I). In affected individuals, disease manifests predominantly as heart failure (HF) and cardiomyopathy (CM), with atrial fibrillation (AF) or atrial flutter (AFL), carpal tunnel syndrome (CTS), spinal stenosis (SS), and neuropathy also common. OBJECTIVES: The aim of this study was to investigate the association of TTR V142I carrier status with these established outcomes. METHODS: A retrospective cohort study was conducted among individuals of African ancestry enrolled in the MVP (Million Veteran Program). Participants with at least 1 V142I allele were matched to control subjects on the basis of race, sex, and birth year. Outcomes included HF or CM, AF or AFL, CTS, SS, neuropathy, all-cause mortality, cardiovascular mortality, and HF-related hospitalization. Cumulative incidence and multivariable Cox proportional hazards regression models were used to compare V142I carriers with control subjects. RESULTS: The final study cohort included 2,658 V142I carriers and 13,459 matched control subjects. After multivariable adjustment, V142I carriers had significantly higher risks for HF or CM (HR: 1.20; 95% CI: 1.10-1.31), AF or AFL (HR: 1.26; 95% CI: 1.13-1.40), CTS (HR: 1.43; 95% CI: 1.30-1.57), SS (HR: 1.17; 95% CI: 1.07-1.28), and neuropathy (HR: 1.24; 95% CI: 1.13-1.36) compared with control subjects. A higher risk for HF or CM was observed among V142I carriers than matched control subjects with the following amyloidosis-related red-flag symptoms: AF or AFL (HR: 1.26; 95% CI: 1.03-1.52), CTS (HR: 1.40; 95% CI: 1.20-1.64), SS (HR: 1.26; 95% CI: 1.06-1.49), and neuropathy (HR: 1.28; 95% CI: 1.11-1.48). V142I carriers also had a significantly higher risk for all-cause mortality (HR: 1.12; 95% CI: 1.01-1.25), cardiovascular mortality (HR: 1.37; 95% CI: 1.14-1.65), and HF-related hospitalization (HR: 1.25; 95% CI: 1.07-1.45). CONCLUSIONS: These findings highlight the systemic manifestations of variant transthyretin amyloidosis associated with the TTR V142I variant and underscore the need for increased awareness and earlier diagnostic efforts in high-risk populations.
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Sideris et al. (2026) conducted a cohort in Variant transthyretin amyloidosis (n=16,117). TTR V142I carrier status vs. Matched control subjects was evaluated on Heart failure or cardiomyopathy (HR 1.20, 95% CI 1.10-1.31). TTR V142I carriers of African ancestry had a significantly higher risk of heart failure or cardiomyopathy compared with matched controls (HR 1.20; 95% CI 1.10-1.31).
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