Evolving knowledge of "red flag" clinical features associated with TTR p.(Val142Ile) in a diverse electronic health record-linked biobank.

Abstract

Purpose: Previous studies have established "red flags" that raise clinical suspicion for the hereditary form of transthyretin amyloidosis (ATTRv). However, these have not been specifically evaluated for the most common associated variant, TTR p.(Val142Ile).

Methods: Using an ancestrally diverse electronic health record-linked biobank with exome sequence data from 27,630 unrelated adults, we evaluated nine ATTRv-related clinical features among TTR p.(Val142Ile) positive and negative individuals.

Results: Among 337 variant positive individuals (median age 63, 60% female), ten (3.0%) were diagnosed with amyloidosis. TTR p.(Val142Ile) was associated with increased odds of cardiomyopathy/heart failure (CM/HF), atrial fibrillation, polyneuropathy, carpal tunnel syndrome, and proteinuria, but only in individuals ≥ 60 years. These features were evident 1.7 to 7.7 years earlier in variant positive vs. negative individuals (HR 1.37, P = 3.99 x 10^-2; HR 1.78, P = 2.52 x 10^-3; HR 1.78, P = 1.70 x 10^-3; HR 1.81, P = 5.14 x 10^-3; HR 1.60, P = 1.94 x 10^-2, respectively). By age 50, the cumulative incidence of CM/HF was 3.5-fold higher, and by age 60, the incidences of CM/HF, polyneuropathy, and proteinuria were 2-fold higher in variant positive individuals.

Conclusions: This study clarifies red flags that are associated with TTR p.(Val142Ile) in an age-dependent manner. With modifying therapies available, early diagnosis of ATTRv in variant positive individuals through recognition of key clinical features is paramount.