Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey)

Abstract

Background: Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis.

Objectives: The goal of this study was to describe ATTR in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry.

Methods: Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared with data from patients from other regions of the world (ROW) (n = 2,140). The focus was on the phenotypic expression and survival in the majority of U.S. subjects with valine-to-isoleucine substitution at position 122 (Val122Ile) (n = 91) and wild-type ATTR (n = 189).

Results: U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%), and more often of African descent (25.4% vs. 0.5%) than the ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 (85%) of 107 patients with Val122Ile were from the United States, where Val122Ile subjects were younger and more often female and black than patients with wild-type disease, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a transthyretin mutation, were independently associated with higher mortality from a multivariate analysis of survival.

Conclusions: In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult male subjects with a cardiac-predominant phenotype. Val122Ile is the most common transthyretin mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey [THAOS]; NCT00628745).

Keywords: aging; amyloid; transthyretin.

Figure 1. THAOS Enrollment by Country

While the largest number of subjects enrolled in THAOS (Transthyretin Amyloid Outcome Survey) were from Portugal, 15.4% came from the United States.

Figure 2. Distribution of Mutations

In THAOS, variations in distribution of mutations were seen in the United States (A) versus the rest of world (ROW) overall (B), as well as by noncardiology (C) or cardiology site (D) in ROW. Abbreviations as in Figure 1.

Figure 3. Time-to-Event Analysis in U.S. Subjects

Time to death (A) did not differ between U.S. subjects with wild-type transthyretin amyloidosis (ATTR) or Val122Ile, but significantly more Val122Ile patients underwent orthotopic heart transplantation, significantly reducing time to death and transplantation (B) compared to wild-type ATTR patients.

Central Illustration. ATTR Characteristics Worldwide

As determined in THAOS, characteristics of patients with transthyretin amyloidosis (ATTR) differed between patients in the United States and the rest of the world. U.S. patients appeared to be older, more often male and of African descent, and more commonly carried the Val122Ile mutation. wt = wild-type.