Expanding the knowledge on transthyretin p.V142I variant‐related cardiomyopathy

Abstract

This article refers to 'Deep phenotyping of p.(V142I)associated variant transthyretin amyloid cardiomyopathy: Distinct from wild-type transthyretin amyloidosis?' by Y. Razvi et al., published in this issue on pages 383-393.Transthyretin amyloidosis (ATTR) is a condition characterized by the extracellular deposition of insoluble protein fibrils within various organs and tissues. 1 Two distinct forms of ATTR have been identified: variant ATTR (ATTRv) and wild-type ATTR (ATTRwt; also referred to as senile amyloidosis). 1,2 ATTRv is a genetic disorder inherited in an autosomal dominant manner, resulting from a pathogenic variant in the TTR gene. 3 To date, more than 140 gene variants have been associated with ATTRv, categorized into cardiac, neurological, and mixed forms based on the clinical phenotype. 3 A deeper understanding of genotype-phenotype correlations in ATTRv is essential for early disease identification, predicting adverse outcomes, and guiding management with approved and upcoming disease-modifying therapies.The p.V142I, the most common identified TTR variant, is significantly prevalent among individuals of African ancestry, being associated with poor outcome. 4 In recent years, significant advancements have been made in understanding the prevalence, clinical phenotypes, and outcomes in patients with p.V142I-associated ATTR (Figure 1). The paper of Razvi et al., 5 published in this issue of the Journal, represents another step forward in the comprehensive understanding of this complex disease.According to the Genome Aggregation Database (GnomAD), the prevalence of p.V142I variant in the general population is estimated to be 0.3%, making it the most common cause of ATTRv and explaining 88% of cases. 6 However, data from study cohorts and genetic biobanks suggest that the prevalence of p.V142I variant is higher among people of African descent, ranging from 1.1% to 9.8%. In a large study population consisting of 9862 non-Hispanic Black/African American women, 3.4% of individuals carried the p.V142I variant, and its presence was associated with a higher risk of coronary artery disease, stroke, acute heart failure (HF), and cardiovascular and all-cause death. 7