DISCOVERY: prevalence of transthyretin (TTR) mutations in a US-centric patient population suspected of having cardiac amyloidosis

Abstract

Background

Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a multisystem disease that presents with polyneuropathy and/or cardiomyopathy.

Methods

DISCOVERY, a multicenter screening study, enrolled patients with clinically suspected cardiac amyloidosis to determine the frequency of transthyretin (TTR) mutations and assess disease characteristics.

Results

Of 1007 patients, the majority were from the US (84%), Black/African American (56%), male (63%), and with a mean (standard deviation) age of 65 (13) years. Among 1001 patients with genotyping results, 74 (7%) had a pathogenic TTR mutation (71/836 [8%] from the US). Val122Ile was the most common mutation, found in 11% of Black/African American patients overall; Black/African American ethnicity was an independent predictor of having a pathogenic TTR mutation. Additional independent predictors of such mutations in the total population and Black/African American group were interventricular septum thickness, low electrocardiogram voltage, and age.

Conclusions

Pathogenic TTR mutations occurred in 8% of US patients with suspected cardiac amyloidosis. Most mutations were Val122Ile, almost exclusively found in Black/African American patients. Disease often remains undetected until advanced and difficult to treat, therefore, clinicians should assess at-risk patients for hATTR amyloidosis as early as possible.

Keywords:

• ATTR amyloidosis
• cardiomyopathy
• heart failure
• transthyretin
• Val122Ile

Acknowledgments

The authors thank the patients who contributed to this study and their families, and the investigators and staff from the additional participating study sites.

Disclosure statement

Keyur Shah reports grants from Alnylam Pharmaceuticals outside the submitted work. Alberta L. Warner reports grants from Alnylam Pharmaceuticals during the conduct of the study. Thibaud Damy reports research grants or scientific meeting expenses or honoraria from Alnylam Pharmaceuticals, Pfizer, Prothena, and GSK. Herman A. Taylor, Verena Karsten, Jared Gollob, and Christine Powell report personal fees from Alnylam Pharmaceuticals during the conduct of the study. John Vest reports personal fees from Alnylam Pharmaceuticals during the conduct of the study and personal fees from Novartis outside the submitted work. Matthew S. Maurer reports grants from NIH (R01HL139671-01, R21AG058348, and K24AG036778), and Alnylam Pharmaceuticals during the conduct of the study; grants from Alnylam Pharmaceuticals, Prothena, GSK, and Eidos outside the submitted work. Ola Akinboboye had nothing to declare.

Additional information

Funding

This study was funded by Alnylam Pharmaceuticals. Medical writing services provided by Stephen Whiting (PhD) of Adelphi Communications Ltd, Macclesfield, UK, were funded by Alnylam Pharmaceuticals, Cambridge, MA, USA, in accordance with Good Publication Practice (GPP3) guidelines.