Abstract 19231: Transthyretin F64L Variant is Associated With Increased Risk of Heart Failure in a Large Clinical Cohort
Introduction: Transthyretin-related cardiac amyloidosis (TTR-CA) is increasingly recognized as a cause of heart failure (HF). While TTR-CA is associated with >100 variants in the TTR gene, the clinical relevance of many of these variants remains unknown due to the lack of large cohorts of phenotyped individuals with corresponding genotype data. One rare TTR variant, a phenylalanine to leucine substitution at position 64 (F64L), has been described in single case reports of individuals with cardiac amyloid and cardiomyopathy, but whether this variant modifies risk for HF is unknown. In this study, we sought to examine the association of the F64L variant with HF in a large, electronic health record (EHR) based clinical cohort.
Methods: The cohort was derived from black and white adult subjects genotyped using the Illumina Infinium Exomechip in BioVU, a Vanderbilt University resource linking DNA samples and genetic data to a de-identified EHR. The Exomechip contains ~250,000 coding variants, including TTR F64L. Subjects with clinically diagnosed HF were identified through ICD-9 billing code queries, problem list searches, echocardiographic data, and manual chart review. Association between the F64L variant and HF was assessed using Fisher’s exact test.
Results: Among 24,608 adult subjects with available genotype data, five were F64L carriers. Carriers were 80% black (N=4), 40% female (N=2), and had a median age of 72 years (range 57-81 years). Non-carriers were 10% black, 55% female, and had a median age of 64 years (IQR 52-76, range 18 to 107 years). The carrier rate was 0.08% in blacks and 0.002% in whites. Overall, the prevalence of clinically apparent HF was 60% (3 of 5) in carriers and 15% in non-carriers (p=0.03). Two F64L carriers without clinically diagnosed HF had evidence of cardiac abnormalities including markedly elevated BNP (415 pg/mL) and left ventricular hypertrophy on electrocardiography, respectively.
Conclusions: These data suggest carriers of the TTR F64L variant may be at a higher risk for developing heart failure and highlight the relevance of rare genetic variation in TTR to clinical cardiac phenotypes. More generally, these data demonstrate the feasibility of leveraging the power of the EHR to explore genotype-phenotype associations.
Author Disclosures: E.K. Zern: None. E.H. Farber-Eger: None. M.A. Blair: None. Q.S. Wells: None.
- © 2016 by American Heart Association, Inc.