A genetic variation believed to increase risk for heart failure in people of African or Latino ancestry has been identified in a new study by researchers from the Icahn School of Medicine at Mount Sinai and Perelman School of Medicine at the University of Pennsylvania.
The study found that the transthyretin or TTR V122I genetic variant was significantly associated with heart failure and that heredity transthyretin amyloid cardiomyopathy (hATTR-CM) caused by this variant was confirmed at appreciable frequency in individuals of African or Latino ancestry. The results suggest a significant under-recognition and under-diagnosis of this potentially fatal disease.
The results of the study were published today in JAMA.
hATTR-CM causes deposits of abnormal proteins called amyloids in the heart, nerves, and sometimes the kidneys and other organs, resulting in progressive organ dysfunction. The condition can run in families. Symptoms may start as early as age 20 or as late as age 80, and the average delay in diagnosis is four years. Treatment was limited to supportive care until May of this year, when the Food and Drug Administration approved tafamidis, the first and only targeted TTR therapy. Even with this new treatment, timely diagnosis is key, as the medication can only delay disease progression, not reverse the symptoms.
"Given recent advances in treatment for hATTR-CM, it is imperative to identify patients at risk for the disease and intervene before noticeable symptoms of the disease appear," said study author Ron Do, PhD, Assistant Professor of Genetics and Genomics Sciences, and co-Director of the BioMe Phenomics Center in The Charles Bronfman Institute for Personalized Medicine at the Icahn School of Medicine at Mount Sinai. "Previous studies have proposed utilizing routine genetic testing for individuals with African ancestry; however, this is not current practice and the scope of the under-diagnosis is not clear."
In this observational study, the association of the TTR V122I variant with the clinical diagnosis of heart failure was evaluated using longitudinal electronic health record-linked genetic data from two large integrated academic health systems, the Icahn School of Medicine at Mount Sinai BioMe biobank (BioMe) and the Penn Medicine Biobank (PMBB). Among carriers of the TTR V122I variant, the rates of evaluation for and diagnosis with hATTR-CM was assessed.
Because the TTR V122I variant predominantly occurs in individuals of African ancestry, researchers analyzed the association between TTR V122I variant carrier status and heart failure in 9,694 individuals of African (BioMe and PMBB) and Latino (BioMe) ancestry enrolled in one of the two biobanks. In PMBB, a cross-sectional analysis was performed, comparing the rate of heart failure between TTR V122I variant carriers and non-carriers in individuals of genetically inferred African ancestry aged 50 years or older. The analysis in BioMe used a case-control design among individuals of self-reported African or Latino ancestry, comparing the number of TTR V122I carriers and non-carriers between all participants with prevalent heart failure cases and individuals over the age of 65 without heart failure.
Patients of African or Latino ancestry with TTR V122I genetic variant are two-fold more likely to have heart failure risk. Across both study samples, researchers also observed left-ventricular-wall thickening, which could be a sign of early subclinical heart failure. Higher rates of left-ventricular-wall thickening among younger TTR V122I carriers without overt heart failure were detected in the BioMe cohort, suggesting subtle changes in the heart may develop years prior to the onset of advanced signs and symptoms of the disease. Finally, only 11 percent of individuals with the genetic variant and heart failure were diagnosed with transthyretin cardiomyopathy, with an average time to diagnosis of three years, indicating both high rates of underdiagnosis and prolonged time to appropriate diagnosis.
"These findings suggest that although the TTR genetic variant is known to cause hereditary TTR amyloidosis cardiomyopathy and heart failure, there is significant under-recognition and under-diagnosis of this disease, particularly in individuals of African and/or Latino ancestry," said study co-author Girish Nadkarni, MD, Assistant Professor of Medicine (Nephrology) and co-Director of the BioMe Phenomics Center in The Charles Bronfman Institute for Personalized Medicine at the Icahn School of Medicine at Mount Sinai. "Of the observed cases, only 11 percent of individuals with the TTR genetic variant were diagnosed appropriately. It's imperative that genetic screening of TTR genetic variants be considered for early diagnosis of the disease and its treatment."
Mount Sinai authors of the study include Kumardeep Chaudhary, PhD; Judy H. Cho, MD; Edgar Argulian, MD; Lili Chan, MD; Amanda Dobbyn, PhD; Aparna Saha, MD; Tielman Van Vleck, MD; Noura S. Abul-Husn, MD; Eimear E. Kenny, PhD; Ruth J. Loos, PhD; and Jagat Narula, MD, PhD.
Perelman School of Medicine at the University of Pennsylvania authors include Daniel J. Rader, MD (corresponding author); Scott M. Damrauer, MD; Lusha W. Liang, MD; Marie A. Guerraty, MD, PhD; Renae Judy, MS; Jenna Kay, MD; Rachel L. Kember, PhD; Michael G. Levin, MD; Shefali S. Verma, PhD; Julio A. Chirinos, MD; JoEllen Weaver, BS; Brian Drachman, MD; Marylyn Ritchie, PhD.
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest integrated delivery system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The Health System includes approximately 7,480 primary and specialty care physicians; 11 joint-venture ambulatory surgery centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools", aligned with a U.S. News & World Report's "Honor Roll" Hospital, No. 12 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 14 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Geriatrics, Gynecology, Nephrology, Neurology/Neurosurgery, and Orthopedics in the 2019-2020 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 12th nationally for Ophthalmology, Mount Sinai St. Lukes and Mount Sinai West are ranked 23rd nationally for Nephrology and 25th for Diabetes/Endocrinology, and Mount Sinai South Nassau is ranked 35th nationally for Urology. Mount Sinai Beth Israel, Mount Sinai St. Luke's, Mount Sinai West, and Mount Sinai South Nassau are ranked regionally.
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