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N Engl J Med. 2015 Jan 1;372(1):21-9. doi: 10.1056/NEJMoa1404852.

The amyloidogenic V122I transthyretin variant in elderly black Americans.

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From the Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston (C.C.Q., A.M.S., R.H.F., B.C., S.D.S.); Institute of Cardiology, University of Bologna and S. Orsola-Malpighi Hospital, Bologna, Italy (C.C.Q.); Scripps Research Institute, La Jolla, CA (J.N.B.); Cardiology and Geriatrics Sections, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.); Department of Medicine-Geriatrics (T.H.M.) and Division of Cardiovascular Diseases (K.R.B.), University of Mississippi Medical Center, Jackson; and the Human Genetics Center, University of Texas Health Science Center School of Public Health, Houston (E.B.).



Approximately 4% of black Americans carry a valine-to-isoleucine substitution (V122I) in the transthyretin protein, which has been associated with late-onset restrictive amyloid cardiomyopathy and increased risks of death and heart failure.


We determined genotype status for the transthyretin gene (TTR) in 3856 black participants in the Atherosclerosis Risk in Communities study and assessed clinical profiles, mortality, and the risk of incident heart failure in V122I TTR variant carriers (124 participants [3%]) versus noncarriers (3732 participants). Cardiac structure and function and features suggestive of cardiac amyloidosis were assessed in participants who underwent echocardiography during visit 5 (2011 to 2013), when they were older than 65 years of age.


After 21.5 years of follow-up, we did not detect a significant difference in mortality between carriers (41 deaths, 33%) and noncarriers (1382 deaths, 37%; age- and sex-stratified hazard ratio among carriers, 0.99; 95% confidence interval [CI], 0.73 to 1.36; P=0.97). The TTR variant was associated with an increased risk of incident heart failure (age- and sex-stratified hazard ratio, 1.47; 95% CI, 1.03 to 2.10; P=0.04). On echocardiography at visit 5, carriers (46 participants) had worse systolic and diastolic function, as well as a higher level of N-terminal pro-brain natriuretic peptide, than noncarriers (1194 participants), although carriers had a low prevalence (7%) of overt manifestations of amyloid cardiomyopathy.


We did not detect a significant difference in mortality between V122I TTR allele carriers and noncarriers, a finding that contrasts with prior observations; however, the risk of heart failure was increased among carriers. The prevalence of overt cardiac abnormalities among V122I TTR carriers was low. (Funded by the National Heart, Lung, and Blood Institute and others.).

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