The amyloidogenic V122I transthyretin variant in elderly black Americans

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.).

Figure 1. Kaplan–Meier Curves for Overall Survival and Freedom from Heart Failure, According to Genotype Status

The analysis, which included black participants in the Atherosclerosis Risk in Communities study, compared carriers of the amyloidogenic V122I transthyretin variant with noncarriers of the variant. Survival estimates as a function of time from visit 1 were obtained.

Figure 2. Kaplan–Meier Curves, with Age as the Underlying Time Variable, for Overall Survival and Freedom from Heart Failure, According to Genotype Status

Participants with prevalent heart failure at the time of the first evaluation or for whom information on heart-failure status at baseline was missing were excluded from the analysis.

Figure 3. Hazard Ratios for Congestive Heart Failure among V122I TTR Variant Carriers as Compared with Noncarriers in Two Population-Based Longitudinal Studies

A fixed-effect meta-analysis was performed with the use of the inverse-variance method. The size of each box is proportional to the number of events in each study; horizontal lines indicate 95% confidence intervals. The dashed red line indicates the overall hazard ratio, with the blue diamond showing the 95% confidence interval for the overall hazard ratio. The I statistic describes the percentage of variation across studies that is due to heterogeneity rather than chance.