Significance of the amyloidogenic transthyretin Val 122 Ile allele in African Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies

Abstract

Many African-Americans carry an amyloidogenic transthyretin mutation (TTR V122I), with a high risk for cardiac TTR amyloid deposition after age 65. We wished to determine the allele frequency and its clinical penetrance in community-dwelling African-Americans.Study subjects-5000 consenting African-Americans, ages 41 to 93, in two community studies of cardiovascular risk (CHS and ARIC).Methods-genotyping of banked DNA for TTR V122I allele status; review of cardiovascular and demographic parameters in CHS and ARIC databases with statistical comparisons of the frequency of congestive heart failure, survival and occurrence of features of cardiac amyloidosis, in carriers of the amyloidogenic allele and controls.Results-119 (3.23%) of 3712 ARIC and 17 (2.12%) of 805 CHS African-Americans carried TTR V122I. After age 65 (CHS) the frequency of congestive heart failure (38% vs 15%, RR 2.62, p = 0.04) and mortality (76% vs 53 %, RR 1.46, p =0.08) were higher in V122I allele carriers than in age, gender and ethnically matched controls. In ARIC (all subjects younger than 65) there were no differences between carriers and non-carriers in mortality, frequency of congestive heart failure or findings consistent with cardiac amyloidosis.Conclusions-Heterozygosity for the amyloidogenic TTR V122I mutation is relatively common in community dwelling African-Americans. Before 65 the allele has no discernible impact on cardiac function or mortality. After age 70carriers show a higher frequency of congestive failure and greater mortality with more echocardiographic evidence suggestive of cardiac amyloidosis, findings consistent with age dependent clinical penetrance of this autosomal dominant gene.

AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin

“…1) (17,18). This allele occurs in 3% to 4% of African-American subjects (∼1.3 million people) and is hypothesized to contribute to the increased prevalence of heart failure among African Americans (14,15,17,19). WT-TTR aggregation underlies the development of senile systemic amyloidosis (SSA), a condition that affects as much as 10% to 20% of the population older than age 65 y and, in some patients, leads to progressive congestive heart failure (20,21).…”

“…S1) (11). These mutations lead to hereditary TTR amyloidoses such as familial amyloid polyneuropathy (FAP) (12,13) and familial amyloid cardiomyopathy (FAC) (14,15), which are autosomaldominant conditions with varying ages of onset and penetrance depending on the TTR mutation and ethnic background of the carriers (summarized in Fig. 1).…”

Nuclear Tracers for Transthyretin Cardiac Amyloidosis

“…5,6 Furthermore, the most common inherited mutation in TTR, a valine-to-isoleucine substitution at position 122 (V122I or Ile122), has an accepted prevalence of 3% to 4% among US blacks and seems to be associated with the development of heart failure in elderly black patients. 7 Thus, as the population ages and longevity increases, the incidence of TTR cardiac amyloidosis, both wild type and variant, will likely increase.…”

Isolated Cardiac Amyloidosis: An Enigma Unravelled

“…15 According to statistics from the U.S. Census, as many as 1.5 million African Americans carry the Val-122-Ile mutation. 16 Data from the Beta-Blocker Evaluation in Survival Trial revealed that around one-tenth of all African Americans aged > 60 years are carriers of Val-122-Ile mutation.…”