Abstract 24: Amyloidogenic V122I Transthyretin Variant is Associated With Progression of Adverse Cardiac Mechanics in Middle-aged African American Adults: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

Abstract

Introduction: Direct-to-consumer testing (e.g. 23andme) reports now include common pathogenic variants in the transthyretin (TTR) gene, such as V122I. TTR cardiac amyloidosis due to V122I is an autosomal dominant disease known to be of variable penetrance in elderly African Americans. However, the association of carrier status for V122I with echocardiographic measures of cardiac mechanics in middle-age African Americans is not known. Hypothesis: Presence of V122I TTR mutation is associated with adverse cardiac mechanics in middle-aged African Americans. Methods: All African Americans from the CARDIA study with imputed genetic data (R 2 = 0.98) and echocardiography at year 25 (Y25) were included. Echo parameters at Y25 and change from Y25 to Y30 were compared between V122I heterozygote carriers and controls using linear regression models. The analysis was adjusted for age, sex, and top 3 principal components of ancestry. Analysis for change from Y25 to Y30 was adjusted for baseline Y25 echo parameters. Results: Of 874 included participants, mean age was 50.2 (3.6) years at Y25. There were 843 controls and 31 carriers for the V122I genotype (3.5% prevalence). There was no difference in age, sex, or clinical characteristics. Carriers of the V122I variant had worse diastolic function as measured by early diastolic tissue Doppler velocity (e’) at Y25 (9.2 [2.1] vs. 10.2 [2.4], p=0.048). From Y25 to Y30, V122I carriers had greater progression of left ventricular (LV) volume and mass as well as greater decline in subclinical LV systolic function as measured by circumferential strain (Table). Conclusions: Prevalence of the carrier status of the V122I genotype in CARDIA is relatively high and consistent with prior studies. Our findings suggest that the V122I mutation may be a unique risk enhancer for heart failure in middle-aged African Americans. Further data are needed for clarity on risk associated with carrier status of V122I and implications for cascade screening given emerging therapies for TTR cardiac amyloidosis.