Transthyretin V122I variant and protein affect cardiac severity and mortality in sickle cell disease

ABSTRACT: The amyloidogenic V122I variant of the transthyretin (TTR) gene is found in ∼3% of African American individuals and increases cardiovascular mortality risk after the age of 65 years. Sickle cell disease (SCD) primarily affects individuals of African descent, leading to multiorgan damage and premature mortality, with cardiopulmonary issues being a major cause of death. We assessed the impact of TTR V122I on cardiac phenotype and survival in a study of 584 patients with SCD (mean age, 35.9 years; 50.7% women). The prevalence was 3.1% (18/584), mainly female (72.2%). Age, blood pressure, body mass index, and liver/renal markers were similar between carriers and noncarriers, except for higher blood urea nitrogen levels in carriers. Echocardiography showed that carriers had increased septal thickness and left ventricular mass index and lower diastolic function indices. Over a median follow-up of 6.5 years, 219 patients died. The coinheritance of TTR V122I with SCD was associated with increased mortality (hazard ratio, 2.82; 95% confidence interval, 1.57-5.06). At 5 years, the cumulative incidence of death was 52.9% among carriers compared with 14.5% among noncarriers, corresponding to an approximate relative risk of 3.6. TTR protein levels were significantly lower in carriers. In conclusion, TTR V122I prevalence in patients with SCD mirrors that of the general African American population but affects cardiovascular function much earlier, and a contributing factor may be the underlying oxidative stress and chronic anemia. Genetic screening for TTR V122I is important and should be considered for patients with SCD. This trial was registered at www.clinicaltrials.gov as NCT00011648.