Blood Adv. 2026 Apr 1:bloodadvances.2026019698. doi: 10.1182/bloodadvances.2026019698. Online ahead of print.
ABSTRACT
The amyloidogenic V122I variant of the transthyretin (TTR) gene is found in about 3% of African-Americans and increases cardiovascular mortality risk after age 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 SCD patients (mean age: 35.9 years, 50.7% women). The prevalence was 3.1% (18/584), mainly female (72.2%). Age, blood pressure, BMI, and liver/renal markers were similar between carriers and non-carriers, except for higher blood urea nitrogen in carriers. Echocardiography showed that carriers had increased septal thickness, left ventricular (LV) mass index, and lower diastolic function indices. Over a median follow-up of 6.5 years, 219 patients died. Co-inheritance 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 non-carriers, corresponding to an approximate relative risk of 3.6. TTR protein levels were significantly lower in carriers. In conclusion, TTR V122I prevalence in SCD patients 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 in SCD patients. This protocol is registered at ClinicalTrials.gov under NCT00011648.
PMID:41921073 | DOI:10.1182/bloodadvances.2026019698