The Amyloidogenic Transthyretin V122I Variant Increase Severity of Cardiac Phenotype and Mortality in Sickle Cell Disease

The amyloidogenic V122I variant (valine to isoleucine substitution at position 122) of the transthyretin (TTR) gene is carried almost exclusively in people of African descent, about 3% African-Americans carry the variant. In the general population, carriers for TTR V122I have a higher risk of heart failure, cardiovascular death and increased mortality after age 65 years compared with non-carriers. Sickle cell disease (SCD), one of the most common genetic blood diseases, predominantly affects individuals of African descent and 1 in 365 African-American births. In adults, SCD manifests as a chronic degenerative illness characterized by progressive multiorgan damage, with cardiopulmonary complications being a leading cause of mortality. The impact of TTR V122I in patients with SCD remains unclear.

Objectives: To examine the association between TTR V122I and cardiac phenotype and survival in a cohort of adults with SCD.

Methods: We conducted a prospective observational study of 584 adult patients with SCD (mean ± SD age: 35.9 ± 12.9 years, 296 women [50.7%]) enrolled at the National Heart, Lung, and Blood Institute (NCT00011648) between Sept 2006 and Feb 2017. The cohort had previously been utilized to develop a phenotypic risk score for disease severity and prediction of mortality. TTR V122I genotype was derived from whole genome sequence data or targeted DNA sequence analysis. Clinical profiles, laboratory variables, cardiac phenotype as assessed by echocardiography, and the NIH phenotypic risk score were compared between TTR V122I carriers and non-carriers. All-cause mortality was ascertained by online obituary search, reporting by patient’s family members, National Death Index, and Social Security Death Index search with a final follow-up in June 2024. The cohort was further stratified by gender to evaluate potential sex differences in genotype and phenotype. All analyses were performed using R 4.3.2 with P<0.05 considered as significant.

Results: The prevalence of TTR V122I carriers (Age, 42.2 ± 17.2) was 3.1% (n/N=18/584), and predominantly female at 72.2% (n/N=13/18) compared to males. TTR V122I carriers and non-carriers were similar in age, with no significant differences in blood pressure, BMI, eGFR, creatine and other serologic markers of liver or renal function, except for a higher blood urea nitrogen among carriers (BUN, 16.6 ± 12.2 vs.12.0 ± 12.6 mg/dL; P=0.032). Carriers also exhibited higher baseline septal thickness (10.7 ± 1.4 vs. 9.7 ± 1.7 mm; P=0.004 and higher left ventricular (LV) mass index (110.7 ± 25.3 vs. 99.1 ± 31.0 g/m²; P=0.029). Indices of diastolic function were also lower in carriers (mitral E/A ratio (1.3 ± 0.5 vs. 1.7 ± 0.6; P=0.020) and septal e’ velocity (8.8 ± 2.0 vs. 10.3 ± 2.9; P=0.020). TTR V122I carriers had an elevated NIH risk score (2.7 ± 1.9 vs. 1.8 ± 3.0; P=0.002). Overall, 219 patients died during a median follow-up of 6.5 years, with TTR V122I TTR carriers showing a higher risk of all-cause mortality (Hazard Ratio [HR] 2.82, 95% CI 1.57-5.06; P<0.001). The median survival time was 4.4 years for carriers versus 12.0 years for non-carriers. Gender differences were evaluated due to the higher prevalence in women, and besides increased septal thickness and LV mass index, female carriers had significantly higher tricuspid regurgitation velocity (TRV, 2.9 ± 0.6 vs. 2.6 ± 0.5 m/s; P=0.032) and a more pronounced risk of mortality (HR 3.48, 95% CI 1.81 – 6.68; P<0.001) compared to female non-carriers.

Conclusion: While prevalence of TTR V122I in patients with SCD is comparable to that in the general African-American population, the variant appears to impact cardiovascular function at a much younger age in SCD patients (mean age ~36 years). SCD patients who are also carriers for TTR V122I have higher septal thickness and LV mass index, lower parameters of diastolic function, a higher NIH risk score, and higher all-cause mortality than non-carriers. It is not clear why females have a higher prevalence of TTR V122I compared to males in our SCD cohort. Female carriers experienced more pronounced cardiac dysfunction with increased mortality compared to female non-carriers. We propose that the high oxidative stress environment and chronic anemia are factors that contribute to the accelerated clinical penetrance of the TTR V122I phenotype in SCD, and that genetic screening for TTR V122I should be included in decision-making in choosing SCD patients for high-risk curative therapies.