# Associations between pathophysiological traits and symptom development in retrospective analysis of V30M and V122I transthyretin amyloidosis

## TL;DR

This study identifies early biomarkers for two types of hereditary amyloidosis, helping detect the disease before symptoms become severe.

## Contribution

The paper introduces mutation-specific clinical and immune biomarkers for early detection of hATTR in V30M and V122I carriers.

## Key findings

- Symptomatic V30M carriers show upregulated neutrophil activity and IL-6/JAK/STAT3 signaling.
- V122I carriers are associated with heart failure, cardiomyopathies, and other comorbidities.
- Echocardiographic traits like higher LVEDV and LA length are linked to V122I mutation.

## Abstract

Mutation-stratified workflow identified traits representative of symptom onset in Val30Met (V30M) and Val122Ile (V122I) hereditary amyloid transthyretin amyloidosis (hATTR). For the V30M portion of the study, microarray gene expression profiling data was analyzed to identify the immune signals differentially upregulated in symptomatic V30M compared to their asymptomatic counterparts. In the V122I cohort, biobank data was studied to determine the pleiotropic and echocardiographic traits associated with the V122I mutation. Traits indicative of symptomatology can be measured by clinicians, demystifying hATTR comorbidities and potentially signaling early-stage disease onset.

Mutation-stratified workflow identified traits representative of symptom onset in Val30Met (V30M) and Val122Ile (V122I) hereditary amyloid transthyretin amyloidosis (hATTR). For the V30M portion of the study, microarray gene expression profiling data was analyzed to identify the immune signals differentially upregulated in symptomatic V30M compared to their asymptomatic counterparts. In the V122I cohort, biobank data was studied to determine the pleiotropic and echocardiographic traits associated with the V122I mutation. Traits indicative of symptomatology can be measured by clinicians, demystifying hATTR comorbidities and potentially signaling early-stage disease onset.

The Val30Met (V30M) and Val122Ile (V122I) transthyretin (TTR) mutations often beget hereditary amyloid transthyretin amyloidosis (hATTR). Since symptoms are progressively debilitating and potentially fatal if untreated, low survival rates result from late diagnoses of hATTR patients. This retrospective analysis of microarray and biobank data helped establish clinical biomarkers for early hATTR detection.

In a Portuguese sample of V30M carriers (n = 183), gene profiling identified dysregulated immune markers. Among African Americans (AA) and Hispanic/Latinx Americans (HA) from the Mount Sinai BioMe Biobank (n = 28,718), a case-control style Phenome-Wide Association Study (PheWAS; odds ratio [95% confidence interval]) of V122I for phenotypic and echocardiogram traits (β coefficients [95 % CI]) determined gene pleiotropy.

Among V30M profiles, 96 (52.4%) were symptomatic, expressing upregulated neutrophil activity (p < 10-16), IL-6/JAK/STAT3 signaling (p < 10-3), and downregulated CD4+T cell expression (p = 0.009), compared to their asymptomatic counterparts. In BioMe, 562 (2.0%) were V122I carriers, demonstrating associations with heart failure (1.71 [1.23–2.39]; p = 0.0014), amyloidosis (20.79 [8.42–51.31]; p = 4.67 × 10−11), secondary/extrinsic cardiomyopathies (17.73 [7.25–43.37]; p = 2.97 × 10−10), peripheral nerve disorders (4.14 [2.42–7.09]; p = 2.26 × 10−7), primary angle-closure glaucoma (8.03 [3.15–20.46]; p = 1.27 × 10−5), malignant neoplasm of the female breast (4.48 [2.23–9.00]; p = 2.48 × 10−5), fracture of tibia and fibula (8.42 [3.25–21.89]; p = 1.19 × 10−5), and Carpal tunnel syndrome (2.62 [1.68–4.11]; p = 2.44 × 10−5). Echocardiographic presentations included higher LVEDV (15.87 [9.63–22.10]; p = 6.04 × 10−7) and LA length (1.52 [0.69–2.35]; p = 3.31 × 10−4). Race-stratified associations identified that AA presented more severe cardiac abnormalities than HA.

This study identified inflammatory biomarkers upregulated in symptomatic V30M carriers and phenotypic/echocardiographic traits associated with V122I, representing comorbidities of hATTR pathology. Such markers can provide the basis for future improvements in diagnostic regimes to deliver early therapies.