Associations between pathophysiological traits and symptom development in retrospective analysis of V30M and V122I transthyretin amyloidosis
Background: 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. Thi...
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Elsevier
2025-06-01
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| Series: | International Journal of Cardiology: Heart & Vasculature |
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| author | Sameer U. Kini Ha My Thi Vy Madhav Subramanian Parasuram M. Krishnamoorthy Son Q. Duong Ghislain Rocheleau Jagat Narula Ron Do Girish N. Nadkarni |
| author_facet | Sameer U. Kini Ha My Thi Vy Madhav Subramanian Parasuram M. Krishnamoorthy Son Q. Duong Ghislain Rocheleau Jagat Narula Ron Do Girish N. Nadkarni |
| author_sort | Sameer U. Kini |
| collection | DOAJ |
| description | Background: 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. Methods: 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. Results: 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. Conclusions: 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. |
| format | Article |
| id | doaj-art-bc63e145784a43e0be55130ff5f6c2eb |
| institution | DOAJ |
| issn | 2352-9067 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
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| series | International Journal of Cardiology: Heart & Vasculature |
| spelling | doaj-art-bc63e145784a43e0be55130ff5f6c2eb2025-08-20T03:09:44ZengElsevierInternational Journal of Cardiology: Heart & Vasculature2352-90672025-06-015810166310.1016/j.ijcha.2025.101663Associations between pathophysiological traits and symptom development in retrospective analysis of V30M and V122I transthyretin amyloidosisSameer U. Kini0Ha My Thi Vy1Madhav Subramanian2Parasuram M. Krishnamoorthy3Son Q. Duong4Ghislain Rocheleau5Jagat Narula6Ron Do7Girish N. Nadkarni8Scarsdale High School, Scarsdale, NY, United States of America; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of AmericaThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America; The Bio Me Phenomics Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of AmericaWashington University School of Medicine, Department of Pathology and Immunology, St. Louis, MO, United States of AmericaDepartment of Medicine, Division of Cardiology, Mount Sinai Hospital, New York, NY, United States of AmericaThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America; Division of Pediatric Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of AmericaThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of AmericaMount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, United States of AmericaThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America; The Bio Me Phenomics Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America; Corresponding authors at: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, P.O. Box 1003, New York, NY 10029, United States of America.The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America; The Bio Me Phenomics Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America; Division of Data Driven and Digital Medicine (D3M), Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America; The Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America; Corresponding authors at: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, P.O. Box 1003, New York, NY 10029, United States of America.Background: 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. Methods: 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. Results: 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. Conclusions: 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.http://www.sciencedirect.com/science/article/pii/S2352906725000661Heart failureSymptom onsetPhenome-Wide Association Study (PheWAS)EchocardiogramInflammatory markersAfrican American |
| spellingShingle | Sameer U. Kini Ha My Thi Vy Madhav Subramanian Parasuram M. Krishnamoorthy Son Q. Duong Ghislain Rocheleau Jagat Narula Ron Do Girish N. Nadkarni Associations between pathophysiological traits and symptom development in retrospective analysis of V30M and V122I transthyretin amyloidosis International Journal of Cardiology: Heart & Vasculature Heart failure Symptom onset Phenome-Wide Association Study (PheWAS) Echocardiogram Inflammatory markers African American |
| title | Associations between pathophysiological traits and symptom development in retrospective analysis of V30M and V122I transthyretin amyloidosis |
| title_full | Associations between pathophysiological traits and symptom development in retrospective analysis of V30M and V122I transthyretin amyloidosis |
| title_fullStr | Associations between pathophysiological traits and symptom development in retrospective analysis of V30M and V122I transthyretin amyloidosis |
| title_full_unstemmed | Associations between pathophysiological traits and symptom development in retrospective analysis of V30M and V122I transthyretin amyloidosis |
| title_short | Associations between pathophysiological traits and symptom development in retrospective analysis of V30M and V122I transthyretin amyloidosis |
| title_sort | associations between pathophysiological traits and symptom development in retrospective analysis of v30m and v122i transthyretin amyloidosis |
| topic | Heart failure Symptom onset Phenome-Wide Association Study (PheWAS) Echocardiogram Inflammatory markers African American |
| url | http://www.sciencedirect.com/science/article/pii/S2352906725000661 |
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