Peripheral Blood Cell Gene Expression Diagnostic for Identifying Symptomatic Transthyretin Amyloidosis Patients: Male and Female Specific Signatures

Autor: Sunil M. Kurian, Terri Gelbart, Thomas Whisenant, Teresa Coelho, Jeffery W. Kelly, Marta Novais, Joel N. Buxbaum, Daniel R. Salomon
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Tafamidis
Adult
Male
Pathology
medicine.medical_specialty
Heterozygote
Medicine (miscellaneous)
Gene Expression
Asymptomatic
Gastroenterology
Cohort Studies
03 medical and health sciences
Amyloid disease
chemistry.chemical_compound
0302 clinical medicine
Internal medicine
medicine
Humans
Prealbumin
Pharmacology
Toxicology and Pharmaceutics (miscellaneous)
Inflammation
Amyloid Neuropathies
Familial
Benzoxazoles
Sex Characteristics
familial transthyretin
Blood Cells
biology
business.industry
Amyloidosis
Gene Expression Profiling
medicine.disease
3. Good health
Transthyretin
Amyloid Neuropathy
030104 developmental biology
chemistry
biology.protein
Biomarker (medicine)
RNA
Female
medicine.symptom
business
Asymptomatic carrier
030217 neurology & neurosurgery
Biomarkers
Research Paper
Zdroj: Theranostics
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Agência para a Sociedade do Conhecimento (UMIC)-FCT-Sociedade da Informação
instacron:RCAAP
ISSN: 1838-7640
Popis: BACKGROUND: Early diagnosis of familial transthyretin (TTR) amyloid diseases remains challenging because of variable disease penetrance. Currently, patients must have an amyloid positive tissue biopsy to be eligible for disease-modifying therapies. Endomyocardial biopsies are typically amyloid positive when cardiomyopathy is suspected, but this disease manifestation is generally diagnosed late. Early diagnosis is often difficult because patients exhibit apparent symptoms of polyneuropathy, but have a negative amyloid biopsy. Thus, there is a pressing need for an additional early diagnostic strategy for TTR-aggregation-associated polyneuropathy and cardiomyopathy. METHODS AND FINDINGS: Global peripheral blood cell mRNA expression profiles from 263 tafamidis-treated and untreated V30M Familiar Amyloid Neuropathy patients, asymptomatic V30M carriers, and healthy, age- and sex-matched controls without TTR mutations were used to differentiate symptomatic from asymptomatic patients. We demonstrate that blood cell gene expression patterns reveal sex-independent, as well as male- and female-specific inflammatory signatures in symptomatic FAP patients, but not in asymptomatic carriers. These signatures differentiated symptomatic patients from asymptomatic V30M carriers with >80% accuracy. There was a global downregulation of the eIF2 pathway and its associated genes in all symptomatic FAP patients. We also demonstrated that the molecular scores based on these signatures significantly trended toward normalized values in an independent cohort of 46 FAP patients after only 3 months of tafamidis treatment. CONCLUSIONS: This study identifies novel molecular signatures that differentiate symptomatic FAP patients from asymptomatic V30M carriers as well as affected males and females. We envision using this approach, initially in parallel with amyloid biopsies, to identify individuals who are asymptomatic gene carriers that may convert to FAP patients. Upon further validation, peripheral blood cell mRNA expression profiling could become an independent early diagnostic. This quantitative gene expression signature for symptomatic FAP could also become a biomarker to demonstrate significant disease-modifying effects of drugs and drug candidates. For example, when new disease modifiers are being evaluated in a FAP clinical trial, such surrogate biomarkers have the potential to provide an objective, quantitative and mechanistic molecular diagnostic of disease response to therapy. We acknowledge the following sources of research funding: NIH U19 A1063603 (DRS, SMK), NIH DK46335 (JWK) and NIH R01AG19259 (JNB) info:eu-repo/semantics/publishedVersion
Databáze: OpenAIRE
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