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

Abstract

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.

Predictive model of response to tafamidis in hereditary ATTR polyneuropathy

“…Our data show that female sex is a clear predictor of a positive response to tafamidis. These data raise the possibility that sex differences influence underlying disease mechanisms, a hypothesis that is also supported by the peripheral blood cell transcriptional profiling differences between men and women reported previously (30). Future studies of disease-specific and response-to-therapy biomarkers should take sex in consideration.…”

Inflammatory profiling of patients with familial amyloid polyneuropathy

“…We couldn’t test sex-specific differences in our cohort due to the small number of male and female patients. However, Kurian and colleagues have observed sex-specific changes in blood cells gene expression from ATTRv patients, suggesting that inflammatory gene markers in circulating blood cells might be influenced by sexual dimorphisms [31]. Curiously, in their study, a correlation of upregulated immune/inflammatory genes was observed among symptomatic versus asymptomatic males, but not in in females [31].…”

The Role of Inflammation in Amyloid Diseases

“…The study showed the increased levels of inflammationrelated transcripts in both liver and heart of transgenic mice, strengthening the concept that inflammation might play an important role in FAP progression [68]. Additionally, Kurian and colleagues have observed sex-specific changes in blood cell gene expression in FAP patients, suggesting that inflammatory gene markers in circulating blood cells might be influenced by sexual dimorphisms [69]. More recently, new evidence shows the presence of elevated levels of IL-6 in FAP carriers that may be produced by myeloid cells and T cells [70].…”