Transthyretin (TTR), normally a plasma circulating protein, can become misfolded 
and aggregated, ultimately leading to extracellular deposition of amyloid 
fibrils usually targeted to heart or nerve tissues. Referred to as 
TTR-associated amyloidoses (ATTR), this group of diseases is frequently life 
threatening and fatal if untreated. ATTR, caused by amyloid-forming variant TTR 
proteins (ATTRm) that arise from point mutations in the TTR gene, were 
classically referred to as familial amyloid cardiomyopathy (FAC) or familial 
amyloid polyneuropathy (FAP), reflecting the clinical phenotype. FAC and FAP are 
pathologies that can be challenging to diagnose as there are no definitive 
biomarkers of disease; moreover, disease-specific measures of progression are 
lacking, and treatment options are limited. Thus, the discovery of sensitive and 
specific indicators of disease has the potential to improve recognition, enable 
accurate measurement of amyloid progression and response to treatment, and 
reveal key information regarding FAC and FAP pathobiological mechanisms. In this 
study, the goal was to investigate serum proteomic features unique to FAC and 
FAP types of ATTRm. Multiple-reaction monitoring mass spectrometry (MRM-MS), a 
powerful technique in profiling proteomes, was used to measure the serum 
concentrations of 160 proteins in samples from FAC and FAP patients. Results 
were compared to data from healthy control sera obtained from individuals 
matched to age (≥60 years), gender (male), and race (Caucasian). Proteomic 
analyses of ATTRm (FAC and FAP) and control samples showed significant 
concentration differences in 107 of 192 (56%) of the serum proteins that were 
studied. In comparing FAC to FAP, differences in concentrations as well as 
interactions and functions of several proteins were identified as unique to each 
disease; significantly lower levels of TTR were specific to FAC, but not to FAP. 
Annotated functional clustering identified extracellular region, signal, and 
signal peptide as terms common to FAC and FAP. Conversely, disulfide bond was 
unique to FAC; secreted, glycosylation site: N-linked, glycosylation, 
glycoprotein, polymorphism, and sequence variant were associated solely with 
FAP. Predicted protein-protein associations in FAC were seen for reaction, 
binding, and activation processes; no associations were found in FAP. This study 
demonstrates significant proteomic differences between ATTRm patient and control 
sera, as well as ATTRm phenotype-associated variations in the circulating levels 
of several proteins including TTR. The identification of serum proteins unique 
to FAC and FAP may have diagnostic and prognostic utility and could possibly 
provide important clues about disease mechanisms.