Inflammation markers linked to symptoms in Val30Met-related FAP
Higher blood levels among patients may mark symptom onset: Study
Among people carrying Val30Met (V30M), the most common cause of familial amyloid polyneuropathy (FAP), those experiencing symptoms have significantly higher blood levels of inflammation markers than those without signs of the rare inherited disease, a study showed.
Symptomatic carriers were also found to have higher activity of neutrophils, a type of immune cells, but lower counts of certain lymphocytes, another type of immune cell, according to the researchers. These immune-related abnormalities could be used as early markers of symptom onset in FAP, the team noted.
“This study identified inflammatory biomarkers upregulated in symptomatic V30M carriers,” the researchers wrote. “Such markers can provide the basis for future improvements in diagnostic regimes to deliver early therapies.”
Additionally, data from people with Val122Ile (V122I), a mutation known to cause damage both in the peripheral nerves, or those outside the brain and spinal cord — similar to FAP — and the heart, showed several early heart abnormalities that may help detect early-stage disease onset, according to the researchers.
The study, “Associations between pathophysiological traits and symptom development in retrospective analysis of V30M and V122I transthyretin amyloidosis,” was published in IJC Heart & Vasculature.
Hereditary transthyretin amyloidosis (hATTR) is a group of progressive conditions in which mutations in the TTR gene result in an unstable transthyretin protein that forms toxic clumps that damage the body’s tissues.
In FAP, these clumps build up in the peripheral nerves, leading to neurological symptoms. When the clumps, or aggregates, build up in the heart, they cause cardiomyopathy, or heart damage.
hATTR is often diagnosed late, however, highlighting the need for identifying early signs, or biological markers, of the disease, the study noted.
Scientists search data for early markers of FAP
To search for such markers, a research team from the U.S. drew on data from carriers of common hATTR-causing mutations.
The retrospective study included 183 adults in Portugal who carried V30M— the most common FAP-causing mutation — with slightly more than half (52.4%) showing symptoms.
Compared with those who were asymptomatic, or without symptoms, the patients with signs of FAP showed more activity in 16,105 immune-related genes. Among these genes, the top 8,000 were selected for further analysis.
The immune markers detected in this study … reside in the [circulating] blood and thus may be indicators of early disease onset for those suspected or known to carry V30M.
Symptomatic patients had significantly higher activity in genes involved in neutrophil activity, as well as those playing a role in inflammatory responses. Specifically, higher activity was seen in the IL-6/JAK/STAT3 and the TNF-alpha/NF-KB pathways.
Those experiencing symptoms also had significantly more activity in genes related to certain types of immune cells, including M2 macrophages and natural killer T-cells, relative to asymptomatic patients.
Individuals with symptoms also had significantly less activity in genes related to CD4-positive memory T-cells, a type of lymphocyte that helps the body remember previous threats and promotes a quick response upon re-exposure.
“The immune markers detected in this study … reside in the [circulating] blood and thus may be indicators of early disease onset for those suspected or known to carry V30M,” the researchers wrote.
Study involved African Americans and Hispanic Americans from US biobank
The study also included 28,718 African American and Hispanic/Latinx Americans from a large U.S. biobank called Mount Sinai BioMe. A total of 562 carried the V122I mutation.
In the BioMe group, V122I carriers were more likely to have several health problems compared with those without the mutation. These included secondary heart problems, amyloidosis or protein buildup, and other peripheral nerve disorders. Other comorbidities, or coexisting conditions, were carpal tunnel syndrome, which affects nerves in the wrist and is often an early hATTR sign, glaucoma — a type of eye disease — malignant breast cancer, and bone fractures.
“The seven hallmark phenotypes [conditions] … could both be [simultaneous] with symptomatic development and, among those suspected or known to be V122I carriers, demarcate the early stages and potential comorbidities in hATTR pathology [disease development],” the researchers wrote.
Heart scans, called echocardiograms, also showed differences between V122I carriers and non-V122I carriers. Those with the mutation had enlarged heart chambers, reflected by higher left ventricular end-diastolic volume (LVEDV) and left atrial (LA) length. These changes suggest that the heart was working harder or becoming damaged, the team noted.
Also, these heart abnormalities were more profound in African American carriers than Hispanic/Latinx carriers, the data showed.
The findings highlight that hATTR symptoms manifest differently depending on the mutation and the person’s background. V30M carriers showed strong immune system changes, while V122I carriers had many health conditions that could help doctors spot the disease earlier, the team noted.
According to the research team, by identifying these early warning signs in the blood and in imaging tests, this research could help improve how hATTR is diagnosed. Earlier diagnosis could lead to faster treatment and better outcomes for patients, the team added.
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