NEW YORK – A genetics-centered study involving hundreds of thousands of UK Biobank participants has unearthed higher-than-anticipated rates of risky mutations linked to a hereditary form of cardiac transthyretin amyloidosis (ATTR), a heart condition marked by misfolded transthyretin protein accumulation that leads to stiff heart tissue, altering the organ's ability to pump blood.
"These findings emphasize the need for clinical vigilance in identifying individuals at risk of developing transthyretin amyloidosis and associated poor outcomes," senior and co-corresponding author Luis Lopes, with St. Bartholomew's Hospital's Barts Heart Centre, and his colleagues wrote in JAMA Cardiology on Wednesday.
Based on exome sequences, electrocardiogram measurements, and cardiovascular magnetic resonance imaging data for 469,789 UK Biobank participants of European, South Asian, East Asian, African, or multiethnic ancestry, the researchers flagged ATTR-related pathogenic or likely pathogenic variants in TTR, a gene coding for the transport protein transthyretin that shuttles the thyroid hormone thyroxine and retinol in blood plasma or cerebrospinal fluid.
"In this cohort study, we established the prevalence of LP/P TTR variants in a large general population cohort and evaluated the associations with cardiac imaging and ECG phenotypes as well as clinical amyloid-associated phenotypes and outcomes," the authors explained.
Overall, the investigators picked up pathogenic or likely pathogenic mutations linked to cardiac ATTR in roughly 1 in every 1,000 individuals considered, or around 0.1 percent of participants. The prevalence was much higher in individuals of African ancestry, with more than 4 percent of the study's 7,533 African ancestry participants carrying risky versions of TTR, consistent with past research showing increased rates of hereditary TTR mutation in populations from Africa, Portugal, Sweden, and Japan.
"We found a higher-than-expected number of people in the UK with potentially harmful genetic variants linked to cardiac ATTR amyloidosis, an often-fatal condition," senior and co-corresponding author Luis Lopes, a researcher with the UCL Institute of Cardiovascular Science, said in a statement.
"Many people with these variants will not go on to develop disease," Lopes added. "However, it is important to try to identify those who do as early as we can, as there are promising new medicines that can effectively treat the condition, and acting earlier with these medicines is likely to help patients more."
When the researchers considered clinical symptoms of cardiac ATTR over a median of 12 years of follow-up, meanwhile, they identified 13 pathogenic or likely pathogenic TTR mutation carriers who had diagnostic codes linked to amyloidosis-affected cardiac or neurological tissue.
They also found that pathogenic or likely pathogenic TTR variants coincided with distinct heart and heart conduction features, along with increased risk of heart conduction disease or heart failure.
"Our study showed that people carrying these potentially harmful variants have a two-to-three-fold increase in the risk of heart failure and cardiac rhythm issues," first author Nay Aung, a researcher with the Queen Mary University of London and St. Bartholomew's Hospital, said in a statement. "This again highlights the need for early detection and monitoring for disease progression."
In a related editorial, investigators at Duke University School of Medicine and University College London suggested that the new work "provides convincing evidence for augmenting both precision medicine approaches and clinical vigilance to improve ATTR-CM diagnosis."
"These data lend greater credence to the concept of genotype-first screening for ATTR," the editorial's corresponding author Senthil Selvaraj, with the Duke Molecular Physiology Institute, and colleagues explained, arguing that phenotype-forward methods also require improvement in the meantime.