The findings could potentially enable patients to be identified and treated before symptoms of ATTR-CM emerge.
The presence of genetic variants that affect the stabilization of the tetrameric protein transthyretin (TTR) is associated with both all-cause and cardiovascular mortality, according to new data from the general Danish population.
Confirming this connection could eventually help clinicians identify and treat patients who will go on to develop TTR amyloid cardiomyopathy (ATTR-CM), a condition with a poor prognosis and few -- costly -- treatment options, the authors say.
"My whole aim with this is really to try and identify these individuals before they become very, very sick," senior author Anne Tybjærg-Hansen, MD, DMSc (Copenhagen University Hospital, Rigshospitalet, Denmark), told TCTMD. "There's a window which is quite long, actually, because it's a disease that develops slowly, I assume, where you can work on that."
Sarah Cuddy, MD (Brigham and Women's Hospital, Boston, MA), who commented on the results for TCTMD, said the findings are largely confirmatory of prior smaller studies, but "it was definitely exciting to see [those] replicated in such a large population."
The value here is that because "we have a clear signal toward mortality" in patients who are genotype positive for the TTR destabilizing gene, "this is something that we could try and harness in our clinical practice," she said.
General Population Findings
For the study, published online last week in JAMA Cardiology, Tybjærg-Hansen, Mette Christoffersen, PhD (Copenhagen University Hospital, Rigshospitalet), and colleagues included 102,204 Danish adults (median age 57 years; 55% female) from the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS), which both included genetic analyses. First examinations of patients from CCHS and CGPS took place in 1991-1994 and 2003-2015, respectively, and all patients were followed through death or 2018.
The researchers identified the four most common genetic variants affecting TTR tetramer stability in the study population. These proved to be the stabilizing variant p.T139M and the destabilizing variants p.H110N, p.D119N, and p.V142I.
Over a median follow-up of 10 years, both noncarriers of the p.T139M variant with intermediate tetramer stability and carriers of p.V142I, p.H110N, and p.D119N with the lowest tetramer stability had an increased risk of all-cause mortality (HR 1.37; 95% CI 1.06-1.77 and HR 1.65; 95% CI 0.95-2.88; P for trend = 0.01) compared with p.T139M carriers. Both groups also demonstrated trends toward increased risk of cardiovascular mortality (HRs 1.63; 95% CI 0.92-2.89 and 2.23; 95% CI 0.78-6.34; P for trend = 0.06).
Additionally, compared with carriers of p.T139M, noncarriers and heterozygotes for the amyloidogenic variants saw plasma TTR decrease stepwise by 18% and 29%, respectively (P for trend < 0.001).
"Therefore, genetically determined, increasingly lower plasma transthyretin could be considered a surrogate marker for transthyretin tetramer destabilization," the authors write. This is important since no robust, high-throughput assays for characterizing TTR stability in large populations are available, they explain.
Tybjærg-Hansen also highlighted that when they looked only at people with the wild-type phenotypes not due to a genetic variant, they still found increased risks of both all-cause and cardiovascular mortality. This suggests that among wild-type individuals, who are more common than those with hereditary phenotypes, "there's a subset of individuals who have destabilization," she said.
Until better assays are available to help measure destabilization, Tybjærg-Hansen said, researchers should look at "red flags," meaning "other diseases or other phenotypes that we think may precede cardiovascular disease of these individuals."
Results in Context
In an accompanying editorial, Anthony Angueira, MD, PhD (University of Pennsylvania Perelman School of Medicine, Philadelphia), and colleagues write that the investigators "offer new insights into the role of TTR stability in the pathogenesis of amyloid-associated disease" that build on prior research.
The editorialists say the results are "consistent" with those seen in the ATTR-ACT of the TTR stabilizer tafamadis (Vyndaqel and Vyndamax; Pfizer), and "additionally provides genetic support" for the HELIOS-B trial findings of vutrisiran (Amvuttra; Alnylam), a new TTR silencer. Whether the findings will influence the choice of candidates, down the road, considered eligible for gene editing remains to be seen.
"The link between TTR-destabilizing genetic variants and all-cause mortality highlights the critical importance of identifying carriers of pathogenic variants in TTR," Angueira and colleagues write. "Further randomized clinical trials identifying whether the relationship between TTR stability and mortality is conserved in cohorts of diverse genetic ancestry would increase generalizability, given that the genetic liability for amyloid-mediated cardiomyopathy is due in part to pathogenic variants that are more commonly found among specific population subgroups."
A focus going forward, they argue, should be to identify the optimal timing to initiate treatment in "presymptomatic" patients either with destabilizing variants or biomarkers like reduced serum TTR levels.