NEW YORK – Only a portion of individuals with truncating mutations in the Titin gene has a diagnosis of dilated cardiomyopathy (DCM), according to a new study, despite the fact that these disruptions are common in DCM patients.
Truncating mutations in the Titin gene (TTN) are commonly found among individuals with idiopathic DCM, a condition that affects about 750,000 people in the US and is marked by an enlarged and weakened left heart ventricle. But it was unclear whether truncating mutations in TTN always lead to dilated cardiomyopathy.
By analyzing exome sequencing and electronic health record data from different cohorts, researchers from the Geisinger Health System and the University of Pennsylvania examined the prevalence of these TTN mutations and whether they were associated with DCM or other cardiac traits. In the cohorts studied — which represented different clinical populations — they found that between 7.5 percent and 30 percent of individuals with truncating TTN mutations had dilated cardiomyopathy.
"It's clear that these gene mutations have a real effect on one's heart, and yet, there are a lot of people carrying the deleterious mutations right now who are fine," corresponding author Zoltan Arany, a professor of cardiovascular medicine at UPenn, said in a statement. He and his colleagues reported their results today in the journal Circulation.
The researchers noted a difference by ancestry: individuals of European ancestry with truncating TTN mutations were at a much higher risk of developing DCM than individuals of African ancestry, where the link between those mutations and disease was not as strong.
Arany and his colleagues examined whole-exome sequencing and electronic medical record data from the Geisinger MyCode Community Health Initiative and the PennMedicine BioBank (PMBB) cohorts, representing more than 71,000 individuals. The two cohorts, they noted, encompass the extremes of the possible clinical context of dilated cardiomyopathy as the Geisinger cohort represents a general clinical population and the PMBB cohort represents a tertiary referral hospital.
Overall, 0.6 percent of the Geisinger cohort and 1.3 percent of the PMBB cohort had a truncating variant in a highly expressed exon of TTN, and 1.0 percent of the Geisinger cohort and 5.6 percent of the PMBB cohort had a diagnosis of dilated cardiomyopathy.
Having a Titin truncation increased their odds of having dilated cardiomyopathy, as 7.5 percent of the Geisinger cohort and 30 percent of the PMBB cohort with a TTN variant had such a diagnosis.
However, truncating variants in highly expressed TTN exons were not associated with DCM among individuals of African ancestry. Additionally, using data from the Jackson Heart Study, a cohort of more than 5,000 African-American individuals from the Jackson, MS, region, the researchers further tested for links between TTN and dilated cardiomyopathy, finding no association.
This could be due to environmental or social factors, or to an increased general rate of DCM among African Americans, the researchers noted, which could affect the ability to pick out the risk conferred by these variants.
People of European ancestry with TTN-truncating mutations were also more likely to have other cardiac traits, like arrhythmias or systolic heart failures. Based on a PheWAS analysis the researchers performed, people in the Geisinger and PMBB cohorts harboring TTN truncating mutations were more likely to have diagnoses such as heart failure, arrhythmia, and the need for a pacemaker or defibrillator.
The links between the variants and some of these other diagnoses, like atrial fibrillation, held even after controlling for a lead cardiomyopathy diagnosis, suggesting that they might have effects beyond cardiomyopathy, they wrote.