Key result
High percentage spliced in TTN truncating variants linked to ~5-fold higher DCM risk.
Why the study?
The effect of hiPSI TTNtvs on DCM risk has historically been studied in populations genetically similar to European references, raising questions about their effect in diverse populations, especially those genetically similar to African reference populations.
Do high percentage spliced in (hiPSI) TTN truncating variants increase the risk of dilated cardiomyopathy in populations genetically similar to African and European reference populations?
Cohort (n=43,731)
No
Do high percentage spliced in (hiPSI) TTN truncating variants increase the risk of dilated cardiomyopathy in populations genetically similar to African and European reference populations?
TTN truncating variants are associated with an increased risk of dilated cardiomyopathy, reduced LVEF, and atrial fibrillation regardless of genetic background, suggesting genetic ancestry should not limit screening for titin-related cardiovascular disease.
Answers are grounded in this paper and cite their sources.
May support ancestry-agnostic DCM screening; extends EUR-focused data to AFR-similar groups yet leaves causal inference open.
The effect of high percentage spliced in (hiPSI) TTN truncating variants (TTNtvs) on risk of dilated cardiomyopathy (DCM) has historically been studied among population subgroups defined by genetic similarity to European reference populations. This has raised questions about the effect of TTNtvs in diverse populations, especially among individuals genetically similar to African reference populations. To determine the effect of TTNtvs on cardiovascular disease risk, we leveraged whole exome sequencing and electronic health record data from 43,731 Penn Medicine Biobank (PMBB) participants recruited from across the Penn Medicine healthcare system. Fraction of genetic similarity to the 1000 Genomes Project (1000G) African (AFR) reference population was determined using ADMIXTURE analysis. Logistic regression was performed to evaluate the association of hiPSI TTNtvs with prevalent DCM and atrial fibrillation (Afib), and linear regression was used to evaluate the association with reduced left ventricular ejection fraction (LVEF) either using dichotomized genetically similar population subgroup analysis or integrating ADMIXTURE population fraction. When individuals were assigned to population subgroups based on genetic similarity to the 1000G reference populations, hiPSI TTNtvs conferred significant risk of DCM among those genetically similar to the 1000G European (EUR) reference population (OR=6.12, 95% confidence intervals [CI] 4.33 to 8.65, P < 0.001) and individuals genetically similar to the AFR reference population (OR=3.44, 95% CI 1.97 to 5.99, P < 0.001). These results were consistent when considering the effect of change in fraction of similarity to the African reference population by ADMIXTURE as a continuous variable. Similar results were observed for the effect of TTNtvs on Afib and LVEF. Our findings demonstrate that TTNtvs are associated with increased risk of DCM, reduced LVEF, and Afib among a diverse cohort. There is no significant difference in effect of TTNtvs across fractions of similarity to the AFR reference population suggesting genetic background should not be considered when screening individuals for titin-related cardiovascular disease.
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Bornstein et al. (2025) conducted a cohort in Dilated cardiomyopathy (n=43,731). High percentage spliced in (hiPSI) TTN truncating variants vs. Non-carriers of hiPSI TTN truncating variants was evaluated on Prevalent dilated cardiomyopathy (DCM) (OR 5.21, 95% CI 3.88 to 6.99, p=<0.001). High percentage spliced in TTN truncating variants significantly increased the risk of dilated cardiomyopathy across both European and African genetically similar populations (Meta OR 5.21).
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