Titin-related familial dilated cardiomyopathy: factors associated with disease onset.
Johnson R., Fletcher RA., Peters S., Ohanian M., Soka M., Smolnikov A., Abihider KE., Ackerman MJ., Ader F., Akhtar MM., Amin AS., Ashley EA., Atherton JJ., Austin R., Baas AF., Bagnall RD., Ross SB., Blouin J-L., Brown EE., Bundgaard H., Cannie D., Chmielewski P., Correnti G., Crespo-Leiro MG., Dal Ferro M., Dellefave-Castillo LM., Dominguez F., Dooijes D., Dybro AM., Ed Demri Y., El Hachmi M., Escobar-Lopez L., Foye SJ., Franaszczyk M., Gigli M., Lopez EG., Goudal A., Graw S., Guipponi M., Haan E., Haas J., Hammersley DJ., Hansen FG., Hayward CS., Hey TM., Heymans S., Ho CY., Houweling AC., Ingles J., Ingrey A., Jabbour A., James PA., Jansweijer JA., Jongbloed JDH., Keogh AM., Larrañaga-Moreira JM., Lekanne Deprez RH., Macciocca I., Macdonald PS., Mansencal N., Mansour J., Martinez-Veira C., McDonough B., McGaughran J., Medo K., Merlo M., Michalak E., Monserrat L., Mountain H., Muller SA., Murphy AM., Murray B., Oates EC., Ormondroyd E., Pachter N., Paldino A., Palmyre A., Pereira NL., Picard KC., Poplawski N., Prasad S., Proukhnitzky J., Pruny J-F., Reant P., Richard P., Ronan A., Sedaghat-Hamedani F., Semsarian C., Storm G., Stroeks S., Syrris P., Taylor MRG., Thomson K., Thompson T., van Tintelen JP., Vissing CR., Waddell-Smith KE., Wallis M., Zentner D., Australian Genomics Cardiac Flagship None., Arnott C., Marian AJ., Oh J., Fokstuen S., James CA., Barriales-Villa R., Meder B., Wahbi K., Giudicessi JR., Parikh VN., Ware JS., Piriou N., Rooryck C., Lakdawala NK., Mestroni L., Sinagra G., Elliott PM., Watkins H., McNally EM., Charron P., van Spaendonck-Zwarts KY., Garcia-Pavia P., Peña-Peña ML., Mogensen J., Christensen AH., Bilińska ZT., Rasmussen TB., Seidman JG., Seidman CE., Te Riele ASJM., Verdonschot JAJ., Pinto YM., Christiaans I., Fatkin D.
BACKGROUND AND AIMS: Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. METHODS: An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. RESULTS: A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80-30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06-5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27-3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35-9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08-.23). CONCLUSIONS: Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.