Single Gene Analyses, TTN Cardiomyopathy, and Polygenic Risk
The variety of mutations and SNPs identified in familial AF and by GWAS has led to comparative analyses of single genes and SNPs between AF and controls. In patients with early-onset AF, approximately 10% have an identifiable variant that is associated with either an inherited arrhythmia or cardiomyopathy syndrome, with the odds of carrying a disease-associated variant increasing by 25% per decade at earlier time of AF diagnosis.49 One such gene that has garnered significant attention is SCN5A , which encodes the sodium channel that controls inward sodium current as part of atrial depolarization.50 SCN5A mutations have been described in long QT syndrome type 3, Brugada syndrome51, familial dilated cardiomyopathy (DCM).52,53 Mutations in SCN5A have been suggested through single gene analyses to be associated with AF development in both lone AF and AF in the context of structural heart disease.54,55
Importantly, there is a growing understanding of the overlap between AF and genetic DCM. The most prominent example is that of TTNcardiomyopathy. TTN encodes the largest human protein, and truncating variants in TTN (TTNtv ) have previously been implicated in 25% of familial cases of DCM56 and linked to increased risk of ventricular arrhythmias.57Patients with TTN DCM are known to have high rates of AF58 and be more likely to develop persistent AF.57 TTNtv also appear to lead to increased risk of AF59, even when controlling for cardiomyopathy status.60 In one population of familial AF,TTNtv were associated with AF onset at median age of 26, and all variants were in the cardiac isoforms of TTN . Of interest, in this analysis, TTNtv carriers did not have echocardiographic evidence of left ventricular (LV) structural dysfunction and had normal left atrial (LA) and LV dimensions at time of diagnosis or at follow-up multiple years later.61 LOF variants in TTN are more common among patients with early-onset AF compared to healthy controls62, with a higher proportion of variants seen in younger patients at time of AF diagnosis.63Additionally, when compared to all patients with AF, early-onset AFTTNtv carriers are at increased risk of reduction in left ventricular ejection fraction and left atrial late gadolinium enhancement on cardiac magnetic resonance imaging, a marker of atrial fibrosis.64
The success of GWAS at identifying SNPs significantly associated with AF sparked interest in using polygenic risk scores (PRS) in the clinic. PRS is calculated by summing over the risk alleles an individual carries, weighted by the effect size derived from a GWAS, and has been established for prediction of AF development.65 An analysis of the FinnGenn biobank, which utilizes patients in a large Finnish database, showed that the top 2.5% of scorers in an AF PRS system have a predicted 61% lifetime risk of AF.66Another PRS in a largely European, United Kingdom population demonstrated that a higher PRS modifies a patient’s risk of AF development in addition to the risk that is predicted by traditional AF risk factors (including hypertension, diabetes, obesity, and smoking).59 This finding was replicated in the Framingham cohort, where clinical risk factors were shown to further modify AF risk within individual PRS subgroups.67Finally, a higher PRS is also associated with higher risk of AF inTTN LOF variant carriers.68 However, there are no current models combining SNPs and clinical risk factors to predict long-term outcomes of patients with AF.