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Variant in titin gene linked to early-onset AF
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A loss-of-function variant in the titin gene, or TTN, was statistically and significantly associated with early-onset atrial fibrillation, according to a study published in JAMA.
Seung Hoan Choi, PhD, of the program in medical and population genetics at The Broad Institute of MIT and Harvard, and colleagues analyzed data from 18,526 participants from the TOPMed Program from the NHLBI with early-onset AF, defined as participants who were diagnosed with AF before aged 66 years. All participants underwent high-depth whole-genome sequencing between 2014 and 2017. A control group was formed with participants with European ancestry who did not have AF.
Data from the UK Biobank (n = 346,546) and MyCode Study (n = 42,782) were used as an independent dataset to replicate common variants linked to AF.
Of the participants who underwent whole-genome sequencing, 2,781 had early-onset AF (mean age, 49 years; 72% men). The mean depth of sequence coverage for 7,740 participants in the case group and the control group was 37.8-fold, with a mean genome coverage of 99.1%.
More participants with early-onset AF had at least one rare loss-of-function variant of titin compared with participants in the control group (2.1% vs. 1.1%; OR = 1.76; 95% CI, 1.04-2.97).
An earlier age of AF onset was associated with the number of participants with a loss-of-function variant of titin (P for trend = 4.92 x 10-4). Of the participants who developed AF before aged 30 years (n = 138), 6.5% of those carried the titin loss-of-function variant (OR = 5.94; 95% CI, 2.64-13.35).
The association between titin loss-of-function variants and early-onset AF was confirmed in an independent dataset of 1,582 participants with early-onset AF and 41,200 participants without AF (OR = 2.16; 95% CI, 1.19-3.92).
The co-occurrence of TTN [loss-of-function] variation in AF and also in dilated cardiomyopathy suggests that impaired sarcomere structure or function may be an overlapping pathophysiologic mechanism in at least some participants with early-onset AF (cases),” Choi and colleagues wrote. “In addition, the optimal treatments for TTN mutation carriers with early-onset AF remains unclear as current antiarrhythmic therapies utilized to treat AF target ion channels.” – by Darlene Dobkowski
Disclosures: Choi reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Kiran Musunuru, MD, PhD, MPH
Mutations that disrupt titin, a core protein in the sarcomere, were known to predispose people with those mutations to developing structural heart disease — in particular, dilated cardiomyopathy. This study shows for the first time that the same mutations in titin are associated with the development of early-onset AF.
We aren’t too far from a time when everybody routinely will have their genomes sequenced. It’s estimated that about 1 in 100 people have the titin mutations. If these people were to be identified early in life, they could be monitored closely for the early onset of AF, perhaps through a wearable device, and treated appropriately if they should show signs of a problem.
This observation is intriguing, but what’s not clear is whether the mutations in titin are directly causing the AF. Much work needs to be done to figure out if there’s a direct relationship and, if so, how the one causes the other.
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