Genetic Basis of Early-Onset AF: The Case Titins

December 18, 2018

A case–control study adds to the list of gene variants associated with atrial fibrillation (AF), this time mutations in the gene for titin (TTN), which has the distinction of being the human body's largest protein.

Titin is involved in the assembly and function of sarcomeres, and TTN mutations have been linked to some cardiomyopathies.

Now, a whole-genome sequencing study of cohorts from nine separate studies suggests that people with early-onset AF have about a 75% increased likelihood of harboring a TTN loss-of-function variant. Such variants were present in 2.1% of cases.

Prevalence of the variants went up as patient age went down. People with AF onset before 30 years of age were almost six times as likely to have a TTN loss-of function variant as the control cohort.

The findings do not show that the TTN variants necessarily cause early-onset AF, observe the authors, led by Seung Hoan Choi, PhD, the Broad Institute of MIT and Harvard, Cambridge, Massachusetts, in their report published in the December 11 issue of JAMA. Moreover, they are based solely on adults of European ancestry.

Also, they write, "due to the low frequency of the TTN mutations among AF case participants, the primary implications of the findings may be for understanding the mechanistic basis of AF rather than for clinical testing."

The analysis drew on 2781 people with early-onset AF, the cases, and 4959 people without that finding, the controls, in studies participating in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Program.

The participants underwent high-depth whole-genome sequencing from 2014 to 2017 and were screened for loss-of-function variants in TTN. Early-onset AF was defined as AF first detected at 65 years or younger. Mean age of onset in the cohort was 48.7 years.

In an analysis of common variants at AF-related loci that had been previously reported, six were significantly associated with early-onset AF at a P-level threshold for significance of <5 × 10−8.

A sensitivity analysis for rare variants was conducted on 2047 cases and 2116 controls that remained after the exclusion of relatives in both groups, and, in the early-AF cohort, of people with a history of heart failure or a left ventricular ejection fraction that was either unknown or less than 50%.

At least one rare loss-of-function TTN variant was present in 2.1% of cases and in 1.1% of controls, for an odds ratio (OR) of 1.76 (95% CI, 1.04 - 2.97; = 3.42 × 10−2).

The prevalence of a loss-of-function TTN variant rose as participant age fell (for trend = 4.92 × 10−4), such that the OR reached 5.94 (95% CI, 2.64 - 13.35; = 1.65 × 10−5) among people younger than 30 years.

Ancillary analysis of independent data on cases and controls in studies participating in the MyCode Community Health Initiative confirmed the main analysis, showing TTN loss-of-function variants associated with early onset AF, with an OR of 2.16 (95% CI, 1.19 - 3.92; = .01).

In a meta-analysis of the MyCode data and the cohorts from the main analysis, the corresponding OR was 2.74 (95% CI, 1.67 - 4.44; = 6.03 × 10−5).

"Although only a small percentage of patients with AF carried TTN loss-of-function mutations, the study findings support the role for abnormalities in cardiac structural or sarcomeric proteins in the pathogenesis of AF," the group writes.

"Further research is necessary to determine whether individuals with TTN loss-of-function variants will respond to conventional AF treatments, including antiarrhythmic therapy or ablation."

Choi had no relevant disclosures. Disclosures for the other authors are in the report.

JAMA. 2018;320:2354-2364. Abstract

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