Genome-wide identification of a MINK1 variant associated with asymptomatic paroxysmal atrial fibrillation

Symptom heterogeneity in atrial fibrillation (AF) remains poorly understood, and its biological basis, including genetic influences, is unclear.

To identify clinical and genetic determinants of symptom heterogeneity in AF.

We enrolled 1052 patients with paroxysmal AF who underwent first-time catheter ablation at Hiroshima University Hospital after genetic quality control. Symptom status during AF episodes was assessed using the modified European Heart Rhythm Association score. A genome-wide association study was conducted, and significant findings were validated in an independent cohort of 357 patients.

Asymptomatic AF was observed in 27.6% of participants. Compared with symptomatic AF, asymptomatic AF was associated with male sex, higher body mass index, higher congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke/transient ischemic attack score, larger left atrial and left ventricular dimensions, and lower left ventricular ejection fraction. In patients with asymptomatic AF, the electrophysiological testing results indicated a longer maximum sinus node recovery time and impaired atrioventricular nodal conduction. The genome-wide association study identified a genome-wide significant association between asymptomatic AF and rs143663734 within the MINK1 gene (P = 2.78 × 10^-8; odds ratio [OR], 3.46), which was replicated in the allelic (P = 2.5 × 10^-3; OR, 2.95) and dominant models (P = 2.0 × 10^-3; OR, 3.13). In the multivariable analyses, rs143663734 remained the strongest independent correlate of asymptomatic AF (P = 5.9 × 10^-8; OR, 3.62).

The MINK1 variant rs143663734 was significantly associated with asymptomatic AF. MINK1, a serine/threonine-protein kinase highly expressed in the central nervous system, may modulate the interoceptive neural processing of cardiac sensations.