Copy number variation of gasdermin D gene is associated with atrial fibrillation-related thromboembolic stroke

Aims: Atrial fibrillation (AF) is one of the major causes of ischaemic stroke. In addition to clinical risk evaluated by the CHA2DS2-VASC score, the impact of genetic factors on the risk of AF-related thromboembolic stroke has been largely unknown. We found several copy number variations (CNVs) in novel genes that were associated with thromboembolic stroke risk in our AF patients by genome-wide approach. Among them, the gasdermin D (GSDMD) gene was related to inflammation. We aimed to test whether GSDMD deletion was associated with AF-related stroke.

Methods and results: A total of 400 patients with documented non-familial AF were selected, of which 100 patients were diagnosed with ischaemic stroke. The baseline characteristics of age, sex, valvular heart disease, coronary artery disease, heart failure, and CHA2DS2-VASc scores were not statistically different between cases and controls. We found that individuals who carried GSDMD homozygous deletion genotype had a higher risk for ischaemic stroke (odds ratio 2.195; 95% confidence interval, 1.24-3.90; P = 0.007), even adjusted by CHA2DS2-VASc scores. We also validated the association of GSDMD with AF stroke in a large Caucasian population (UK Biobank).

Conclusion: We found a link between the homozygous deletion of the GSDMD gene and an increased risk of stroke in patients with AF. This may implicate the use of therapy targeting GSDMD in the prevention of ischaemic stroke for AF patients.