Key result
AF polygenic risk is linked to incident AF with a ~5% sex interaction across clinical risk.
Why the study?
The role of sex in modulating genetic susceptibility to incident atrial fibrillation remains poorly characterized.
Does sex modify the association between polygenic risk score and incident atrial fibrillation in AF-free adults?
Cohort (n=444,463)
Does sex modify the association between polygenic risk score and incident atrial fibrillation in AF-free adults?
Hazard Ratio: 0.95 (95% CI 0.91–1)
p-value: p=0.031
The genetic susceptibility to incident atrial fibrillation is modified by sex and clinical risk burden, suggesting a need for sex-specific approaches in AF risk stratification.
BACKGROUND: Although sex disparities in atrial fibrillation (AF) epidemiology and outcomes are well documented, the role of sex in modulating genetic susceptibility to incident AF remains poorly characterized. In this study we assessed sex-specific effects of polygenic risk score (PRS) on AF incidence and the sex-specific PRS effects, stratified by the Cohorts for Heart and Aging Research in Genomic Epidemiology for Atrial Fibrillation (CHARGE-AF) clinical risk score. METHODS: This prospective cohort study included 444,463 AF-free UK Biobank participants (54.67% women; mean age 56.46 ± 8.09 years). Participants were stratified by sex, AF-PRS (cutoff ≥ 0.295), and CHARGE-AF clinical risk score (cutoff ≥ 12.048). Incident AF was ascertained via ICD-10 codes. Cox hazards regression (adjusting for clinical, metabolic, lifestyle, and socioeconomic covariables) was used to evaluate the multiplicative interactions among AF-PRS, sex, and CHARGE-AF. RESULTS: Over 14.67 ± 3.01 years, 31,070 participants experienced incident AF. A significant interaction between male sex and higher AF-PRS emerged (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.91-1.00; P = 0.031). Women were more genetically susceptible to AF at higher CHARGE-AF (HR 1.99 vs 1.83 in men) and men at lower CHARGE-AF (HR 2.33 vs 2.11 in women). In addition, the tripartite interaction (AF-PRS × sex × CHARGE-AF, HR 0.84; P < 0.001) further validated the sex-specific results stratified by CHARGE-AF. CONCLUSIONS: The association between AF-PRS and incident AF is modified by sex, with clinical risk burden modifying sex-related PRS effects. Women presented with higher genetic susceptibility at higher CHARGE-AF, and men at lower CHARGE-AF. Rethinking AF genetic susceptibility in a sex- and context-dependent manner may enhance precise prevention.
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Zhang et al. (2025) conducted a cohort in Atrial Fibrillation (n=444,463). Polygenic risk score (AF-PRS) vs. Lower AF-PRS was evaluated on Incident atrial fibrillation (HR 0.95, 95% CI 0.91-1.00, p=0.031). The association between polygenic risk score and incident AF was modified by sex (interaction HR 0.95; 95% CI 0.91-1.00; P=0.031), with women more susceptible at higher clinical risk and men at lower.
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