| Title: | Sex Differences in the Association Between Polygenic Risk Score and Atrial Fibrillation Incidence: A Prospective Cohort Study |
| Journal: | Canadian Journal of Cardiology |
| Published: | 25 Sep 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41015248/ |
| DOI: | https://doi.org/10.1016/j.cjca.2025.09.034 |
Publication 19410
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Abstract
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.</p>
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.</p>
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.</p>
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.</p>
15 Keywords
- Aged
- Atrial Fibrillation
- Female
- Genetic Predisposition to Disease
- Genetic Risk Score
- Humans
- Incidence
- Male
- Middle Aged
- Multifactorial Inheritance
- Prospective Studies
- Risk Assessment
- Risk Factors
- Sex Factors
- United Kingdom
9 Authors
- Feilong Zhang
- Yuhao Hu
- Jinfeng Wang
- Qie Zhang
- Xinlin Yang
- Zhou Du
- Yuting Chen
- Zhenhua Lu
- Ronghui Yu
1 Application
| Application ID | Title |
|---|---|
| 280417 | Comorbidity and lifestyle on the outcome of cardiovascular diseases |
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