Klotho Gene Variant Raises Atrial Fibrillation Risk Fivefold in Dialysis Patients

Cardiovascular disease is the leading cause of death in patients on maintenance hemodialysis (MHD), accounting for roughly 40% of all MHD mortality. Atrial fibrillation (AF) is a particularly dangerous arrhythmia in this population, but traditional risk factors like hypertension and volume overload do not fully explain its occurrence. This study investigated whether a specific genetic variant in the Klotho gene — the G-395A single-nucleotide polymorphism (SNP, rs1207568) — contributes to AF risk in MHD patients.

The study enrolled 120 MHD patients stratified into three groups: 30 with persistent AF, 30 with paroxysmal AF, and 60 with normal sinus rhythm, plus 120 age-matched healthy controls. Klotho G-395A genotyping was performed using TaqMan fluorescence quantitative PCR. Serum soluble Klotho (sKl) and intact fibroblast growth factor 23 (iFGF23) were measured via ELISA, and left atrial diameter (LAD) was assessed by echocardiography after dialysis to minimize fluid overload confounding.

Three genotypes were identified — GG, GA, and AA. The combined GA/AA genotype frequency was significantly higher in MHD patients (50%) than in healthy controls (34.17%), as was the A allele frequency (26.67% vs. 18.33%). Within MHD patients, GA/AA prevalence was dramatically higher in the AF group than in the sinus rhythm group, and higher still in persistent versus paroxysmal AF. Binary logistic regression confirmed that the GA/AA genotype conferred a 5.444-fold increased odds of AF compared to GG homozygotes.

Serum sKl levels were significantly lower and iFGF23 levels significantly higher in AF patients versus sinus rhythm patients, with the most extreme differences seen in persistent AF. Spearman correlation analysis revealed sKl was negatively correlated with both iFGF23 and LAD, while iFGF23 was positively correlated with LAD. These findings support a mechanistic model in which Klotho deficiency — partly genetically determined — elevates FGF23, promotes left atrial enlargement through fibrotic and inflammatory pathways, and ultimately predisposes to AF.

The study concludes that the Klotho G-395A A allele is a promising genetic risk marker for AF in MHD patients, and that sKl deficiency may be an early, modifiable contributor to cardiac remodeling in this population. The authors propose that Klotho genotyping and sKl monitoring could complement standard cardiovascular risk stratification in dialysis care.