FGF-23 is associated with increased risk of abdominal aortic calcification: A Mendelian randomization study with phosphate as a potential mediator.

Fibroblast growth factor 23 (FGF23) is involved in the regulation of phosphate metabolism and has been linked to vascular calcification. However, the genetic association between FGF23 and abdominal aortic calcification (AAC) remains unclear. We conducted a bidirectional two-sample Mendelian randomization (MR) study to evaluate the association between genetically predicted circulating FGF23 levels and AAC. Univariable MR was performed to assess the primary association, followed by multivariable MR adjusting for serum calcium, 25-hydroxyvitamin D, parathyroid hormone, and chronic kidney disease. In addition, a two-step MR mediation analysis was used to assess whether phosphate might mediate this association. Univariable MR analysis suggested a modest association between genetically predicted circulating FGF23 levels and a higher risk of AAC (odds ratio = 1.082, 95% confidence interval = 1.016-1.151, P = .013). This association remained directionally consistent after separate adjustment for serum calcium, 25-hydroxyvitamin D, parathyroid hormone, and chronic kidney disease. In a secondary multivariable Mendelian randomization analysis using an alternative FGF23 genome-wide association study, the association was no longer statistically significant after adjustment for phosphate (odds ratio = 1.064, 95% confidence interval = 0.962-1.179, P = .224). Two-step MR mediation analysis suggested that serum phosphate may partially mediate the association between FGF23 and AAC, with a marginally significant indirect effect (inverse-variance weighted: β = 0.024, P = .049), accounting for approximately 30% of the total effect. Our findings provide suggestive evidence that genetically predicted higher FGF23 levels may be modestly associated with an increased risk of AAC, with serum phosphate potentially acting as a partial mediator.