FGFR4 and Klotho Polymorphisms Are Not Associated with Cardiovascular Outcomes in Chronic Kidney Disease

• Published in: American journal of nephrology Vol. 52; no. 10-11; p. 808
• Main Authors: Sellier, Alexander B, Seiler-Mußler, Sarah, Emrich, Insa E, Böhm, Michael, Fliser, Danilo, Zawada, Adam M, Heine, Gunnar H
• Format: Journal Article
• Language: English
• Published: Switzerland 01-12-2021
• Subjects: Aged; Cardiovascular Diseases - etiology; Female; Humans; Klotho Proteins - genetics; Male; Mendelian Randomization Analysis; Middle Aged; Polymorphism, Single Nucleotide; Receptor, Fibroblast Growth Factor, Type 4 - genetics; Renal Insufficiency, Chronic - complications; Renal Insufficiency, Chronic - genetics; Heart failure; Cardiovascular disease; Chronic kidney disease; Left-ventricular hypertrophy; Gene polymorphism
• ISSN: 1421-9670
• DOI: 10.1159/000519274

High plasma fibroblast growth factor 23 (FGF-23) predicts cardiovascular events in chronic kidney disease (CKD) patients. Experimental evidence suggests FGF receptor 4 (FGFR4) activation by FGF-23, and deficiency of the soluble form of its co-receptor Klotho promotes left-ventricular hypertrophy (LVH). To evaluate the clinical relevance of these findings, a Mendelian randomization study analyzed the association of genetic variants of FGFR4 and Klotho with echocardiographic parameters and cardiac events in CKD patients.
The prospective Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Fourth Homburg Evaluation study recruited CKD G2-G4 patients, of whom 519 consented to SNP genotyping (FGFR4: rs351855; Klotho: rs9536314). Echocardiographic examinations at baseline and 5 years later assessed prevalence of LVH by measurement of left-ventricular mass index (LVMI). Patients were followed for 5.1 ± 2.1 years for the primary endpoints of cardiac decompensation and atherosclerotic cardiovascular disease (ASCVD).
Carriers of the different alleles did neither differ in baseline LVMI (rs351855: p = 0.861; rs9536314: p = 0.379) nor in LVMI changes between baseline and follow-up (rs351855: p = 0.181; rs9536314: p = 0.995). Hundred and four patients suffered cardiac decompensation, and 144 patients had ASCVD. Time to cardiac decompensation (rs351855: p = 0.316; rs9536314: p = 0.765) and ASCVD (p = 0.508 and p = 0.800, respectively) did not differ between carriers of different alleles.
rs351855 and rs9536314 were not associated with LVMI or cardiac events. These findings do not provide evidence for a relevant clinical role of either FGFR4 stimulation or soluble form of Klotho deficiency in LVH development.