Association of a single nucleotide polymorphism combination pattern of the Klotho gene with non-cardiovascular death in patients with chronic kidney disease

Serafi Cambray; Marcelino Bermudez-Lopez; Milica Bozic; Jose M Valdivielso; NEFRONA investigators

doi:10.1093/ckj/sfaa014

Association of a single nucleotide polymorphism combination pattern of the Klotho gene with non-cardiovascular death in patients with chronic kidney disease

Clin Kidney J. 2020 Mar 14;13(6):1017-1024. doi: 10.1093/ckj/sfaa014. eCollection 2020 Dec.

Authors

Serafi Cambray¹, Marcelino Bermudez-Lopez¹, Milica Bozic¹, Jose M Valdivielso¹; NEFRONA investigators

Affiliation

¹ Vascular and Renal Translational Research Group, Institute for Biomedical Research Dr. Pifarré Foundation, IRBLleida and RedinRen RETIC, ISCIII, Lleida, Spain.

Abstract

Background: Chronic kidney disease (CKD) is associated with an elevated risk of all-cause mortality, with cardiovascular death being extensively investigated. However, non-cardiovascular mortality represents the biggest percentage, showing an evident increase in recent years. Klotho is a gene highly expressed in the kidney, with a clear influence on lifespan. Low levels of Klotho have been linked to CKD progression and adverse outcomes. Single nucleotide polymorphisms (SNPs) of the Klotho gene have been associated with several diseases, but studies investigating the association of Klotho SNPs with non-cardiovascular death in CKD populations are lacking.

Methods: The main aim of this study was to assess whether 11 Klotho SNPs were associated with non-cardiovascular death in a subpopulation of the National Observatory of Atherosclerosis in Nephrology (NEFRONA) study (n = 2185 CKD patients).

Results: After 48 months of follow-up, 62 cardiovascular deaths and 108 non-cardiovascular deaths were recorded. We identified a high non-cardiovascular death risk combination of SNPs corresponding to individuals carrying the most frequent allele (G) at rs562020, the rare allele (C) at rs2283368 and homozygotes for the rare allele (G) at rs2320762 (rs562020 GG/AG + rs2283368 CC/CT + rs2320762 GG). Among the patients with the three SNPs genotyped (n = 1016), 75 (7.4%) showed this combination. Furthermore, 95 (9.3%) patients showed a low-risk combination carrying all the opposite genotypes (rs562020 AA + rs2283368 TT + rs2320762 GT/TT). All the other combinations [n = 846 (83.3%)] were considered as normal risk. Using competing risk regression analysis, we confirmed that the proposed combinations are independently associated with a higher {hazard ratio [HR] 3.28 [confidence interval (CI) 1.51-7.12]} and lower [HR 6 × 10^-6 (95% CI 3.3 × 10^-7-1.1 × 10^-5)] risk of suffering a non-cardiovascular death in the CKD population of the NEFRONA cohort compared with patients with the normal-risk combination.

Conclusions: Determination of three SNPs of the Klotho gene could help in the prediction of non-cardiovascular death in CKD.

Keywords: Klotho; chronic kidney disease; non-cardiovascular death; polymorphisms.