Klotho variants and chronic hemodialysis mortality.

Abstract

Patients with end-stage renal disease (ESRD) suffer exceptionally high mortality rates in their first year of chronic hemodialysis. Both vitamin D and fibroblast growth factor (FGF)-23 levels correlate with survival in these patients. Klotho is a protein in the vitamin D/FGF-23 signaling pathway that has been linked with accelerated aging and early mortality in animal models. We therefore hypothesized that genetic variation in the Klotho gene might be associated with survival in subjects with ESRD. We tested the association between 12 single nucleotide polymorphisms (SNPs) in the Klotho gene and mortality in a cohort of ESRD patients during their first year on hemodialysis (n = 1307 white and Asian). We found a significant association between the CC genotype of one tag SNP, rs577912, and increased risk for 1-yr mortality (RR, 1.76; 95% CI, 1.19-2.59; p = 0.003). This effect was even more marked among patients who were not treated with activated vitamin D supplementation (HR, 2.51; 95% CI, 1.18-5.34; p = 0.005). In lymphoblastoid cell lines derived from HapMap subjects, the CC genotype was associated with a 16-21% lower Klotho expression compared with the AA/AC genotype. Our data suggest that a specific Klotho variant (rs577912) is linked to survival in ESRD patients initiating chronic hemodialysis and that therapy with activated vitamin D may modify this risk.

• Authors: David J Friedman, Maryam Afkarian, Hector Tamez, Ishir Bhan, Tamara Isakova, Myles Wolf, Elizabeth Ankers, Jun Ye, Marcello Tonelli, Carmine Zoccali, Makoto Kuro-o, Orson Moe, S Ananth Karumanchi, Ravi Thadhani
• Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res) Vol. 24 Issue 11 Pg. 1847-55 (Nov 2009) ISSN: 1523-4681 [Electronic] United States
• PMID: 19419323 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• FGF23 protein, human
• RNA, Messenger
• Fibroblast Growth Factor-23
• Glucuronidase
• Klotho Proteins

Topics

• Aged
• Female
• Fibroblast Growth Factor-23
• Gene Frequency (genetics)
• Genotype
• Glucuronidase (genetics, metabolism)
• Humans
• Kaplan-Meier Estimate
• Klotho Proteins
• Linkage Disequilibrium (genetics)
• Male
• Polymorphism, Single Nucleotide (genetics)
• RNA, Messenger (genetics, metabolism)
• Renal Dialysis (mortality)