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Klotho Variants and Chronic Hemodialysis Mortality
Author(s) -
Friedman David J.,
Afkarian Maryam,
Tamez Hector,
Bhan Ishir,
Isakova Tamara,
Wolf Myles,
Ankers Elizabeth,
Ye Jun,
Tonelli Marcello,
Zoccali Carmine,
Kuroo Makoto,
Moe Orson,
Karumanchi S. Ananth,
Thadhani Ravi
Publication year - 2009
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.090516
Subject(s) - klotho , hemodialysis , medicine , fibroblast growth factor 23 , single nucleotide polymorphism , kidney disease , proportional hazards model , genotype , vitamin d and neurology , international hapmap project , risk factor , cohort , endocrinology , biology , kidney , gene , genetics , parathyroid hormone , calcium
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.