Klotho variants and chronic hemodialysis mortality.
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.
Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
David J
DJ
Friedman
Maryam
M
Afkarian
Hector
H
Tamez
Ishir
I
Bhan
Tamara
T
Isakova
Myles
M
Wolf
Elizabeth
E
Ankers
Jun
J
Ye
Marcello
M
Tonelli
Carmine
C
Zoccali
Makoto
M
Kuro-o
Orson
O
Moe
S Ananth
SA
Karumanchi
Ravi
R
Thadhani
D000368:Aged; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D000090265:Klotho Proteins; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D006435:Renal Dialysis / Q000401:mortality*
C000717427:FGF23 protein, human; D012333:RNA, Messenger; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins