Association of polymorphisms in the klotho gene with severity of non-diabetic ESRD in African Americans.
BACKGROUND
Non-diabetic forms of nephropathy commonly lead to end-stage renal disease (non-DM ESRD). Previous studies have demonstrated that African Americans are more susceptible to non-DM ESRD compared to other ethnic groups, and this risk has a strong genetic component. A genome-wide scan for ESRD in African American families enriched for non-DM ESRD showed evidence for linkage in chromosome 13q33.3, and a candidate gene in this region, klotho, was selected for a detailed analysis in a follow-up case-control association study.


METHODS
Thirty-four single-nucleotide polymorphisms (SNPs) in the klotho gene were genotyped in 317 unrelated African American non-DM ESRD cases and 354 non-nephropathy controls, including 12 SNPs identified by re-sequencing a region around exon 4.


RESULTS
Two SNPs demonstrated modest admixture-adjusted evidence of association with non-DM ESRD, rs650439 (P = 0.013, recessive model) and rs643780 (P = 0.017, recessive model), while rs17643698 approached significance (P = 0.0953, two degrees of freedom test). Eight of the most significant SNPs were tested for replication in a second case-control collection (557 African American non-DM ESRD cases and 187 controls), and there was no evidence of association in replicate cases and controls; nor when the samples were combined for a total of 874 non-DM cases and 541 controls. Cox proportional hazards models were computed to test for association between polymorphisms in klotho and age at onset of ESRD. A three-SNP haplotype, rs526906, rs525014 and rs571118 (T/T/A), was associated with age of onset of ESRD [P = 0.007, recessive model; hazard ratio (HR) = 0.70]. Subjects homozygous for this haplotype had a mean 4 years later onset of ESRD, suggesting a slower disease progression. HapMap subjects homozygous for this haplotype had increased expression of klotho, further supporting a protective role of this variant in ESRD.


CONCLUSIONS
We conclude that three SNPs in intron 1 of the klotho gene are associated with delayed age at onset of non-DM ESRD in African Americans.
Bostrom
Meredith A
MA
Department of Biochemistry, Center for HumanGenomics, Wake Forest University School of Medicine, Winston-Salem, NC USA.
Hicks
Pamela J
PJ
Lu
Lingyi
L
Langefeld
Carl D
CD
Freedman
Barry I
BI
Bowden
Donald W
DW
D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D005260:Female; D005966:Glucuronidase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics*; D000090265:Klotho Proteins; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
D005966:Glucuronidase; D000090265:Klotho Proteins
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