NDT Advance Access originally published online on January 18, 2006
Nephrology Dialysis Transplantation 2006 21(4):1124-1125; doi:10.1093/ndt/gfk100
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Non-association of VEGF genetic polymorphisms in promoter – 5' UTR with end-stage renal disease
Email: noiri-tky{at}umin.ac.jpSir,
The kidney is a highly vascularized organ and vascular endothelial growth factor (VEGF) might play an important role in kidney diseases. VEGF gene was reported to be polymorphic, especially in promotor region, 5' untranslated region (UTR) and in 3' UTR [1,2] and the single nucleotide polymorphisms (SNPs) in these regions were reported to be associated with VEGF levels [2,3]. Recently, Summers et al. [4] reported a significant association of the –460 (–1498; nucleotide positions are relative to the translation start [1]) SNP in the promoter region with progression to chronic kidney disease (CKD) stage 5 in the November issue of Nephrology Dialysis Transplantation.
We performed SNP typing on five SNPs (–2578C/A, –1455T/C, –1190G/A, –1154G/A and –634C/G; nucleotide positions are relative to the translation start [1]) in the promoter region and 5' UTR of the VEGF gene, and compared the distribution of each estimated haplotype in 476 end-stage renal disease (ESRD) patients and 502 healthy controls. The causes of ESRD were: chronic glomerulonephritis (n = 230), diabetic nephropathy (n = 129), nephrosclerosis (n = 62) and miscellaneous other conditions (n = 55). The healthy control group consisted of 502 unrelated healthy individuals who showed no urinary abnormality or renal dysfunction; they reported no use of medication. In all, 978 cases and control samples were genotyped using CE-SSCP analysis, which we have recently developed [5] or direct-sequencing. The calculations were performed using a commercial program (SNPAlyze Ver3.2 Pro; Dynacom Co. Ltd, Chiba, Japan).
First, we evaluated linkage disequilibrium (LD) in the promoter – 5' UTR with 157 unrelated healthy individuals. Calculation of Lewontin's coefficient D' indicated that the five SNPs were in strong LD (Table 1). Furthermore, the –2578C/A, –1455T/C and –1190G/A SNPs were revealed to be in almost absolute LD because not only Lewontin's coefficient D' but also r2 among these three SNPs were >0.95. This indicated that these three SNPs were inherited almost completely together from generation to generation. Therefore, we examined only the –2578C/A, –1154G/A and –634C/G SNP on 476 ESRD patients and 502 healthy controls in the further evaluation.
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The frequencies of genotypes in the ESRD patients and the healthy controls did not differ significantly from those expected under Hardy-Weinberg equilibrium. The three SNPs (–2578C/A, –1455T/C and –1190G/A) showed no significant association in terms of the frequencies of genotypes, alleles or mutant carriers. Table 2 shows that four common haplotypes were presumed in the promoter – 5' UTR. The frequencies of estimated haplotypes in the groups were mutually similar and showed no significant difference by the permutation test. The distribution of estimated haplotypes in this study accorded with data of a previous report from Japan [6].
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We could not find any association of SNPs in promoter – 5' UTR of VEGF gene with ESRD by a larger-scale case-control study in contrary to the report by Summers et al. [4]. The –460 (–1498) SNP they have shown a significant association with CKD was reported to be in complete concordance with the –1190 SNP [6]. Therefore, the –460 (–1498) SNP should be also in absolute LD with the –2578 SNP. However, the –2578C/A showed no significant association with ESRD. Further evaluations should be indispensable to confirm the association of VEGF genetic polymorphisms with progression of CKD to ESRD.
Conflict of interest statement. None declared.
1 Department of Nephrology & Endocrinology2 Department of Human Genetics Graduate School of Medicine University of Tokyo 7-3-1 Hongo, Bunkyo Tokyo 113-8655 Japan
References
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[Abstract/Free Full Text]
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