NDT Advance Access originally published online on July 26, 2005
Nephrology Dialysis Transplantation 2005 20(11):2427-2432; doi:10.1093/ndt/gfi029
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VEGF –460 genotype plays an important role in progression to chronic kidney disease stage 5
Manchester Institute of Nephrology and Transplantation, Manchester Royal Infirmary, Manchester M13 9WL, UK
Correspondence and offprint requests to: Dr Angela M. Summers, Department of Renal Research, Manchester Institute of Nephrology and Transplantation, Manchester Royal Infirmary, Manchester M13 9WL, UK. Email: Angela.Summers{at}cmmc.nhs.uk
Background. Changes in renal vasculature, with vascular and interstitial fibrosis, are hallmarks of progression to chronic kidney disease (CKD) stage 5. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor. Transforming growth factor-ß1 (TGF-ß1) plays a critical role in promoting extracellular matrix (ECM) deposition and fibrosis. This study investigates whether genetic polymorphisms of VEGF or TGF-ß1 are associated with (i) progressive decline in renal function in patients with glomerular disorders (cohort 1) and (ii) predisposition to CKD stage 5 in a separate group of renal transplant recipients with various primary diseases (cohort 2).
Methods. Two patient groups were studied. Cohort 1 comprised 91 patients with biopsy-proven glomerular disease who were followed-up for 5 years before categorization as either non-progressors (with stable serum creatinine or 
30% increase over 5 years, n = 39) or progressors (requiring dialysis, transplantation or whose serum creatinine increased by >30% over 5 years, n = 52). Cohort 2 comprised 107 patients with various primary renal diseases, who had reached CKD stage 5 and undergone renal transplantation at the time of study. All patients were genotyped for the VEGF polymorphisms at positions –460 (C/T) and +405 (G/C). Linkage disequilibrium (LD) was established using EHplus. SNPHAP was used to estimate haplotype frequency and to infer haplotypes to all patients. Cohort 1 patients were genotyped for the TGF-ß1 polymorphisms at positions –800, –509, codons 10 and 25. Genotyping was performed by polymerase chain reaction-restriction length polymorphism (PCR-RFLP).
Results. In cohort 1, there was a significant increase in frequency of the –460 VEGF CC genotype 30.8 vs 5.1%, P = 0.008; odds ratio (OR), CC vs TT 10.67, 95% confidence interval (CI), 1.94–58.72 and C allele 56.7 vs 37.2%, P = 0.009; OR 2.22, 95% CI, 1.21–4.04, in the progressor patients when compared with the non-progressors. In cohort 2, there was a significant increase in the VEGF –460 CC genotype when compared with healthy volunteers 37 vs 20.8%, P = 0.011; OR CC vs TT 1.59, 95% CI, 0.72–3.51. The –460 and +405 polymorphisms were in LD P<0.00007. There were significant differences in diplotype (haplotype pair) frequencies in cohort 1 and 2, P = 0.018, which confirmed the importance of the –460C allele. There were no associations between the VEGF +405 or TGF-ß1 polymorphisms and progressive renal disease.
Conclusion. In this study, we have demonstrated an association between the VEGF –460 polymorphism and progression to CKD stage 5. The function of this polymorphism remains unclear although previous evidence suggests that promoter constructs containing this single nucleotide polymorphism (SNP) have been associated with increased activity. Clearly there is a role for TGF-ß1 in chronic kidney disease. However, this study found no associations with four TGF-ß1 polymorphisms in this cohort.
Keywords: chronic kidney disease stage 5; haplotypes; polymorphisms; progressive renal disease; transforming growth factor ß-1; vascular endothelial growth factor
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