Glucose transporter polymorphisms are associated with clear-cell renal carcinoma.

Clear-cell renal cell carcinoma (CCRCC) is identified by abundant glycogen-rich cytoplasm, due to the aberrant influx and storage of glucose. The objective was to investigate the frequency of polymorphisms of the facilitative glucose transporter (GLUT1). GLUT1 is a downstream target of Hypoxia-inducible factor (HIF-1alpha), a mediator of hypoxia-controlled angiogenesis. In this study, we examine the allelic frequency of polymorphisms in the promoter and the second intron of the GLUT1 gene. Genomic DNA was extracted from normal tissue of 92 patients undergoing nephrectomy for CCRCC, and 99 normal cord blood DNA samples were used to provide control frequencies. The regions of DNA encompassing the polymorphisms were amplified and digested with appropriate endonuclases. The products were separated and viewed by gel electrophoresis. There was a highly significant decrease in the A-2841 genotype (P=0.0004) in the promoter region of those patients with CCRCC compared to the control population. There was also a significant decrease in the T+22999 allele in the intron 2 of those patents with CCRCC (P=0.004) compared to the same control population. This study suggests that GLUT1 is one of a number of genes that may increase susceptibility to developing CCRCC.

Polymorphisms in the hypoxia inducible factor-1alpha gene (HIF1A) are associated with the renal cell carcinoma phenotype.

Hypoxia inducible factor 1 (HIF-1) is a key regulator of the genes involved in the cellular response to hypoxia. HIF consists of alpha and beta subunits, with the alpha subunit being degraded under normoxic conditions and stabilized under hypoxia. We investigated C1772T and G1790A polymorphisms in exon 12 of the HIF gene, which result in an amino acid change from proline 582 to serine and from alanine 588 to threonine, respectively. These polymorphisms are found within the oxygen-dependent degradation domain of the HIF-1alpha protein and may be important in the oxygen regulation of the protein via hydroxylation of the proline residue at position 564 (P564) by HIF-alpha prolyl hydroxylase (HIF-PH). The frequency of these polymorphisms was studied in 160 nontumor DNA samples from patients with renal cell carcinoma (RCC). There was a highly significant increase in the frequency of both the G/A1790 (45.9 vs. 13.5%, P < 0.00001) and C/C1772 (10 vs. 0.7%, P=0.0004) genotypes in patients with RCC compared with normal healthy controls. A decrease was seen for the GG (44.5 vs. 83%, P < 0.00001) and CT (33.8 vs. 55.5%, P=0.0001) genotypes in patients compared with controls. There was a marked increase in the T-A haplotype (22.8 vs. 9.5%, P=0.00008) and an increase in the C-A haplotype (4.9 vs. 1.1%, P=0.02) in patients compared with controls, and a decrease in the T-G haplotype (53.4 vs. 65.1%, P=0.01). No statistical difference was found for the other haplotypes. These findings show that polymorphisms of the HIF1A gene may confer susceptibility to RCC.

Polymorphisms of the vascular endothelial growth factor and susceptibility to diabetic microvascular complications in patients with type 1 diabetes mellitus.

There is increasing evidence implicating genetic factors in the susceptibility to diabetic microvascular complications. Recent studies suggest that increased expression of the cytokine vascular endothelial growth factor (VEGF) may play a role in the pathogenesis of diabetic complications. A number of polymorphisms in the promoter region of the VEGF gene have been identified. The aim was to investigate whether an 18 base pair (bp) deletion (D)/insertion (I) polymorphism at position -2549 in the promoter region of the VEGF gene is associated with the susceptibility to diabetic microvascular complications. Two hundred and thirty-two patients with type 1 diabetes mellitus (T1DM) and 141 normal healthy controls were studied. The D/D genotype was significantly increased in those patients with nephropathy (n=102) compared to those with no complications after 20 years duration of diabetes (uncomplicated, n=66) (40.2% vs. 22.7%, respectively, chi(2)=5.5, P<.05). The combination of polymorphisms of VEGF together with the aldose reductase (ALR2) gene showed that in the nephropaths, 8 of the 83 subjects had the VEGF I allele together with the Z+2 5'ALR2 allele compared with 27 of the 62 uncomplicated patients (chi(2)=26.7, P<.00001). The functional role of the D/I polymorphism was examined by cloning the region into a luciferase reporter assay system and transient transfection into HepG2 cells. The construct containing the 18 bp deletion had a 1.95-fold increase in transcriptional activity compared with its counterpart that had the insert (P<.01). These results suggest that polymorphisms in the promoter region of the VEGF gene together with the ALR2 may be associated with the pathogenesis of diabetic nephropathy.