Impact of polymorphisms in the genes encoding xylosyltransferase I and a homologue in type 1 diabetic patients with and without nephropathy

Background. Xylosyltransferase I (XT-I) is the chain-initiating enzyme in the biosynthesis of heparan sulfate proteoglycans (HSPGs). It catalyses the transfer of xylose to specific serine residues in the core protein. The XYLT-II gene codes for a protein highly homologous to the XT-I but its biologic function is not yet known. HSPGs are thought to play an important role in the permeability properties of the glomerular basement membrane (GBM) and thus the xylotransferase genes might be potential candidate genes predisposing to diabetic nephropathy in type 1 diabetic patients. Methods. We screened all XYLT-I and XYLT-II exons and flanking intron regions in 96 Caucasians with type 1 diabetes (48 with and 48 without diabetic nephropathy) using denaturing high-performance liquid chromatography (DHPLC). We also studied a nondiabetic control group. Results. Applying this technique we identified 13 variations in XYLT-I and 20 in XYLT-II. The variations IVS6-9T>C and IVS6-14_IVS6-13insG in XYLT-II were found with a frequency of 5.2% (5/96) rn nondiabetic nephropathy patients, while all nephropathy patients were negative (P = 0.06). Non-diabetic controls also showed the single nucleotide polymorphisms (SNP) at a frequency of 1.1% (5/440). The Investigation of the SNPs' influence on clinical characteristics revealed significant associations for c.1989T>C (XYLT-I) and c.2402C>G (XYLT-II) with patients' blood pressure. Conclusion. We detected in our cohort associations between DNA sequence variations of genes encoding xylosyltransferases and the occurrence of altered clinical characteristics.