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Polymorphisms in IGF-Binding Protein 1 Are Associated With Impaired Renal Function in Type 2 Diabetes

¹ Vascular Research Group, Clinical Sciences Building, Hope Hospital, Salford, U.K.
² Evidence for Population Health Unit, School of Epidemiology and Health Sciences, University of Manchester, Manchester, U.K.
³ ARC Epidemiology Research Unit, University of Manchester, Manchester, U.K.
⁴ Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, U.K.

The dysregulation of the IGF system has been implicated in the pathogenesis of obesity, diabetes, and diabetes complications such as nephropathy, but little is known about the genomics of the IGF system in health and disease. We genotyped 13 single nucleotide polymorphisms (SNPs) in IGFBP1 gene in 732 representative type 2 diabetic patients from the Salford Diabetes Register. Of the 13 SNPs, 8 were polymorphic and 7 of those had minor allele frequencies >0.1, one of which was in the gene promoter and one of which was nonsynonymous in exon 4. The minor alleles of these SNPs and two others were associated with a reduced prevalence of diabetic nephropathy. Haplotype analysis revealed that 97% of the genetic variation for IGFBP1 in the population sample could be accounted for using two of the "reno-protective" SNPs, with other SNPs adding little extra information. One of these two SNPs was the nonsynonymous mutation in exon 4, lying close to the integrin-binding RGD motif, which is thought to affect tissue delivery of IGF-I by IGF-binding protein 1 (IGFBP-1), possibly suggesting a "reno-protective" effect via altered IGFBP-1 binding. In conclusion, we have described the first genomic markers to be associated with diabetic microvascular complications within the human IGFBP1 gene.

Abbreviations: ACR, albumin-to-creatinine ratio; GFR, glomerular filtration rate; HIF-1a, hypoxia-inducible transcription factor 1a; HNF-3ß, hepatocyte nuclear factor-3ß; IGFBP, IGF-binding protein; LD, linkage disequilibrium; SNP, single nucleotide polymorphism; USF-1, upstream stimulatory factor 1

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