Minor Effect of GLUT1 Polymorphisms on Susceptibility to Diabetic Nephropathy in Type 1 Diabetes
- Daniel P.K. Ng12,
- Luis Canani12,
- Shin-ichi Araki12,
- Adam Smiles1,
- Dariusz Moczulski12,
- James H. Warram1 and
- Andrzej S. Krolewski12
- 1Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, Massachusetts
- 2Department of Medicine, Harvard Medical School, Boston, Massachusetts
Elevation of intracellular glucose in mesangial cells as mediated by GLUT1 may be important in initiating cellular mechanisms that cause diabetic nephropathy. To determine whether DNA sequence differences in GLUT1 confer susceptibility to this complication, single-nucleotide polymorphisms (SNPs) in this gene were examined using a large case-control study. SNPs examined included the known XbaI (intron 2) and HaeIII SNPs (exon 2). Four novel SNPs located in three putative enhancers were also investigated. Homozygosity for the XbaI(-) allele was associated with diabetic nephropathy (odds ratio 1.83 [95% CI 1.01–3.33]). Furthermore, homozygosity for the A allele for a novel SNP (enhancer-2 SNP 1) located in a putative insulin-responsive enhancer-2 was associated with diabetic nephropathy (2.38 [1.16–4.90]). Patients who were homozygous for risk alleles at both XbaI SNP and enhancer-2 SNP 1 [i.e., homozygosity for XbaI(-)/A haplotype] also had an increased risk of diabetic nephropathy (2.40 [1.13–5.07]). Because enhancer-2 SNP 1 may directly control GLUT1 expression, the strong linkage disequilibrium between the two SNPs likely accounts for XbaI SNP being associated with diabetic nephropathy. In conclusion, our study confirms that SNPs at the GLUT1 locus are associated with susceptibility to diabetic nephropathy in type 1 diabetes. Although these SNPs confer a considerable personal risk for diabetic nephropathy, they account for a limited proportion of cases among type 1 diabetic patients.
Address correspondence and reprint requests to Andrzej S. Krolewski, MD, PHD, Section on Genetics and Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail:.
Received for publication 6 December 2001 and accepted in revised form 3 April 2002.
Additional information can be found in an online appendix at http://diabetes.diabetesjournals.org.
ACR, albumin-to-creatinine ratio; ASO, allele-specific oligonucleotide; ESRD, end-stage renal disease; OR, odds ratio; PAR%, population attributable-risk percent; SNP, single-nucleotide polymorphism; USF, upstream stimulatory factor.