Minor effect of GLUT1 polymorphisms on susceptibility to diabetic nephropathy in type 1 diabetes.
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.
Ng
Daniel P K
DP
Section on Genetics and Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA.
Canani
Luis
L
Araki
Shin-ichi
S
Smiles
Adam
A
Moczulski
Dariusz
D
Warram
James H
JH
Krolewski
Andrzej S
AS
D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D003929:Diabetic Neuropathies / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D005091:Exons; D020022:Genetic Predisposition to Disease; D051272:Glucose Transporter Type 1; D006801:Humans; D009004:Monosaccharide Transport Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015183:Restriction Mapping
D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; C495677:SLC2A1 protein, human