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Common Variants in Glutamine:Fructose-6-Phosphate Amidotransferase 2 (GFPT2) Gene Are Associated with Type 2 Diabetes, Diabetic Nephropathy, and Increased GFPT2 mRNA Levels

Department of Medicine (H.Z., Y.J., J.J.C., T.H., Z.Z., S.C.E.), University of Arkansas for Medical Sciences; and Endocrinology Section, Department of Medicine (S.C.E.), Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 77205

Address all correspondence and requests for reprints to: Steven C. Elbein, M.D., Professor of Medicine, Central Arkansas Veterans Healthcare System, Endocrinology 111J/LR, 4300 West 7th Street, Little Rock, Arkansas 72205. E-mail: elbeinstevenc{at}uams.edu.

Increased flux of glucose through the hexosamine biosynthetic pathway has been implicated in insulin resistance, altered insulin secretion, and diabetic nephropathy. Glutamine:fructose-6-phosphate amidotransferase (GFPT), the rate limiting enzyme in hexosamine biosynthesis, is encoded by the unlinked but highly homologous genes GFPT1 and GFPT2. We tested the hypothesis that GFPT2 sequence variation contributed to the susceptibility to type 2 diabetes mellitus (T2DM) and diabetic nephropathy in Caucasian and African-American individuals. We identified 11 single nucleotide polymorphisms (SNPs), of which seven were common. A single variant in exon 14, I471V, altered the amino acid sequence, is conserved between human and mouse genes, and was associated with T2DM among Caucasians (P = 0.05). A trend to an association was noted with diabetic nephropathy among African-American individuals (P = 0.15). Several variants in the 3' untranslated region (UTR) and exon 18 were also associated with T2DM in Caucasian individuals (P < 0.05), and the SNP in the 3' UTR was associated with diabetic nephropathy in African-American subjects (P = 0.047). GFPT2 mRNA levels in transformed lymphocytes from study subjects were significantly increased among African-American subjects compared with Caucasian individuals, regardless of diagnosis. Furthermore, the associated allele of the 3' UTR SNP was approximately 2-fold overexpressed. We propose that the 3' UTR variant results in increased GFPT2 mRNA levels with resultant increased hexosamine flux. The I471V variant may contribute to altered protein function or may simply be in linkage disequilibrium with the 3' UTR.

This work was supported by Grants DK54636 and DK39311 from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases and by the Department of Veterans Affairs. Subject ascertainment was supported in part by a GENNID Family Center Acquisition grant from the American Diabetes Association. Clinical studies were supported by grants from National Institutes of Health/National Center for Research Resources to the General Clinical Research Centers of the University of Utah (M01RR03655) and the University of Arkansas for Medical Sciences (M01RR14288).

Abbreviations: AIR_G, Acute insulin response to glucose; GFPT, glutamine:fructose-6-phosphate amidotransferase; LD, linkage disequilibrium; S_I, insulin sensitivity; SNP, single nucleotide polymorphism; T2DM, type 2 diabetes mellitus; UTR, untranslated region.

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