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

@article{citeulike:4251934, abstract = {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. 10.1210/jc.2003-031286}, author = {Zhang, Hailing and Jia, Yiwen and Cooper, Judith J. and Hale, Terri and Zhang, Zhengxian and Elbein, Steven C.}, citeulike-article-id = {4251934}, citeulike-linkout-0 = {http://dx.doi.org/10.1210/jc.2003-031286}, citeulike-linkout-1 = {http://jcem.endojournals.org/cgi/content/abstract/89/2/748}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/14764791}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=14764791}, day = {1}, doi = {10.1210/jc.2003-031286}, journal = {J Clin Endocrinol Metab}, keywords = {gfat, hexosamine-pathway}, month = {February}, number = {2}, pages = {748--755}, posted-at = {2009-04-01 04:43:28}, priority = {2}, title = {Common Variants in Glutamine:Fructose-6-Phosphate Amidotransferase 2 (GFPT2) Gene Are Associated with Type 2 Diabetes, Diabetic Nephropathy, and Increased GFPT2 mRNA Levels}, url = {http://dx.doi.org/10.1210/jc.2003-031286}, volume = {89}, year = {2004} }

TY - JOUR ID - citeulike:4251934 L3 - citeulike-article-id:4251934 N2 - 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. 10.1210/jc.2003-031286 IS - 2 JF - J Clin Endocrinol Metab EP - 755 TI - Common Variants in Glutamine:Fructose-6-Phosphate Amidotransferase 2 (GFPT2) Gene Are Associated with Type 2 Diabetes, Diabetic Nephropathy, and Increased GFPT2 mRNA Levels VL - 89 SP - 748 KW - gfat KW - hexosamine-pathway AU - Zhang, Hailing AU - Jia, Yiwen AU - Cooper, Judith AU - Hale, Terri AU - Zhang, Zhengxian AU - Elbein, Steven PY - 2004/02/01/ UR - http://dx.doi.org/10.1210/jc.2003-031286 ER -