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The –913 G/A Glutamine:Fructose-6-Phosphate Aminotransferase Gene Polymorphism Is Associated with Measures of Obesity and Intramyocellular Lipid Content in Nondiabetic Subjects

Department of Internal Medicine, Division of Endocrinology, Metabolism, and Pathobiochemistry (C.W., C.T., K.B., A.G., F.M., M.S., A.F., H.U.H., E.D.S.), and Section of Experimental Radiology, Department of Diagnostic Radiology (J.M., F.S.), University of Tubingen, D-72076 Tubingen, Germany

Address all correspondence and requests for reprints to: Dr. Erwin D. Schleicher, Department of Internal Medicine, Division of Endocrinology, Metabolism, and Pathobiochemistry, University of Tubingen, Otfried Müller Strasse 10, D-72076 Tubingen, Germany. E-mail: enschlei{at}med.uni-tuebingen.de.

Increases in glutamine:fructose-6-phosphate aminotransferase (GFAT) protein levels directly activate flux through the hexosamine biosynthetic pathway. This pathway has been involved as a fuel sensor in energy metabolism and development of insulin resistance. We screened the 5'-flanking region of the human GFAT gene for polymorphisms and subsequently genotyped 412 nondiabetic, metabolically characterized Caucasians for the two single-nucleotide polymorphisms (SNP) at positions –913 (G/A) and –1412 (C/G) with rare allele frequencies of 42% and 16%, respectively. The –913 G SNP was associated with significantly higher body mass index and percent body fat in men (P = 0.02 and 0.004, respectively), but not in women (P = 0.47 and 0.26, respectively). In the subgroup of individuals (n = 193) who underwent hyperinsulinemic-euglycemic clamp, an association of the –913 G SNP with insulin sensitivity independent of body mass index was not detected. Moreover, the –913 G allele in a group of 71 individuals who had undergone magnetic resonance spectroscopy was associated with higher intramyocellular lipid content (IMCL) in tibialis anterior muscle (4.21 ± 0.31 vs. 3.36 ± 0.35; P = 0.04) independent of percent body fat and maximal aerobic power. The –1412 SNP had no effect on percent body fat, insulin sensitivity, or IMCL. In conclusion, we identified two polymorphisms in the 5'-flanking region of GFAT, of which the –913 SNP seems to alter the risk for obesity and IMCL accumulation in male subjects.

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