The -913 G/A glutamine:fructose-6-phosphate aminotransferase gene polymorphism is associated with measures of obesity and intramyocellular lipid content in nondiabetic subjects.
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.
Weigert
Cora
C
Department of Internal Medicine, Division of Endocrinology, Metabolism, and Pathobiochemistry, University of Tubingen, Otfried Müller Strasse 10, D-72076 Tubingen, Germany.
Thamer
Claus
C
Brodbeck
Katrin
K
Guirguis
Alke
A
Machicao
Fausto
F
Machann
Jürgen
J
Schick
Fritz
F
Stumvoll
Michael
M
Fritsche
Andreas
A
Häring
Hans U
HU
Schleicher
Erwin D
ED
D000328:Adult; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D005838:Genotype; D015309:Glucose Clamp Technique; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000235:genetics*; D006595:Hexosamines / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism; D008297:Male; D009765:Obesity / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D006595:Hexosamines; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)