Association of a microsatellite in FASL to type II diabetes and of the FAS-670G>A genotype to insulin resistance.
Type II diabetes is caused by a failure of the pancreatic beta-cells to compensate for insulin resistance leading to hyperglycaemia. There is evidence for an essential role of an increased beta-cell apoptosis in type II diabetes. High glucose concentrations induce IL-1beta production in human beta-cells, Fas expression and concomitant apoptosis owing to a constitutive expression of FasL. FASL and FAS map to loci linked to type II diabetes and estimates of insulin resistance, respectively. We have tested two functional promoter polymorphisms, FAS-670 G>A and FASL-844C>T as well as a microsatellite in the 3' UTR of FASL for association to type II diabetes in 549 type II diabetic patients and 525 normal-glucose-tolerant (NGT) control subjects. Furthermore, we have tested these polymorphisms for association to estimates of beta-cell function and insulin resistance in NGT subjects. We found significant association to type II diabetes for the allele distribution of the FASL microsatellite (P-value 0.02, Bonferroni corrected). The FAS-670G>A was associated with homeostasis model assessment insulin resistance index and body mass index (P-values 0.02 and 0.02). We conclude that polymorphisms of FASL and FAS associate with type II diabetes and estimates of insulin resistance in Danish white subjects.
Nolsøe
R L
RL
Steno Diabetes Center, Gentofte, Denmark.
Hamid
Y H
YH
Pociot
F
F
Paulsen
S
S
Andersen
K M
KM
Borch-Johnsen
K
K
Drivsholm
T
T
Hansen
T
T
Pedersen
O
O
Mandrup-Poulsen
T
T
D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D017209:Apoptosis; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000166:cytology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D018895:Microsatellite Repeats; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D019655:Quantitative Trait, Heritable; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D048069:Tumor Necrosis Factors / Q000235:genetics*; D019014:fas Receptor
D020413:3' Untranslated Regions; C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D048069:Tumor Necrosis Factors; D019014:fas Receptor