TY - JOUR

T1 - Association of a microsatellite in FASL to type II diabetes and of the FAS-670G>A genotype to insulin resistance

AU - Nolsøe, R L

AU - Hamid, Y H

AU - Pociot, F

AU - Paulsen, S

AU - Andersen, K M

AU - Borch-Johnsen, K

AU - Drivsholm, T

AU - Hansen, T

AU - Pedersen, O

AU - Mandrup-Poulsen, T

PY - 2006/6/1

Y1 - 2006/6/1

N2 - 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.

AB - 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.

KW - 3' Untranslated Regions

KW - Adult

KW - Aged

KW - Antigens, CD95

KW - Apoptosis

KW - Denmark

KW - Diabetes Mellitus, Type 2

KW - Fas Ligand Protein

KW - Female

KW - Humans

KW - Insulin Resistance

KW - Insulin-Secreting Cells

KW - Male

KW - Membrane Glycoproteins

KW - Microsatellite Repeats

KW - Middle Aged

KW - Polymorphism, Genetic

KW - Promoter Regions, Genetic

KW - Quantitative Trait, Heritable

KW - Receptors, Tumor Necrosis Factor

KW - Tumor Necrosis Factors

U2 - 10.1038/sj.gene.6364300

DO - 10.1038/sj.gene.6364300

M3 - Journal article

C2 - 16691186

VL - 7

SP - 316

EP - 321

JO - Genes and Immunity

JF - Genes and Immunity

SN - 1466-4879

IS - 4

ER -