A novel -192c/g Mutation in the Proximal P2 Promoter of the Hepatocyte Nuclear Factor-4α Gene (HNF4A) Associates With Late-onset Diabetes
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A novel -192c/g Mutation in the Proximal P2 Promoter of the Hepatocyte Nuclear Factor-4α Gene (HNF4A) Associates With Late-onset Diabetes. / Ek, Jakob; Hansen, Sara P; Lajer, Maria; Nicot, Carine; Boesgaard, Trine W; Pruhova, Stepanka; Johansen, Anders; Albrechtsen, Anders; Yderstraede, Knud; Lauenborg, Jeannet; Parrizas, Marcelina; Boj, Sylvia F; Jørgensen, Torben; Borch-Johnsen, Knut; Damm, Peter; Ferrer, Jorge; Lebl, Jan; Pedersen, Oluf; Hansen, Torben.
In: Diabetes, Vol. 55, No. 6, 2006, p. 1869-73.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - A novel -192c/g Mutation in the Proximal P2 Promoter of the Hepatocyte Nuclear Factor-4α Gene (HNF4A) Associates With Late-onset Diabetes
AU - Ek, Jakob
AU - Hansen, Sara P
AU - Lajer, Maria
AU - Nicot, Carine
AU - Boesgaard, Trine W
AU - Pruhova, Stepanka
AU - Johansen, Anders
AU - Albrechtsen, Anders
AU - Yderstraede, Knud
AU - Lauenborg, Jeannet
AU - Parrizas, Marcelina
AU - Boj, Sylvia F
AU - Jørgensen, Torben
AU - Borch-Johnsen, Knut
AU - Damm, Peter
AU - Ferrer, Jorge
AU - Lebl, Jan
AU - Pedersen, Oluf
AU - Hansen, Torben
PY - 2006
Y1 - 2006
N2 - Recently, it has been shown that mutations in the P2 promoter of the hepatocyte nuclear factor (HNF)-4 alpha gene (HNF4A) cause maturity-onset diabetes of the young (MODY), while single nucleotide polymorphisms in this locus are associated with type 2 diabetes. In this study, we examined 1,189 bp of the P2 promoter and the associated exon 1D of HNF4A for variations associated with diabetes in 114 patients with type 2 diabetes, 72 MODYX probands, and 85 women with previous gestational diabetes mellitus. A -192c/g mutation was found in five patients. We screened 1,587 diabetic subjects and 4,812 glucose-tolerant subjects for the -192c/g mutation and identified 5 diabetic and 1 glucose-tolerant mutation carriers (P=0.004). Examination of the families showed that carriers of the -192c/g mutation had a significantly impaired glucose-stimulated insulin release and lower levels of serum total cholesterol compared with matched control subjects. Furthermore, the mutation disrupted the binding of an unidentified sequence-specific DNA binding complex present in human islet extracts. Also, two novel linked polymorphisms in the P2 promoter at positions -1107g/t and -858c/t were identified. These variants were not significantly associated with type 2 diabetes or any pre-diabetic traits. In conclusion, a rare, novel mutation that disrupts a protein binding site in the pancreatic HNF4A promoter associates with late-onset diabetes.
AB - Recently, it has been shown that mutations in the P2 promoter of the hepatocyte nuclear factor (HNF)-4 alpha gene (HNF4A) cause maturity-onset diabetes of the young (MODY), while single nucleotide polymorphisms in this locus are associated with type 2 diabetes. In this study, we examined 1,189 bp of the P2 promoter and the associated exon 1D of HNF4A for variations associated with diabetes in 114 patients with type 2 diabetes, 72 MODYX probands, and 85 women with previous gestational diabetes mellitus. A -192c/g mutation was found in five patients. We screened 1,587 diabetic subjects and 4,812 glucose-tolerant subjects for the -192c/g mutation and identified 5 diabetic and 1 glucose-tolerant mutation carriers (P=0.004). Examination of the families showed that carriers of the -192c/g mutation had a significantly impaired glucose-stimulated insulin release and lower levels of serum total cholesterol compared with matched control subjects. Furthermore, the mutation disrupted the binding of an unidentified sequence-specific DNA binding complex present in human islet extracts. Also, two novel linked polymorphisms in the P2 promoter at positions -1107g/t and -858c/t were identified. These variants were not significantly associated with type 2 diabetes or any pre-diabetic traits. In conclusion, a rare, novel mutation that disrupts a protein binding site in the pancreatic HNF4A promoter associates with late-onset diabetes.
KW - Adult
KW - Age Factors
KW - Aged
KW - Binding Sites
KW - Blood Glucose
KW - Body Mass Index
KW - Diabetes Mellitus, Type 2
KW - Electrophoretic Mobility Shift Assay
KW - Female
KW - Genotype
KW - Haplotypes
KW - Hepatocyte Nuclear Factor 4
KW - Humans
KW - Male
KW - Middle Aged
KW - Mutation
KW - Pedigree
KW - Polymorphism, Single Nucleotide
KW - Promoter Regions, Genetic
KW - Protein Binding
KW - Sex Factors
U2 - 10.2337/db05-1684
DO - 10.2337/db05-1684
M3 - Journal article
C2 - 16731855
VL - 55
SP - 1869
EP - 1873
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 6
ER -
ID: 38455421