A novel -192c/g mutation in the proximal P2 promoter of the hepatocyte nuclear factor-4 alpha gene (HNF4A) associates with late-onset diabetes

Jakob Ek; Sara P Hansen; Maria Lajer; Carine Nicot; Trine W Boesgaard; Stepanka Pruhova; Anders Johansen; Anders Albrechtsen; Knud Yderstraede; Jeannet Lauenborg; Marcelina Parrizas; Sylvia F Boj; Torben Jørgensen; Knut Borch-Johnsen; Peter Damm; Jorge Ferrer; Jan Lebl; Oluf Pedersen; Torben Hansen

doi:10.2337/db05-1684

A novel -192c/g mutation in the proximal P2 promoter of the hepatocyte nuclear factor-4 alpha gene (HNF4A) associates with late-onset diabetes

Jakob Ek, Sara P Hansen, Maria Lajer, Carine Nicot, Trine W Boesgaard, Stepanka Pruhova, Anders Johansen, Anders Albrechtsen, Knud Yderstraede, Jeannet Lauenborg, Marcelina Parrizas, Sylvia F Boj, Torben Jørgensen, Knut Borch-Johnsen, Peter Damm, Jorge Ferrer, Jan Lebl, Oluf Pedersen, Torben Hansen

7 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Diabetes
Vol/bind	55
Udgave nummer	6
Sider (fra-til)	1869-73
Antal sider	5
ISSN	0012-1797
DOI	https://doi.org/10.2337/db05-1684
Status	Udgivet - 2006

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10.2337/db05-1684

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Ek, J., Hansen, S. P., Lajer, M., Nicot, C., Boesgaard, T. W., Pruhova, S., Johansen, A., Albrechtsen, A., Yderstraede, K., Lauenborg, J., Parrizas, M., Boj, S. F., Jørgensen, T., Borch-Johnsen, K., Damm, P., Ferrer, J., Lebl, J., Pedersen, O., & Hansen, T. (2006). A novel -192c/g mutation in the proximal P2 promoter of the hepatocyte nuclear factor-4 alpha gene (HNF4A) associates with late-onset diabetes. Diabetes, 55(6), 1869-73. https://doi.org/10.2337/db05-1684

Ek, J, Hansen, SP, Lajer, M, Nicot, C, Boesgaard, TW, Pruhova, S, Johansen, A, Albrechtsen, A, Yderstraede, K, Lauenborg, J, Parrizas, M, Boj, SF, Jørgensen, T, Borch-Johnsen, K, Damm, P, Ferrer, J, Lebl, J, Pedersen, O & Hansen, T 2006, 'A novel -192c/g mutation in the proximal P2 promoter of the hepatocyte nuclear factor-4 alpha gene (HNF4A) associates with late-onset diabetes', Diabetes, bind 55, nr. 6, s. 1869-73. https://doi.org/10.2337/db05-1684

@article{bb923c81d81440128ef8bda09ee9329c,

title = "A novel -192c/g mutation in the proximal P2 promoter of the hepatocyte nuclear factor-4 alpha gene (HNF4A) associates with late-onset diabetes",

abstract = "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.",

keywords = "Adult, Age Factors, Aged, Binding Sites, Blood Glucose, Body Mass Index, Diabetes Mellitus, Type 2, Electrophoretic Mobility Shift Assay, Female, Genotype, Haplotypes, Hepatocyte Nuclear Factor 4, Humans, Male, Middle Aged, Mutation, Pedigree, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Protein Binding, Sex Factors",

author = "Jakob Ek and Hansen, {Sara P} and Maria Lajer and Carine Nicot and Boesgaard, {Trine W} and Stepanka Pruhova and Anders Johansen and Anders Albrechtsen and Knud Yderstraede and Jeannet Lauenborg and Marcelina Parrizas and Boj, {Sylvia F} and Torben J{\o}rgensen and Knut Borch-Johnsen and Peter Damm and Jorge Ferrer and Jan Lebl and Oluf Pedersen and Torben Hansen",

year = "2006",

doi = "10.2337/db05-1684",

language = "English",

volume = "55",

pages = "1869--73",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "6",

}

TY - JOUR

T1 - A novel -192c/g mutation in the proximal P2 promoter of the hepatocyte nuclear factor-4 alpha 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

SN - 0012-1797

VL - 55

SP - 1869

EP - 1873

JO - Diabetes

JF - Diabetes

IS - 6

ER -

A novel -192c/g mutation in the proximal P2 promoter of the hepatocyte nuclear factor-4 alpha gene (HNF4A) associates with late-onset diabetes

Abstract

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