TY - JOUR
T1 - The functional Thr130Ile and Val255Met polymorphisms of the hepatocyte nuclear factor-4alpha (HNF4A)
T2 - gene associations with type 2 diabetes or altered beta-cell function among Danes
AU - Ek, Jakob
AU - Rose, Christian Schack
AU - Jensen, Dorit Packert
AU - Glümer, Charlotte
AU - Borch-Johnsen, Knut
AU - Jørgensen, Torben
AU - Pedersen, Oluf
AU - Hansen, Torben
PY - 2005
Y1 - 2005
N2 - HNF4A encodes an orphan nuclear receptor that plays crucial roles in regulating hepatic gluconeogenesis and insulin secretion. The aim of the present study was to examine two rare missense polymorphisms of HNF4A, Thr130Ile and Val255Met, for altered function and for association with type 2 diabetes (T2D). We have examined these polymorphisms 1) by in vitro transactivation studies and 2) by genotyping the variants in 1409 T2D patients and in 4726 glucose-tolerant Danish white subjects. When tested in COS7 cells, both the Thr130Ile and the Val255Met variants showed a significant decrease in transactivation activity compared with wild-type (73% of wild-type, P = 0.02, and 76%, P = 0.04, respectively). The Thr130Ile variant had a significantly increased carrier frequency among T2D patients compared with glucose-tolerant subjects [odds ratio, 1.26 (1.01-1.57); P = 0.04]. The rare Val255Met polymorphism had a similar frequency among T2D patients and glucose-tolerant subjects. Heterozygous glucose-tolerant carriers of the variant showed, however, decreased levels of fasting serum C-peptide (76%; P = 0.03) and decreased fasting serum triglyceride (58%; P = 0.02). In conclusion, The Thr130Ile and the Val255Met polymorphisms decrease the transcriptional activity of HNF4A, and the Thr130Ile polymorphism associates with T2D, whereas the Val255Met variant associates with a decrease in fasting serum C-peptide.
AB - HNF4A encodes an orphan nuclear receptor that plays crucial roles in regulating hepatic gluconeogenesis and insulin secretion. The aim of the present study was to examine two rare missense polymorphisms of HNF4A, Thr130Ile and Val255Met, for altered function and for association with type 2 diabetes (T2D). We have examined these polymorphisms 1) by in vitro transactivation studies and 2) by genotyping the variants in 1409 T2D patients and in 4726 glucose-tolerant Danish white subjects. When tested in COS7 cells, both the Thr130Ile and the Val255Met variants showed a significant decrease in transactivation activity compared with wild-type (73% of wild-type, P = 0.02, and 76%, P = 0.04, respectively). The Thr130Ile variant had a significantly increased carrier frequency among T2D patients compared with glucose-tolerant subjects [odds ratio, 1.26 (1.01-1.57); P = 0.04]. The rare Val255Met polymorphism had a similar frequency among T2D patients and glucose-tolerant subjects. Heterozygous glucose-tolerant carriers of the variant showed, however, decreased levels of fasting serum C-peptide (76%; P = 0.03) and decreased fasting serum triglyceride (58%; P = 0.02). In conclusion, The Thr130Ile and the Val255Met polymorphisms decrease the transcriptional activity of HNF4A, and the Thr130Ile polymorphism associates with T2D, whereas the Val255Met variant associates with a decrease in fasting serum C-peptide.
KW - Adult
KW - Aged
KW - Animals
KW - C-Peptide
KW - COS Cells
KW - DNA-Binding Proteins
KW - Diabetes Mellitus, Type 2
KW - Female
KW - Hepatocyte Nuclear Factor 4
KW - Humans
KW - Islets of Langerhans
KW - Male
KW - Middle Aged
KW - Phosphoproteins
KW - Polymorphism, Genetic
KW - Transcription Factors
U2 - 10.1210/jc.2004-2159
DO - 10.1210/jc.2004-2159
M3 - Journal article
C2 - 15728204
SN - 0021-972X
VL - 90
SP - 3054
EP - 3059
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 5
ER -
