title: The functional Thr130Ile and Val255Met polymorphisms of the hepatocyte nuclear factor-4alpha (HNF4A): gene associations with type 2 diabetes or altered beta-cell function among Danes.
abstract: 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.
authors.affiliation: Steno Diabetes Center and Hagedorn Research Institute, Niels Steensens Vej 6, NSK1.14, DK-2820 Gentofte, Denmark. jaek@steno.dk
authors.forename: Jakob
authors.initials: J
authors.lastname: Ek
authors.forename: Christian Schack
authors.initials: CS
authors.lastname: Rose
authors.forename: Dorit Packert
authors.initials: DP
authors.lastname: Jensen
authors.forename: Charlotte
authors.initials: C
authors.lastname: Glümer
authors.forename: Knut
authors.initials: K
authors.lastname: Borch-Johnsen
authors.forename: Torben
authors.initials: T
authors.lastname: Jørgensen
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002096:C-Peptide / Q000032:analysis; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D007515:Islets of Langerhans / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D002096:C-Peptide; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D010750:Phosphoproteins; D014157:Transcription Factors