The functional Thr130Ile and Val255Met polymorphisms of the hepatocyte nuclear factor-4α (HNF4A): Gene associations with type 2 diabetes or altered β-cell function among danes

Jakob Ek*, Christian Schack Rose, Dorit Packert Jensen, Charlotte Glümer, Knut Borch-Johnsen, Torben Jørgensen, Oluf Pedersen, Torben Hansen

*Corresponding author af dette arbejde

    Publikation: Bidrag til tidsskriftArtikelForskningpeer review

    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.

    OriginalsprogEngelsk
    Sider (fra-til)3054-3059
    Antal sider6
    TidsskriftJournal of Clinical Endocrinology and Metabolism
    Vol/bind90
    Udgave nummer5
    DOI
    StatusUdgivet - 1 maj 2005

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