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A Novel –192c/g Mutation in the Proximal P2 Promoter of the Hepatocyte Nuclear Factor-4 Gene (HNF4A) Associates With Late-Onset Diabetes

¹ Steno Diabetes Center and Hagedorn Research Institute, Gentofte, Denmark
² National Eye Clinic, Kennedy Institute, Glostrup, Denmark
³ Endocrinology Unit, Institut d’Investigacions Biomédiques August Pi i Sunyer, Hospital Clinic de Barcelona, Barcelona, Spain
⁴ Department of Pediatrics, Third Faculty of Medicine, Charles University, Prague, Czech Republic
⁵ Department of Medical Endocrinology M, Odense University Hospital, Odense, Denmark
⁶ Department of Obstetrics, Rigshospitalet, Copenhagen, Denmark
⁷ Research Centre for Prevention and Health, Glostrup University Hospital, Copenhagen, Denmark
⁸ Faculty of Health Science, University of Aarhus, Aarhus, Denmark

Address correspondence and reprint requests to Torben Hansen, MD, PhD, Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark. E-mail: toha{at}steno.dk

Abbreviations: GDM, gestational diabetes mellitus; HNF, hepatocyte nuclear factor; IGT, impaired glucose tolerance; MODY, maturity-onset diabetes of the young; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test

Recently, it has been shown that mutations in the P2 promoter of the hepatocyte nuclear factor (HNF)-4 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.

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