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Diabetes 55:1899-1903, 2006
DOI: 10.2337/db05-1677
© 2006 by the American Diabetes Association
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Brief Genetics Reports

A Hepatocyte Nuclear Factor-4{alpha} Gene (HNF4A) P2 Promoter Haplotype Linked With Late-Onset Diabetes

Studies of HNF4A Variants in the Norwegian MODY Registry

Helge Ræder1,2, Lise Bjørkhaug1,2, Stefan Johansson1,2, Kjersti Mangseth1,2, Jørn V. Sagen1,3, Anne Hunting4, Ivar Følling5, Odd Johansen6, Marit Bjørgaas7, Povel N. Paus8, Oddmund Søvik1, Anders Molven9,10, and Pål R. Njølstad1,11

1 Section for Pediatrics, Department of Clinical Medicine, University of Bergen, Bergen, Norway
2 Section for Medical Genetics and Molecular Medicine, Department of Clinical Medicine, University of Bergen, Bergen, Norway
3 Hormone Laboratory, Haukeland University Hospital, Bergen, Bergen, Norway
4 Department of Anesthesiology, The Norwegian Radium Hospital, Oslo, Norway
5 Section of Endocrinology, Akershus University Hospital, University of Oslo, Oslo, Norway
6 Department of Internal Medicine, Asker and Baerum Hospital, Baerum, Norway
7 Department of Internal Medicine, Trondheim University Hospital, Trondheim, Norway
8 Department of Nephrology, Ullevaal University Hospital, Oslo, Norway
9 Section for Pathology, The Gade Institute, University of Bergen, Bergen, Norway
10 Department of Pathology, Haukeland University Hospital, Bergen, Norway
11 Department of Pediatrics, Haukeland University Hospital, Bergen, Norway

Address correspondence reprint requests to Dr. Pål R. Njølstad, Section for Pediatrics, Department of Clinical Medicine, University of Bergen, N-5020 Bergen, Norway. E-mail: pal.njolstad{at}uib.no

Abbreviations: HNF, hepatocyte nuclear factor; LOD, logarithm of odds; MODY, maturity-onset diabetes of the young; SNP, single nucleotide polymorphism

Variants in hepatocyte nuclear factor (HNF)-4{alpha} cause maturity-onset diabetes of the young, type 1 (MODY1) and may also be risk factors for type 2 diabetes. We sequenced the HNF4A gene of 95 MODY3-negative probands from the Norwegian MODY Registry. We found three novel coding variants in exon 8 of HNF4A: G326R, T339I, and W340X. In intron 7, we noted a single nucleotide polymorphism in the binding site of a previously published primer pair, which in some cases caused allelic drop out when amplifying exon 8. We also detected two novel sequence variants of the P2 promoter region, of which P2 –192C>G showed linkage with diabetes in two families (maximal logarithm of odds score of 3.1 and 0.8, respectively). This variant and a surrounding haplotype restricted by 3.7 Mb was also found in two Danish MODY pedigrees. The age of onset was higher in the P2 –192C>G carriers (median 45 years) compared with that reported for other MODY1 individuals. We could not support a biological role of the P2 promoter variant by in vitro transfection assays. In conclusion, we have identified three novel HNF4A mutations and a 3.7-Mb haplotype, including the HNF4A P2 promoter, which was linked with diabetes.


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