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Diabetes. 2017 Feb;66(2):335-346. doi: 10.2337/db16-0460. Epub 2016 Nov 29.

Functional Investigations of HNF1A Identify Rare Variants as Risk Factors for Type 2 Diabetes in the General Population.

Author information

1
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
2
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
3
Department of Biomedicine, University of Bergen, Bergen, Norway.
4
Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA.
5
Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
6
Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
7
Department of Pathology, Haukeland University Hospital, Bergen, Norway.
8
Department of Clinical Sciences, Diabetes and Endocrinology, Clinical Research Center, Lund University, Malmö, Sweden.
9
Departments of Genetics and Medicine, Harvard Medical School, Boston, MA.
10
Departments of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, MA.
11
Department of Biomedical Laboratory Sciences, Bergen University College, Bergen, Norway.
12
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway pal.njolstad@uib.no lise.b.gundersen@hvl.no.

Abstract

Variants in HNF1A encoding hepatocyte nuclear factor 1α (HNF-1A) are associated with maturity-onset diabetes of the young form 3 (MODY 3) and type 2 diabetes. We investigated whether functional classification of HNF1A rare coding variants can inform models of diabetes risk prediction in the general population by analyzing the effect of 27 HNF1A variants identified in well-phenotyped populations (n = 4,115). Bioinformatics tools classified 11 variants as likely pathogenic and showed no association with diabetes risk (combined minor allele frequency [MAF] 0.22%; odds ratio [OR] 2.02; 95% CI 0.73-5.60; P = 0.18). However, a different set of 11 variants that reduced HNF-1A transcriptional activity to <60% of normal (wild-type) activity was strongly associated with diabetes in the general population (combined MAF 0.22%; OR 5.04; 95% CI 1.99-12.80; P = 0.0007). Our functional investigations indicate that 0.44% of the population carry HNF1A variants that result in a substantially increased risk for developing diabetes. These results suggest that functional characterization of variants within MODY genes may overcome the limitations of bioinformatics tools for the purposes of presymptomatic diabetes risk prediction in the general population.

PMID:
27899486
PMCID:
PMC5860263
DOI:
10.2337/db16-0460
[Indexed for MEDLINE]
Free PMC Article

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