title: Functional Investigations of HNF1A Identify Rare Variants as Risk Factors for Type 2 Diabetes in the General Population.
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.
authors.affiliation: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.|Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Laeya Abdoli
authors.initials: LA
authors.lastname: Najmi
authors.affiliation: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Ingvild
authors.initials: I
authors.lastname: Aukrust
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA.
authors.forename: Jason
authors.initials: J
authors.lastname: Flannick
authors.affiliation: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Janne
authors.initials: J
authors.lastname: Molnes
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA.
authors.forename: Noel
authors.initials: N
authors.lastname: Burtt
authors.affiliation: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.|Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.|Department of Pathology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Molven
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Clinical Research Center, Lund University, Malmö, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA.|Departments of Genetics and Medicine, Harvard Medical School, Boston, MA.|Departments of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, MA.
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.affiliation: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.affiliation: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Biomedical Laboratory Sciences, Bergen University College, Bergen, Norway.
authors.forename: Lise
authors.identifier: 0000-0002-9695-4559
authors.initials: L
authors.lastname: Bjørkhaug
authors.affiliation: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway pal.njolstad@uib.no lise.b.gundersen@hvl.no.|Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Pål Rasmus
authors.initials: PR
authors.lastname: Njølstad
mesh_terms: D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006367:HeLa Cells; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D006801:Humans; D008297:Male; D016017:Odds Ratio; D015533:Transcriptional Activation
chemical_list: C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha