Mutations in HNF1A Result in Marked Alterations of Plasma Glycan Profile
- Gaya Thanabalasingham1,2,
- Jennifer E. Huffman3,
- Jayesh J. Kattla4,
- Mislav Novokmet5,
- Igor Rudan6,7,
- Anna L. Gloyn1,2,
- Caroline Hayward3,
- Barbara Adamczyk4,
- Rebecca M. Reynolds8,
- Ana Muzinic5,
- Neelam Hassanali1,
- Maja Pucic5,
- Amanda J. Bennett1,
- Abdelkader Essafi3,
- Ozren Polasek7,
- Saima A. Mughal1,2,
- Irma Redzic9,
- Dragan Primorac7,10,
- Lina Zgaga6,
- Ivana Kolcic7,
- Torben Hansen11,12,13,
- Daniela Gasperikova14,
- Erling Tjora15,16,
- Mark W.J. Strachan17,
- Trine Nielsen11,
- Juraj Stanik14,18,
- Iwar Klimes14,
- Oluf B. Pedersen11,19,20,
- Pål R. Njølstad15,16,
- Sarah H. Wild6,
- Ulf Gyllensten21,
- Olga Gornik9,
- James F. Wilson6,
- Nicholas D. Hastie3,
- Harry Campbell6,
- Mark I. McCarthy1,2,22,
- Pauline M. Rudd4,
- Katharine R. Owen1,2,
- Gordan Lauc5,9 and
- Alan F. Wright3⇑
- 1Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.
- 2Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
- 3MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, U.K.
- 4Dublin-Oxford Glycobiology Laboratory, National Institute for Bioprocessing Research and Training (NIBRT), Dublin, Ireland
- 5Genos Ltd., Glycobiology Division, Zagreb, Croatia
- 6Centre for Population Health Sciences, University of Edinburgh Medical School, Edinburgh, U.K.
- 7University of Split School of Medicine, Split, Croatia
- 8Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, U.K.
- 9Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
- 10University of Osijek School of Medicine, Osijek, Croatia
- 11Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- 12Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
- 13Steno Diabetes Center, Gentofte, Denmark
- 14DIABGENE and Diabetes Laboratory, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia
- 15Department of Clinical Medicine, University of Bergen, Bergen, Norway
- 16Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
- 17Metabolic Unit, Western General Hospital, Edinburgh, U.K.
- 18Children Diabetes Centre at the First Department of Paediatrics, Faculty of Medicine at the Comenius University, Bratislava, Slovakia
- 19Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
- 20Hagedorn Research Institute, Copenhagen, Denmark
- 21Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
- 22Wellcome Trust for Human Genetics, University of Oxford, Oxford, U.K.
- Corresponding author: Alan F. Wright, .
G.T., J.E.H., J.J.K., M.N., I.Ru., and A.L.G. contributed equally to this study.
H.C., M.I.M., P.M.R., K.R.O., G.L., and A.F.W. contributed equally to this study.
A recent genome-wide association study identified hepatocyte nuclear factor 1-α (HNF1A) as a key regulator of fucosylation. We hypothesized that loss-of-function HNF1A mutations causal for maturity-onset diabetes of the young (MODY) would display altered fucosylation of N-linked glycans on plasma proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNF1A-MODY. In a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups. The DG9-glycan index, which is the ratio of fucosylated to nonfucosylated triantennary glycans, provided optimum discrimination in the pilot study and was examined further among additional subjects with HNF1A-MODY (n = 188), glucokinase (GCK)-MODY (n = 118), hepatocyte nuclear factor 4-α (HNF4A)-MODY (n = 40), type 1 diabetes (n = 98), type 2 diabetes (n = 167), and nondiabetic controls (n = 98). The DG9-glycan index was markedly lower in HNF1A-MODY than in controls or other diabetes subtypes, offered good discrimination between HNF1A-MODY and both type 1 and type 2 diabetes (C statistic ≥0.90), and enabled us to detect three previously undetected HNF1A mutations in patients with diabetes. In conclusion, glycan profiles are altered substantially in HNF1A-MODY, and the DG9-glycan index has potential clinical value as a diagnostic biomarker of HNF1A dysfunction.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0880/-/DC1.
- Received June 30, 2012.
- Accepted October 17, 2012.
- © 2013 by the American Diabetes Association.
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