title: Mutations in HNF1A result in marked alterations of plasma glycan profile.
abstract: 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.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
authors.forename: Gaya
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authors.lastname: Thanabalasingham
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Huffman
authors.forename: Jayesh J
authors.initials: JJ
authors.lastname: Kattla
authors.forename: Mislav
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authors.lastname: Novokmet
authors.forename: Igor
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authors.lastname: Rudan
authors.forename: Anna L
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authors.forename: Caroline
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authors.lastname: Hayward
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authors.lastname: Adamczyk
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Reynolds
authors.forename: Ana
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authors.lastname: Muzinic
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authors.forename: Maja
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authors.lastname: Pucic
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Bennett
authors.forename: Abdelkader
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authors.lastname: Essafi
authors.forename: Ozren
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authors.lastname: Polasek
authors.forename: Saima A
authors.initials: SA
authors.lastname: Mughal
authors.forename: Irma
authors.initials: I
authors.lastname: Redzic
authors.forename: Dragan
authors.initials: D
authors.lastname: Primorac
authors.forename: Lina
authors.initials: L
authors.lastname: Zgaga
authors.forename: Ivana
authors.initials: I
authors.lastname: Kolcic
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Daniela
authors.initials: D
authors.lastname: Gasperikova
authors.forename: Erling
authors.initials: E
authors.lastname: Tjora
authors.forename: Mark W J
authors.initials: MW
authors.lastname: Strachan
authors.forename: Trine
authors.initials: T
authors.lastname: Nielsen
authors.forename: Juraj
authors.initials: J
authors.lastname: Stanik
authors.forename: Iwar
authors.initials: I
authors.lastname: Klimes
authors.forename: Oluf B
authors.initials: OB
authors.lastname: Pedersen
authors.forename: Pål R
authors.initials: PR
authors.lastname: Njølstad
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Wild
authors.forename: Ulf
authors.initials: U
authors.lastname: Gyllensten
authors.forename: Olga
authors.initials: O
authors.lastname: Gornik
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Hastie
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Rudd
authors.forename: Katharine R
authors.initials: KR
authors.lastname: Owen
authors.forename: Gordan
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authors.lastname: Lauc
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D011134:Polysaccharides / Q000097:blood* / Q000378:metabolism; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D015415:Biomarkers; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D011134:Polysaccharides