Mutations in HNF1A result in marked alterations of plasma glycan profile

Gaya Thanabalasingham; Jennifer E Huffman; Jayesh J Kattla; Mislav Novokmet; Igor Rudan; Anna L Gloyn; Caroline Hayward; Barbara Adamczyk; Rebecca M Reynolds; Ana Muzinic; Neelam Hassanali; Maja Pucic; Amanda J Bennett; Abdelkader Essafi; Ozren Polasek; Saima A Mughal; Irma Redzic; Dragan Primorac; Lina Zgaga; Ivana Kolcic; Torben Hansen; Daniela Gasperikova; Erling Tjora; Mark W J Strachan; Trine Nielsen; Juraj Stanik; Iwar Klimes; Oluf B Pedersen; Pål R Njølstad; Sarah H Wild; Ulf Gyllensten; Olga Gornik; James F Wilson; Nicholas D Hastie; Harry Campbell; Mark I McCarthy; Pauline M Rudd; Katharine R Owen; Gordan Lauc; Alan F Wright

doi:10.2337/db12-0880

Mutations in HNF1A result in marked alterations of plasma glycan profile

Gaya Thanabalasingham, Jennifer E Huffman, Jayesh J Kattla, Mislav Novokmet, Igor Rudan, Anna L Gloyn, Caroline Hayward, Barbara Adamczyk, Rebecca M Reynolds, Ana Muzinic, Neelam Hassanali, Maja Pucic, Amanda J Bennett, Abdelkader Essafi, Ozren Polasek, Saima A Mughal, Irma Redzic, Dragan Primorac, Lina Zgaga, Ivana KolcicTorben Hansen, Daniela Gasperikova, Erling Tjora, Mark W J Strachan, Trine Nielsen, Juraj Stanik, Iwar Klimes, Oluf B Pedersen, Pål R Njølstad, Sarah H Wild, Ulf Gyllensten, Olga Gornik, James F Wilson, Nicholas D Hastie, Harry Campbell, Mark I McCarthy, Pauline M Rudd, Katharine R Owen, Gordan Lauc, Alan F Wright

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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.

Original language	English
Pages (from-to)	1329-37
Number of pages	9
Journal	Diabetes
Volume	62
Issue number	4
DOIs	https://doi.org/10.2337/db12-0880
Publication status	Published - Apr 2013

Keywords

Adolescent
Adult
Biomarkers
Diabetes Mellitus, Type 1
Diabetes Mellitus, Type 2
Female
Gene Expression Regulation
Hepatocyte Nuclear Factor 1-alpha
Humans
Male
Middle Aged
Mutation, Missense
Polymorphism, Single Nucleotide
Polysaccharides
Reproducibility of Results
Young Adult
Journal Article
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Thanabalasingham, G., Huffman, J. E., Kattla, J. J., Novokmet, M., Rudan, I., Gloyn, A. L., Hayward, C., Adamczyk, B., Reynolds, R. M., Muzinic, A., Hassanali, N., Pucic, M., Bennett, A. J., Essafi, A., Polasek, O., Mughal, S. A., Redzic, I., Primorac, D., Zgaga, L., ... Wright, A. F. (2013). Mutations in HNF1A result in marked alterations of plasma glycan profile. Diabetes, 62(4), 1329-37. https://doi.org/10.2337/db12-0880

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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.",

keywords = "Adolescent, Adult, Biomarkers, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Female, Gene Expression Regulation, Hepatocyte Nuclear Factor 1-alpha, Humans, Male, Middle Aged, Mutation, Missense, Polymorphism, Single Nucleotide, Polysaccharides, Reproducibility of Results, Young Adult, Journal Article, Research Support, Non-U.S. Gov't",

author = "Gaya Thanabalasingham and Huffman, {Jennifer E} and Kattla, {Jayesh J} and Mislav Novokmet and Igor Rudan and Gloyn, {Anna L} and Caroline Hayward and Barbara Adamczyk and Reynolds, {Rebecca M} and Ana Muzinic and Neelam Hassanali and Maja Pucic and Bennett, {Amanda J} and Abdelkader Essafi and Ozren Polasek and Mughal, {Saima A} and Irma Redzic and Dragan Primorac and Lina Zgaga and Ivana Kolcic and Torben Hansen and Daniela Gasperikova and Erling Tjora and Strachan, {Mark W J} and Trine Nielsen and Juraj Stanik and Iwar Klimes and Pedersen, {Oluf B} and Nj{\o}lstad, {P{\aa}l R} and Wild, {Sarah H} and Ulf Gyllensten and Olga Gornik and Wilson, {James F} and Hastie, {Nicholas D} and Harry Campbell and McCarthy, {Mark I} and Rudd, {Pauline M} and Owen, {Katharine R} and Gordan Lauc and Wright, {Alan F}",

year = "2013",

month = apr,

doi = "10.2337/db12-0880",

language = "English",

volume = "62",

pages = "1329--37",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

number = "4",

}

Thanabalasingham, G, Huffman, JE, Kattla, JJ, Novokmet, M, Rudan, I, Gloyn, AL, Hayward, C, Adamczyk, B, Reynolds, RM, Muzinic, A, Hassanali, N, Pucic, M, Bennett, AJ, Essafi, A, Polasek, O, Mughal, SA, Redzic, I, Primorac, D, Zgaga, L, Kolcic, I, Hansen, T, Gasperikova, D, Tjora, E, Strachan, MWJ, Nielsen, T, Stanik, J, Klimes, I, Pedersen, OB, Njølstad, PR, Wild, SH, Gyllensten, U, Gornik, O, Wilson, JF, Hastie, ND, Campbell, H, McCarthy, MI, Rudd, PM, Owen, KR, Lauc, G & Wright, AF 2013, 'Mutations in HNF1A result in marked alterations of plasma glycan profile', Diabetes, vol. 62, no. 4, pp. 1329-37. https://doi.org/10.2337/db12-0880

TY - JOUR

T1 - Mutations in HNF1A result in marked alterations of plasma glycan profile

AU - Thanabalasingham, Gaya

AU - Huffman, Jennifer E

AU - Kattla, Jayesh J

AU - Novokmet, Mislav

AU - Rudan, Igor

AU - Gloyn, Anna L

AU - Hayward, Caroline

AU - Adamczyk, Barbara

AU - Reynolds, Rebecca M

AU - Muzinic, Ana

AU - Hassanali, Neelam

AU - Pucic, Maja

AU - Bennett, Amanda J

AU - Essafi, Abdelkader

AU - Polasek, Ozren

AU - Mughal, Saima A

AU - Redzic, Irma

AU - Primorac, Dragan

AU - Zgaga, Lina

AU - Kolcic, Ivana

AU - Hansen, Torben

AU - Gasperikova, Daniela

AU - Tjora, Erling

AU - Strachan, Mark W J

AU - Nielsen, Trine

AU - Stanik, Juraj

AU - Klimes, Iwar

AU - Pedersen, Oluf B

AU - Njølstad, Pål R

AU - Wild, Sarah H

AU - Gyllensten, Ulf

AU - Gornik, Olga

AU - Wilson, James F

AU - Hastie, Nicholas D

AU - Campbell, Harry

AU - McCarthy, Mark I

AU - Rudd, Pauline M

AU - Owen, Katharine R

AU - Lauc, Gordan

AU - Wright, Alan F

PY - 2013/4

Y1 - 2013/4

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Biomarkers

KW - Diabetes Mellitus, Type 1

KW - Diabetes Mellitus, Type 2

KW - Female

KW - Gene Expression Regulation

KW - Hepatocyte Nuclear Factor 1-alpha

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation, Missense

KW - Polymorphism, Single Nucleotide

KW - Polysaccharides

KW - Reproducibility of Results

KW - Young Adult

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.2337/db12-0880

DO - 10.2337/db12-0880

M3 - Article (Academic Journal)

C2 - 23274891

SN - 0012-1797

VL - 62

SP - 1329

EP - 1337

JO - Diabetes

JF - Diabetes

IS - 4

ER -

Mutations in HNF1A result in marked alterations of plasma glycan profile

Abstract

Keywords

UN SDGs

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