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

55 Citationer (Scopus)

Abstract

A recent genome-wide association study identified hepatocyte nuclear factor 1-a (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 HNF1AMODY 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.

Originalsprog	Engelsk
Tidsskrift	Diabetes
Vol/bind	62
Udgave nummer	4
Sider (fra-til)	1329-37
Antal sider	9
ISSN	0046-0192
DOI	https://doi.org/10.2337/db12-0880
Status	Udgivet - apr. 2013

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10.2337/db12-0880

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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

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, bind 62, nr. 4, s. 1329-37. https://doi.org/10.2337/db12-0880

@article{6f274b2872a84e548f155398359f85ee,

title = "Mutations in HNF1A result in marked alterations of plasma glycan profile",

abstract = "A recent genome-wide association study identified hepatocyte nuclear factor 1-a (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 HNF1AMODY 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, Biological Markers, 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",

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",

number = "4",

}

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-a (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 HNF1AMODY 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-a (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 HNF1AMODY 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 - Biological Markers

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

U2 - 10.2337/db12-0880

DO - 10.2337/db12-0880

M3 - Journal article

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

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