A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes

G. Thanabalasingham; N. Shah; M. Vaxillaire; T. Hansen; T. Tuomi; D. Gašperíková; M. Szopa; E. Tjora; T. J. James; P. Kokko; F. Loiseleur; E. Andersson; S. Gaget; B. Isomaa; N. Nowak; H. Raeder; J. Stanik; P. R. Njolstad; M. T. Malecki; I. Klimes; L. Groop; O. Pedersen; P. Froguel; M. I. McCarthy; A. L. Gloyn; K. R. Owen

doi:10.1007/s00125-011-2261-y

A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes

G. Thanabalasingham, N. Shah, M. Vaxillaire, T. Hansen, T. Tuomi, D. Gašperíková, M. Szopa, E. Tjora, T. J. James, P. Kokko, F. Loiseleur, E. Andersson, S. Gaget, B. Isomaa, N. Nowak, H. Raeder, J. Stanik, P. R. Njolstad, M. T. Malecki, I. KlimesL. Groop, O. Pedersen, P. Froguel, M. I. McCarthy, A. L. Gloyn, K. R. Owen

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Abstract

Aims/hypothesis: An accurate molecular diagnosis of diabetes subtype confers clinical benefits; however, many individuals with monogenic diabetes remain undiagnosed. Biomarkers could help to prioritise patients for genetic investigation. We recently demonstrated that high-sensitivity C-reactive protein (hsCRP) levels are lower in UK patients with hepatocyte nuclear factor 1 alpha (HNF1A)-MODY than in other diabetes subtypes. In this large multi-centre study we aimed to assess the clinical validity of hsCRP as a diagnostic biomarker, examine the genotype-phenotype relationship and compare different hsCRP assays. Methods: High-sensitivity CRP levels were analysed in individuals with HNF1A-MODY (n = 457), glucokinase (GCK)-MODY (n = 404), hepatocyte nuclear factor 4 alpha (HNF4A)-MODY (n = 54) and type 2 diabetes (n = 582) from seven European centres. Three common assays for hsCRP analysis were evaluated. We excluded 121 participants (8.1%) with hsCRP values >10 mg/l. The discriminative power of hsCRP with respect to diabetes aetiology was assessed by receiver operating characteristic curve-derived C-statistic. Results: In all centres and irrespective of the assay method, meta-analysis confirmed significantly lower hsCRP levels in those with HNF1A-MODY than in those with other aetiologies (z score -21.8, p < 5 × 10^-105). HNF1A-MODY cases with missense mutations had lower hsCRP levels than those with truncating mutations (0.03 vs 0.08 mg/l, p < 5 × 10^-5). High-sensitivity CRP values between assays were strongly correlated (r ² ≥ 0.91, p ≤ 1 × 10^-5). Across the seven centres, the C-statistic for distinguishing HNF1A-MODY from young adult-onset type 2 diabetes ranged from 0.79 to 0.97, indicating high discriminative accuracy. Conclusions/interpretation: In the largest study to date, we have established that hsCRP is a clinically valid biomarker for HNF1A-MODY in European populations. Given the modest costs and wide availability, hsCRP could translate rapidly into clinical practice, considerably improving diagnosis rates in monogenic diabetes.

Original language	English
Pages (from-to)	2801-2810
Number of pages	10
Journal	Diabetologia
Volume	54
Issue number	11
DOIs	https://doi.org/10.1007/s00125-011-2261-y
State	Published - Nov 2011
Externally published	Yes

Keywords

Biomarker
High-sensitivity C-reactive protein
MODY
Maturity-onset diabetes of the young
hsCRP

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10.1007/s00125-011-2261-y

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Thanabalasingham, G., Shah, N., Vaxillaire, M., Hansen, T., Tuomi, T., Gašperíková, D., Szopa, M., Tjora, E., James, T. J., Kokko, P., Loiseleur, F., Andersson, E., Gaget, S., Isomaa, B., Nowak, N., Raeder, H., Stanik, J., Njolstad, P. R., Malecki, M. T., ... Owen, K. R. (2011). A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes. Diabetologia, 54(11), 2801-2810. https://doi.org/10.1007/s00125-011-2261-y

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title = "A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes",

abstract = "Aims/hypothesis: An accurate molecular diagnosis of diabetes subtype confers clinical benefits; however, many individuals with monogenic diabetes remain undiagnosed. Biomarkers could help to prioritise patients for genetic investigation. We recently demonstrated that high-sensitivity C-reactive protein (hsCRP) levels are lower in UK patients with hepatocyte nuclear factor 1 alpha (HNF1A)-MODY than in other diabetes subtypes. In this large multi-centre study we aimed to assess the clinical validity of hsCRP as a diagnostic biomarker, examine the genotype-phenotype relationship and compare different hsCRP assays. Methods: High-sensitivity CRP levels were analysed in individuals with HNF1A-MODY (n = 457), glucokinase (GCK)-MODY (n = 404), hepatocyte nuclear factor 4 alpha (HNF4A)-MODY (n = 54) and type 2 diabetes (n = 582) from seven European centres. Three common assays for hsCRP analysis were evaluated. We excluded 121 participants (8.1%) with hsCRP values >10 mg/l. The discriminative power of hsCRP with respect to diabetes aetiology was assessed by receiver operating characteristic curve-derived C-statistic. Results: In all centres and irrespective of the assay method, meta-analysis confirmed significantly lower hsCRP levels in those with HNF1A-MODY than in those with other aetiologies (z score -21.8, p < 5 × 10-105). HNF1A-MODY cases with missense mutations had lower hsCRP levels than those with truncating mutations (0.03 vs 0.08 mg/l, p < 5 × 10-5). High-sensitivity CRP values between assays were strongly correlated (r 2 ≥ 0.91, p ≤ 1 × 10-5). Across the seven centres, the C-statistic for distinguishing HNF1A-MODY from young adult-onset type 2 diabetes ranged from 0.79 to 0.97, indicating high discriminative accuracy. Conclusions/interpretation: In the largest study to date, we have established that hsCRP is a clinically valid biomarker for HNF1A-MODY in European populations. Given the modest costs and wide availability, hsCRP could translate rapidly into clinical practice, considerably improving diagnosis rates in monogenic diabetes.",

keywords = "Biomarker, High-sensitivity C-reactive protein, MODY, Maturity-onset diabetes of the young, hsCRP",

author = "G. Thanabalasingham and N. Shah and M. Vaxillaire and T. Hansen and T. Tuomi and D. Ga{\v s}per{\'i}kov{\'a} and M. Szopa and E. Tjora and James, {T. J.} and P. Kokko and F. Loiseleur and E. Andersson and S. Gaget and B. Isomaa and N. Nowak and H. Raeder and J. Stanik and Njolstad, {P. R.} and Malecki, {M. T.} and I. Klimes and L. Groop and O. Pedersen and P. Froguel and McCarthy, {M. I.} and Gloyn, {A. L.} and Owen, {K. R.}",

note = "Funding Information: Acknowledgements We thank the patients and families for taking part in this study. We also thank M. Huckova and L. Valentinova for their help with the DNA analysis (Slovakian samples). K.R. Owen is an NIHR-funded Clinician Scientist. A.L. Gloyn is a Medical Research Council (MRC) New Investigator (81696). E. Tjora, H. Raeder and P.R. Njolstad were funded by the University of Bergen, Helse Vest, Innovest and the Research Council of Norway. D. Ga{\v s}per{\'i}kov{\'a}, J. Stanik and I. Klimes acknowledge grant support from BITCET and VEGA 2/0151/11. The study was funded by the Oxford (NIHR) Biomedical Research Centre, Diabetes UK and the European Community FP7 programmes CEED3 (HEALTH-F2-2008-223211) and ENGAGE (HEALTH-F4-2007-201413). The Danish part of the study was supported by grants from the Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care (LuCAMP), the Danish Diabetes Association and the Danish Research Council. The Marie Krogh Centre for Metabolic Research is funded by the Novo Nordisk Foundation.",

year = "2011",

month = nov,

doi = "10.1007/s00125-011-2261-y",

language = "English",

volume = "54",

pages = "2801--2810",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer Verlag",

number = "11",

}

Thanabalasingham, G, Shah, N, Vaxillaire, M, Hansen, T, Tuomi, T, Gašperíková, D, Szopa, M, Tjora, E, James, TJ, Kokko, P, Loiseleur, F, Andersson, E, Gaget, S, Isomaa, B, Nowak, N, Raeder, H, Stanik, J, Njolstad, PR, Malecki, MT, Klimes, I, Groop, L, Pedersen, O, Froguel, P, McCarthy, MI, Gloyn, AL & Owen, KR 2011, 'A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes', Diabetologia, vol. 54, no. 11, pp. 2801-2810. https://doi.org/10.1007/s00125-011-2261-y

TY - JOUR

T1 - A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes

AU - Thanabalasingham, G.

AU - Shah, N.

AU - Vaxillaire, M.

AU - Hansen, T.

AU - Tuomi, T.

AU - Gašperíková, D.

AU - Szopa, M.

AU - Tjora, E.

AU - James, T. J.

AU - Kokko, P.

AU - Loiseleur, F.

AU - Andersson, E.

AU - Gaget, S.

AU - Isomaa, B.

AU - Nowak, N.

AU - Raeder, H.

AU - Stanik, J.

AU - Njolstad, P. R.

AU - Malecki, M. T.

AU - Klimes, I.

AU - Groop, L.

AU - Pedersen, O.

AU - Froguel, P.

AU - McCarthy, M. I.

AU - Gloyn, A. L.

AU - Owen, K. R.

N1 - Funding Information: Acknowledgements We thank the patients and families for taking part in this study. We also thank M. Huckova and L. Valentinova for their help with the DNA analysis (Slovakian samples). K.R. Owen is an NIHR-funded Clinician Scientist. A.L. Gloyn is a Medical Research Council (MRC) New Investigator (81696). E. Tjora, H. Raeder and P.R. Njolstad were funded by the University of Bergen, Helse Vest, Innovest and the Research Council of Norway. D. Gašperíková, J. Stanik and I. Klimes acknowledge grant support from BITCET and VEGA 2/0151/11. The study was funded by the Oxford (NIHR) Biomedical Research Centre, Diabetes UK and the European Community FP7 programmes CEED3 (HEALTH-F2-2008-223211) and ENGAGE (HEALTH-F4-2007-201413). The Danish part of the study was supported by grants from the Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care (LuCAMP), the Danish Diabetes Association and the Danish Research Council. The Marie Krogh Centre for Metabolic Research is funded by the Novo Nordisk Foundation.

PY - 2011/11

Y1 - 2011/11

N2 - Aims/hypothesis: An accurate molecular diagnosis of diabetes subtype confers clinical benefits; however, many individuals with monogenic diabetes remain undiagnosed. Biomarkers could help to prioritise patients for genetic investigation. We recently demonstrated that high-sensitivity C-reactive protein (hsCRP) levels are lower in UK patients with hepatocyte nuclear factor 1 alpha (HNF1A)-MODY than in other diabetes subtypes. In this large multi-centre study we aimed to assess the clinical validity of hsCRP as a diagnostic biomarker, examine the genotype-phenotype relationship and compare different hsCRP assays. Methods: High-sensitivity CRP levels were analysed in individuals with HNF1A-MODY (n = 457), glucokinase (GCK)-MODY (n = 404), hepatocyte nuclear factor 4 alpha (HNF4A)-MODY (n = 54) and type 2 diabetes (n = 582) from seven European centres. Three common assays for hsCRP analysis were evaluated. We excluded 121 participants (8.1%) with hsCRP values >10 mg/l. The discriminative power of hsCRP with respect to diabetes aetiology was assessed by receiver operating characteristic curve-derived C-statistic. Results: In all centres and irrespective of the assay method, meta-analysis confirmed significantly lower hsCRP levels in those with HNF1A-MODY than in those with other aetiologies (z score -21.8, p < 5 × 10-105). HNF1A-MODY cases with missense mutations had lower hsCRP levels than those with truncating mutations (0.03 vs 0.08 mg/l, p < 5 × 10-5). High-sensitivity CRP values between assays were strongly correlated (r 2 ≥ 0.91, p ≤ 1 × 10-5). Across the seven centres, the C-statistic for distinguishing HNF1A-MODY from young adult-onset type 2 diabetes ranged from 0.79 to 0.97, indicating high discriminative accuracy. Conclusions/interpretation: In the largest study to date, we have established that hsCRP is a clinically valid biomarker for HNF1A-MODY in European populations. Given the modest costs and wide availability, hsCRP could translate rapidly into clinical practice, considerably improving diagnosis rates in monogenic diabetes.

AB - Aims/hypothesis: An accurate molecular diagnosis of diabetes subtype confers clinical benefits; however, many individuals with monogenic diabetes remain undiagnosed. Biomarkers could help to prioritise patients for genetic investigation. We recently demonstrated that high-sensitivity C-reactive protein (hsCRP) levels are lower in UK patients with hepatocyte nuclear factor 1 alpha (HNF1A)-MODY than in other diabetes subtypes. In this large multi-centre study we aimed to assess the clinical validity of hsCRP as a diagnostic biomarker, examine the genotype-phenotype relationship and compare different hsCRP assays. Methods: High-sensitivity CRP levels were analysed in individuals with HNF1A-MODY (n = 457), glucokinase (GCK)-MODY (n = 404), hepatocyte nuclear factor 4 alpha (HNF4A)-MODY (n = 54) and type 2 diabetes (n = 582) from seven European centres. Three common assays for hsCRP analysis were evaluated. We excluded 121 participants (8.1%) with hsCRP values >10 mg/l. The discriminative power of hsCRP with respect to diabetes aetiology was assessed by receiver operating characteristic curve-derived C-statistic. Results: In all centres and irrespective of the assay method, meta-analysis confirmed significantly lower hsCRP levels in those with HNF1A-MODY than in those with other aetiologies (z score -21.8, p < 5 × 10-105). HNF1A-MODY cases with missense mutations had lower hsCRP levels than those with truncating mutations (0.03 vs 0.08 mg/l, p < 5 × 10-5). High-sensitivity CRP values between assays were strongly correlated (r 2 ≥ 0.91, p ≤ 1 × 10-5). Across the seven centres, the C-statistic for distinguishing HNF1A-MODY from young adult-onset type 2 diabetes ranged from 0.79 to 0.97, indicating high discriminative accuracy. Conclusions/interpretation: In the largest study to date, we have established that hsCRP is a clinically valid biomarker for HNF1A-MODY in European populations. Given the modest costs and wide availability, hsCRP could translate rapidly into clinical practice, considerably improving diagnosis rates in monogenic diabetes.

KW - Biomarker

KW - High-sensitivity C-reactive protein

KW - MODY

KW - Maturity-onset diabetes of the young

KW - hsCRP

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U2 - 10.1007/s00125-011-2261-y

DO - 10.1007/s00125-011-2261-y

M3 - Article

C2 - 21814873

AN - SCOPUS:80054692207

SN - 0012-186X

VL - 54

SP - 2801

EP - 2810

JO - Diabetologia

JF - Diabetologia

IS - 11

ER -

A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes

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