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: OBJECTIVE
  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
  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.
authors.affiliation: Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford, OX3 7LJ, UK.
authors.forename: G
authors.initials: G
authors.lastname: Thanabalasingham
authors.forename: N
authors.initials: N
authors.lastname: Shah
authors.forename: M
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: T
authors.initials: T
authors.lastname: Tuomi
authors.forename: D
authors.initials: D
authors.lastname: Gašperíková
authors.forename: M
authors.initials: M
authors.lastname: Szopa
authors.forename: E
authors.initials: E
authors.lastname: Tjora
authors.forename: T J
authors.initials: TJ
authors.lastname: James
authors.forename: P
authors.initials: P
authors.lastname: Kokko
authors.forename: F
authors.initials: F
authors.lastname: Loiseleur
authors.forename: E
authors.initials: E
authors.lastname: Andersson
authors.forename: S
authors.initials: S
authors.lastname: Gaget
authors.forename: B
authors.initials: B
authors.lastname: Isomaa
authors.forename: N
authors.initials: N
authors.lastname: Nowak
authors.forename: H
authors.initials: H
authors.lastname: Raeder
authors.forename: J
authors.initials: J
authors.lastname: Stanik
authors.forename: P R
authors.initials: PR
authors.lastname: Njolstad
authors.forename: M T
authors.initials: MT
authors.lastname: Malecki
authors.forename: I
authors.initials: I
authors.lastname: Klimes
authors.forename: L
authors.initials: L
authors.lastname: Groop
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
authors.forename: P
authors.initials: P
authors.lastname: Froguel
authors.forename: M I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: A L
authors.initials: AL
authors.lastname: Gloyn
authors.forename: K R
authors.initials: KR
authors.lastname: Owen
mesh_terms: D000328:Adult; D017668:Age of Onset; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D005060:Europe; D005941:Glucokinase / Q000737:chemistry / Q000235:genetics; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000737:chemistry / Q000235:genetics*; D051557:Hepatocyte Nuclear Factor 4 / Q000737:chemistry / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D055815:Young Adult
chemical_list: D015415:Biomarkers; C496487:HNF1A protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D002097:C-Reactive Protein; D005941:Glucokinase