Skip to main content
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • Log out
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes Care

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • Log out
  • My Cart

Search

  • Advanced search
Diabetes Care
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Original Research

High-Sensitivity CRP Discriminates HNF1A-MODY From Other Subtypes of Diabetes

  1. Tim J. McDonald, MSC1,2⇓,
  2. Beverley M. Shields, PHD1,
  3. Jane Lawry, BSC2,
  4. Katharine R. Owen, MD3,4,
  5. Anna L. Gloyn, DPHIL3,4,
  6. Sian Ellard, PHD1,5 and
  7. Andrew T. Hattersley, DM1
  1. 1Peninsula College of Medicine and Dentistry (University of Exeter), Peninsula NIHR Clinical Research Facility, Exeter, Devon, U.K.
  2. 2Royal Devon and Exeter NHS Foundation Trust, Department of Clinical Chemistry, Exeter, Devon, U.K.
  3. 3University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, U.K.
  4. 4Churchill Hospital, Oxford National Institute for Health Research Biomedical Research Centre, Oxford, U.K.
  5. 5Royal Devon and Exeter NHS Foundation Trust, Department of Molecular Genetics, Exeter, U.K.
  1. Corresponding author: Tim J. McDonald, tim.mcdonald{at}rdeft.nhs.uk.
Diabetes Care 2011 Aug; 34(8): 1860-1862. https://doi.org/10.2337/dc11-0323
PreviousNext
  • Article
  • Figures & Tables
  • Suppl Material
  • Info & Metrics
  • PDF
Loading

Abstract

OBJECTIVE Maturity-onset diabetes of the young (MODY) as a result of mutations in hepatocyte nuclear factor 1-α (HNF1A) is often misdiagnosed as type 1 diabetes or type 2 diabetes. Recent work has shown that high-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY than type 1 diabetes, type 2 diabetes, or glucokinase (GCK)-MODY. We aim to replicate these findings in larger numbers and other MODY subtypes.

RESEARCH DESIGN AND METHODS hs-CRP levels were assessed in 750 patients (220 HNF1A, 245 GCK, 54 HNF4-α [HNF4A], 21 HNF1-β (HNF1B), 53 type 1 diabetes, and 157 type 2 diabetes).

RESULTS hs-CRP was lower in HNF1A-MODY (median [IQR] 0.3 [0.1–0.6] mg/L) than type 2 diabetes (1.40 [0.60–3.45] mg/L; P < 0.001) and type 1 diabetes (1.10 [0.50–1.85] mg/L; P < 0.001), HNF4A-MODY (1.45 [0.46–2.88] mg/L; P < 0.001), GCK-MODY (0.60 [0.30–1.80] mg/L; P < 0.001), and HNF1B-MODY (0.60 [0.10–2.8] mg/L; P = 0.07). hs-CRP discriminated HNF1A-MODY from type 2 diabetes with hs-CRP <0.75 mg/L showing 79% sensitivity and 70% specificity (receiver operating characteristic area under the curve = 0.84).

CONCLUSIONS hs-CRP levels are lower in HNF1A-MODY than other forms of diabetes and may be used as a biomarker to select patients for diagnostic HNF1A genetic testing.

Maturity-onset diabetes of the young (MODY) is a rare monogenic form of diabetes and is often misdiagnosed as type 1 diabetes or type 2 diabetes (1,2). A correct genetic diagnosis of MODY is important for predicting the clinical course of disease, risk to relatives, and optimizing treatment. Therefore, cheap and novel biomarkers that help identify these patients are desirable.

The CRP gene has hepatocyte nuclear factor 1-α (HNF1A) binding sites in its promoter, and common variants in and around HNF1A are associated with circulating high-sensitivity C-reactive protein (hs-CRP) levels (3,4). Recently, Owen et al. (5) demonstrated that hs-CRP levels were reduced in 31 HNF1A-MODY patients compared with type 1 diabetes, type 2 diabetes, glucokinase (GCK) MODY, and normal control subjects, making it potentially a useful clinical test.

We aim to replicate this initial study in a larger cohort of patients and assess whether the reduction in hs-CRP is also seen in patients with mutations of other genes encoding hepatic nuclear factors (hepatocyte nuclear factor 4-α [HNF4A] and hepatocyte nuclear factor 4-β [HNF1B]).

RESEARCH DESIGN AND METHODS

Additional information about laboratory methods, study participants, and statistical analysis can be found in the Supplementary Data.

Study participants

hs-CRP level was assessed in plasma from 750 patients: 540 with a confirmed genetic diagnosis of MODY (220 HNF1A, 245 GCK, 54 HNF4A, and 21 HNF1B), 53 patients with type 1 diabetes, and 157 patients with type 2 diabetes.

RESULTS

Patient characteristics are presented in Supplementary Table 1. Subjects (29/750; 10.5%) had hs-CRP results >10 mg/L (n = 16 GCK-MODY, n = 10 type 2 diabetes, and n = 3 HNF4A-MODY) and were considered to have an acute inflammatory response and excluded from further analysis. This is in line with the protocol used by Owen et al. and previous studies of CRP (5,6).

HNF1A-MODY versus type 2 diabetes and type 1 diabetes

Plasma hs-CRP was significantly lower in HNF1A-MODY than type 1 diabetes and type 2 diabetes (median [IQR] 0.3 [0.1–0.6] versus 1.1 [0.5–1.85] mg/L [P < 0.001] and 1.4 [0.6–3.45] mg/L; P < 0.001), respectively (Fig. 1).

Figure 1
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1

Boxplot to show serum hs-CRP in type 1 diabetes (n = 53), type 2 diabetes (n = 157), HNF1A-MODY (n = 220), HNF4A-MODY (n = 54), HNF1B-MODY (n = 21), and GCK-MODY (n = 245). Box, median and IQR; whiskers, data range. ○, outliers (>1.5× IQR); ★, extreme values (>3× IQR). The data exclude all subjects with hs-CRP levels >10 mg/L.

For discriminating HNF1A-MODY from type 2 diabetes, receiver operating characteristic (ROC) curve showed good discrimination (area under the curve [AUC] 0.84) and identified a cutoff hs-CRP of 0.75 mg/L with 79% sensitivity and 71% specificity (Supplementary Fig. 1). This equates to a positive predictive value (PPV) of 2.7% and a negative predictive value (NPV) of 99.7%, assuming a MODY prevalence of 1% (7). hs-CRP was less discriminative between HNF1A-MODY and type 1 diabetes with a ROC AUC of 0.78 (79% sensitivity and 67% specificity at a cutoff of <0.75 mg/L). This equates to a PPV of 2.4% and an NPV of 99.7%.

HNF1A-MODY versus other MODY subtypes

hs-CRP was lower in HNF1A-MODY (median [IQR] 0.3 [0.1–0.6]) than GCK-MODY (1.45 [0.46–2.88] mg/L; P < 0.001), HNF4A-MODY (0.6 [0.3–1.8] mg/L; P < 0.001), and HNF1B-MODY, although this did not reach statistical significance (0.6 [0.1–2.85] mg/L; P = 0.07).

To discriminate HNF1A-MODY from HNF4A-MODY, ROC curve analysis identified a cutoff hs-CRP <0.55 mg/L (AUC 0.76) achieving a sensitivity of 71% and a specificity of 70%. Discriminating HNF1A-MODY from all other MODY subtypes (HNF4A-, HNF1B-, GCK-MODY), a cutoff hs-CRP <0.55 mg/L (AUC 0.68) achieved 71% sensitivity and 55% specificity. This relationship persisted when discriminating HNF1A-MODY from all types of diabetes (71% sensitivity, 69% specificity).

Analysis of potential confounders can be found in the Supplementary Results.

CONCLUSIONS

We have confirmed in a large cohort of patients that plasma hs-CRP levels are lower in HNF1A-MODY than type 2 diabetes, type 1 diabetes, and GCK-MODY (5). We have shown for the first time that low hs-CRP levels are not seen in MODY because of mutations in other related transcription factors (HNF4A, HNF1B).

The best discrimination achieved with hs-CRP is between HNF1A-MODY and type 2 diabetes (79% sensitivity, 70% specificity). However, because MODY is rare (∼1% of all diabetes [7]) compared with type 2 diabetes, this equates to a modest PPVof only 2.7%. Therefore, if hs-CRP was used as a marker for identifying HNF1A-MODY (hs-CRP <0.75 mg/L) in isolation the false-positive rate and number of unnecessary genetic testing would be high (37 to 1), suggesting that hs-CRP should be used in combination with other clinical characteristics. In contrast, a negative result (hs-CRP >0.75 mg/L), gives an NPV of 99.7% and therefore is good at ruling out HNF1A-MODY. Unlike type 1 diabetes where robust biomarkers, including pancreatic autoantibodies and persistent C-peptide production (1,8), already exist, few biomarkers currently distinguish type 2 diabetes from MODY.

hs-CRP was only reduced in HNF1A-MODY patients and not in the other genetic subtypes of MODY. This result may have been predicted since the hs-CRP gene has HNF1A binding sites in its promoter (9). This may prove to be useful as a tool to help prioritize the order of gene testing in patients with a high clinical suspicion of MODY. An hs-CRP level <0.55 mg/L should suggest HNF1A sequencing first, and levels >0.55 mg/L may warrant consideration of the other subtypes of MODY. This result may prove to be helpful as an adjunct to identify HNF4A-MODY patients, who are phenotypically similar to HNF1A-MODY.

An advantage of hs-CRP is that it is cheap and widely available. Current CRP assays, used to identify inflammation, measure down to levels of 0.2–0.3 mg/L and, therefore, a specific hs-CRP assay may not be necessary. It would be important to determine the comparability between routine CRP and hs-CRP assays before testing. A limitation of CRP is that it will be raised in inflammatory states, reducing its potential use as a discriminative tool. In addition, certain medications reduce CRP levels, such as statins (10), aspirin (11), and β-blockers (12), which are believed in some cases to reduce CRP by 20–30%. We did not have drug history available on individual patients, so we were unable to assess the impact of pharmacological agents on our results; however, Owen et al. (5) showed that removing subjects on statins and/or aspirin in their study did not alter their results.

In conclusion, we have confirmed that hs-CRP levels are lower in patients with HNF1A-MODY than other types of MODY, type 1 diabetes, and type 2 diabetes. hs-CRP is potentially a cheap, widely available biomarker that might aid in the cost-effective identification of patients with HNF1A-MODY.

Acknowledgments

This study was funded in Exeter by the European Community FP7 program CEED3 (HEALTH-F2-2008-223211). S.E., B.M.S., and A.T.H. are supported by the NIHR Peninsula Clinical Research Facility, University of Exeter. A.L.G. is supported by a Medical Research Council New Investigator Award (81696). K.R.O. is an NIHR-funded Clinician Scientist.

No potential conflicts of interest relevant to this article were reported.

T.J.M. wrote the manuscript and researched data. B.M.S. researched data and reviewed and edited the manuscript. J.L. researched data. K.R.O., A.L.G., and S.E. reviewed and edited the manuscript. A.T.H. researched data and reviewed and edited the manuscript.

The authors thank Annie Goodship (Royal Devon and Exeter NHS Foundation Trust, Department of Clinical Chemistry, Exeter, Devon, U.K.), Kevin Colclough (Royal Devon and Exeter NHS Foundation Trust, Department of Molecular Genetics, Exeter, Devon, U.K.), and Elizabeth Wren (Royal Devon and Exeter NHS Foundation Trust, Department of Clinical Chemistry, Exeter, Devon, U.K.) for their technical assistance with the study.

Footnotes

  • This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc11-0323/-/DC1.

  • Received February 16, 2011.
  • Accepted May 14, 2011.
  • © 2011 by the American Diabetes Association.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

References

  1. ↵
    1. Ellard S,
    2. Bellanné-Chantelot C,
    3. Hattersley AT
    ; European Molecular Genetics Quality Network (EMQN) MODY group. Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia 2008;51:546–553pmid:18297260
    OpenUrlCrossRefPubMed
  2. ↵
    1. Lambert AP,
    2. Ellard S,
    3. Allen LI,
    4. et al
    . Identifying hepatic nuclear factor 1-α mutations in children and young adults with a clinical diagnosis of type 1 diabetes. Diabetes Care 2003;26:333–337pmid:12547858
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Reiner AP,
    2. Barber MJ,
    3. Guan Y,
    4. et al
    . Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. Am J Hum Genet 2008;82:1193–1201pmid:18439552
    OpenUrlCrossRefPubMedWeb of Science
  4. ↵
    1. Ridker PM,
    2. Pare G,
    3. Parker A,
    4. et al
    . Loci related to metabolic-syndrome pathways including LEPR,HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women’s Genome Health Study. Am J Hum Genet 2008;82:1185–1192pmid:18439548
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    1. Owen KR,
    2. Thanabalasingham G,
    3. James TJ,
    4. et al
    . Assessment of high-sensitivity C-reactive protein levels as diagnostic discriminator of maturity-onset diabetes of the young due to HNF1A mutations. Diabetes Care 2010;33:1919–1924pmid:20724646
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Lee CC,
    2. Adler AI,
    3. Sandhu MS,
    4. et al
    . Association of C-reactive protein with type 2 diabetes: prospective analysis and meta-analysis. Diabetologia 2009;52:1040–1047pmid:19326095
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    1. Shepherd M,
    2. Ellis I,
    3. Ahmad AM,
    4. et al
    . Predictive genetic testing in maturity-onset diabetes of the young (MODY). Diabet Med 2001;18:417–421pmid:11472455
    OpenUrlCrossRefPubMed
  8. ↵
    1. Besser REJ, Shepherd MH,
    2. McDonald TJ,
    3. Shields BM,
    4. Knight BA,
    5. Ellard S,
    6. Hattersley AT
    . Urinary C-peptide creatinine ratio is a practical outpatient tool for identifying hepatocyte nuclear factor 1-α/hepatocyte nuclear factor 4-α maturity-onset diabetes of the young from long-duration type 1 diabetes. Diabetes Care 2011;34:286–291
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Toniatti C,
    2. Demartis A,
    3. Monaci P,
    4. Nicosia A,
    5. Ciliberto G
    . Synergistic trans-activation of the human C-reactive protein promoter by transcription factor HNF-1 binding at two distinct sites. EMBO J 1990;9:4467–4475pmid:2265613
    OpenUrlPubMed
  10. ↵
    1. Mora S,
    2. Musunuru K,
    3. Blumenthal RS
    . The clinical utility of high-sensitivity C-reactive protein in cardiovascular disease and the potential implication of JUPITER on current practice guidelines. Clin Chem 2009;55:219–228pmid:19095730
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Ridker PM,
    2. Cushman M,
    3. Stampfer MJ,
    4. Tracy RP,
    5. Hennekens CH
    . Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973–979pmid:9077376
    OpenUrlCrossRefPubMedWeb of Science
  12. ↵
    1. Jenkins NP,
    2. Keevil BG,
    3. Hutchinson IV,
    4. Brooks NH
    . Beta-blockers are associated with lower C-reactive protein concentrations in patients with coronary artery disease. Am J Med 2002;112:269–274pmid:11893365
    OpenUrlCrossRefPubMedWeb of Science
View Abstract
PreviousNext
Back to top
Diabetes Care: 34 (8)

In this Issue

August 2011, 34(8)
  • Table of Contents
  • About the Cover
  • Index by Author
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes Care.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
High-Sensitivity CRP Discriminates HNF1A-MODY From Other Subtypes of Diabetes
(Your Name) has forwarded a page to you from Diabetes Care
(Your Name) thought you would like to see this page from the Diabetes Care web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
High-Sensitivity CRP Discriminates HNF1A-MODY From Other Subtypes of Diabetes
Tim J. McDonald, Beverley M. Shields, Jane Lawry, Katharine R. Owen, Anna L. Gloyn, Sian Ellard, Andrew T. Hattersley
Diabetes Care Aug 2011, 34 (8) 1860-1862; DOI: 10.2337/dc11-0323

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

High-Sensitivity CRP Discriminates HNF1A-MODY From Other Subtypes of Diabetes
Tim J. McDonald, Beverley M. Shields, Jane Lawry, Katharine R. Owen, Anna L. Gloyn, Sian Ellard, Andrew T. Hattersley
Diabetes Care Aug 2011, 34 (8) 1860-1862; DOI: 10.2337/dc11-0323
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • RESEARCH DESIGN AND METHODS
    • RESULTS
    • CONCLUSIONS
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Tables
  • Suppl Material
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

Original Research

  • Insulin Resistance Is Associated With Enhanced Brain Glucose Uptake During Euglycemic Hyperinsulinemia: A Large-Scale PET Cohort
  • Not Only Diabetes but Also Prediabetes Leads to Functional Decline and Disability in Older Adults
  • Changes in Plant-Based Diet Indices and Subsequent Risk of Type 2 Diabetes in Women and Men: Three U.S. Prospective Cohorts
Show more Original Research

Pathophysiology/Complications

  • Diagnosis of Neuropathy and Risk Factors for Corneal Nerve Loss in Type 1 and Type 2 Diabetes: A Corneal Confocal Microscopy Study
  • Plasma Methylglyoxal Levels Are Associated With Amputations and Mortality in Severe Limb Ischemia Patients With and Without Diabetes
  • Intensive Risk Factor Management and Cardiovascular Autonomic Neuropathy in Type 2 Diabetes: The ACCORD Trial
Show more Pathophysiology/Complications

Similar Articles

Navigate

  • Current Issue
  • Standards of Care Guidelines
  • Online Ahead of Print
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Care Print ISSN: 0149-5992, Online ISSN: 1935-5548.