Assessment of high-sensitivity C-reactive protein levels as diagnostic discriminator of maturity-onset diabetes of the young due to HNF1A mutations

Abstract

Objective: Despite the clinical importance of an accurate diagnosis in individuals with monogenic forms of diabetes, restricted access to genetic testing leaves many patients with undiagnosed diabetes. Recently, common variation near the HNF1 homeobox A (HNF1A) gene was shown to influence C-reactive protein levels in healthy adults. We hypothesized that serum levels of high-sensitivity C-reactive protein (hs-CRP) could represent a clinically useful biomarker for the identification of HNF1A mutations causing maturity-onset diabetes of the young (MODY).

Research design and methods: Serum hs-CRP was measured in subjects with HNF1A-MODY (n = 31), autoimmune diabetes (n = 316), type 2 diabetes (n = 240), and glucokinase (GCK) MODY (n = 24) and in nondiabetic individuals (n = 198). The discriminative accuracy of hs-CRP was evaluated through receiver operating characteristic (ROC) curve analysis, and performance was compared with standard diagnostic criteria. Our primary analyses excluded approximately 11% of subjects in whom the single available hs-CRP measurement was >10 mg/l.

Results: Geometric mean (SD range) hs-CRP levels were significantly lower (P <or= 0.009) for HNF1A-MODY individuals, 0.20 (0.03-1.14) mg/l, than for any other group: autoimmune diabetes 0.58 (0.10-2.75) mg/l, type 2 diabetes 1.33 (0.28-6.14) mg/l, GCK-MODY 1.01 (0.19-5.33) mg/l, and nondiabetic 0.48 (0.10-2.42) mg/l. The ROC-derived C-statistic for discriminating HNF1A-MODY and type 2 diabetes was 0.8. Measurement of hs-CRP, either alone or in combination with current diagnostic criteria, was superior to current diagnostic criteria alone. Sensitivity and specificity for the combined criteria approached 80%.

Conclusions: Serum hs-CRP levels are markedly lower in HNF1A-MODY than in other forms of diabetes. hs-CRP has potential as a widely available, cost-effective screening test to support more precise targeting of MODY diagnostic testing.

Figure 1

The analyses included 28 subjects with HNF1A-MODY, 294 with autoimmune diabetes, 187 with type 2 diabetes, and 24 with GCK-MODY and 198 nondiabetic control subjects. Values of hs-CRP >10 mg/l are excluded. A: Geometric mean hs-CRP levels for the different groups; error bars show 95% CI. B: Cumulative percentage plot for hs-CRP levels in the different groups. The dotted reference line corresponds to a hs-CRP value of 0.4 mg/l. hs-CRP levels are plotted on a log₁₀ scale. C: ROC curve illustrating the capacity of hs-CRP to distinguish between HNF1A-MODY and type 2 diabetes. The C-statistic (area under the curve) for this comparison is 0.8.