Plasma Fucosylated Glycans and C-Reactive Protein as Biomarkers of HNF1A-MODY in Young Adult-Onset Nonautoimmune Diabetes.

OBJECTIVE

Maturity-onset diabetes of the young (MODY) due to variants in is the most common type of monogenic diabetes. Frequent misdiagnosis results in missed opportunity to use sulfonylureas as first-line treatment. A nongenetic biomarker could improve selection of subjects for genetic testing and increase diagnosis rates. We previously reported that plasma levels of antennary fucosylated -glycans and high-sensitivity C-reactive protein (hs-CRP) are reduced in individuals with HNF1A-MODY. In this study, we examined the potential use of -glycans and hs-CRP in discriminating individuals with damaging alleles from those without variants in an unselected population of young adults with nonautoimmune diabetes.

RESEARCH DESIGN AND METHODS

We analyzed the plasma -glycan profile, measured hs-CRP, and sequenced in 989 individuals with diabetes diagnosed when younger than age 45, persistent endogenous insulin production, and absence of pancreatic autoimmunity. Systematic assessment of rare variants was performed.

RESULTS

We identified 29 individuals harboring 25 rare alleles, of which 3 were novel, and 12 (in 16 probands) were considered pathogenic. Antennary fucosylated -glycans and hs-CRP were able to differentiate subjects with damaging alleles from those without rare alleles. Glycan GP30 had a receiver operating characteristic curve area under the curve (AUC) of 0.90 (88% sensitivity, 80% specificity, cutoff 0.70%), whereas hs-CRP had an AUC of 0.83 (88% sensitivity, 69% specificity, cutoff 0.81 mg/L).

CONCLUSIONS

Half of rare sequence variants do not cause MODY. -glycan profile and hs-CRP could both be used as tools, alone or as adjuncts to existing pathways, for identifying individuals at high risk of carrying a damaging allele.