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.