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

Abstract

Maturity-onset diabetes of the young (MODY) due to variants in <i>HNF1A</i> 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 <i>N</i>-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 <i>N</i>-glycans and hs-CRP in discriminating individuals with damaging <i>HNF1A</i> alleles from those without <i>HNF1A</i> variants in an unselected population of young adults with nonautoimmune diabetes. We analyzed the plasma <i>N</i>-glycan profile, measured hs-CRP, and sequenced <i>HNF1A</i> in 989 individuals with diabetes diagnosed when younger than age 45, persistent endogenous insulin production, and absence of pancreatic autoimmunity. Systematic assessment of rare <i>HNF1A</i> variants was performed. We identified 29 individuals harboring 25 rare <i>HNF1A</i> alleles, of which 3 were novel, and 12 (in 16 probands) were considered pathogenic. Antennary fucosylated <i>N</i>-glycans and hs-CRP were able to differentiate subjects with damaging <i>HNF1A</i> alleles from those without rare <i>HNF1A</i> 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). Half of rare <i>HNF1A</i> sequence variants do not cause MODY. <i>N</i>-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 <i>HNF1A</i> allele.