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

OBJECTIVE Maturity-onset diabetesof the young(MODY) due to variants in HNF1Ais the commonest type of monogenicdiabetes. Frequent misdiagnosis results in missed opportunity to use sulfonylureasas 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 fucosylatedN - glycansand hs-CRP are reduced in individuals with HNF1A-MODY. In this study, we examined the potential use of N - glycansand hs-CRP in discriminating individuals with damaging HNF1Aalleles from those without HNF1Avariants in an unselected population of young adults with nonautoimmune diabetes. RESEARCH DESIGN AND METHODS We analyzed the plasma N - glycanprofile, measured hs-CRP, and sequenced HNF1Ain 989 individuals with diabetes diagnosed when younger than age 45, persistent endogenous insulin production, and absence of pancreatic autoimmunity. Systematic assessment of rare HNF1Avariants was performed. RESULTS We identified 29 individuals harboring 25 rare HNF1Aalleles, of which 3 were novel, and 12 (in 16 probands) were considered pathogenic. Antennary fucosylatedN - glycansand hs-CRP were able to differentiate subjects with damaging HNF1Aalleles from those without rare HNF1Aalleles. GlycanGP30 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 HNF1Asequence variants do not cause MODY. N - glycanprofile 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 HNF1Aallele.