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

Abstract

OBJECTIVEMaturity-onset diabetes of the young (MODY) due to variants in HNF1A 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 N-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 N-glycans and hs-CRP in discriminating individuals with damaging HNF1A alleles from those without HNF1A variants in an unselected population of young adults with nonautoimmune diabetes. RESEARCH DESIGN AND METHODSWe analyzed the plasma N-glycan profile, measured hs-CRP, and sequenced HNF1A in 989 individuals with diabetes diagnosed when younger than age 45, persistent endogenous insulin production, and absence of pancreatic autoimmunity. Systematic assessment of rare HNF1A variants was performed. RESULTSWe identified 29 individuals harboring 25 rare HNF1A alleles, of which 3 were novel, and 12 (in 16 probands) were considered pathogenic. Antennary fucosylated Nglycans and hs-CRP were able to differentiate subjects with damaging HNF1A alleles from those without rare HNF1A 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). CONCLUSIONSHalf of rare HNF1A sequence variants do not cause MODY. N-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 HNF1A allele.Although a number of genes are implicated in monogenic diabetes, maturity-onset diabetes of the young (MODY) due to variants in HNF1A (HNF1A-MODY) is the most frequent form in adults (1) and has a significant effect on management when the diagnosis is made. Common clinical criteria for selecting individuals for genetic testing for MODY include diabetes onset younger than 25 years of age, preserved

Altered N‐glycosylation profiles as potential biomarkers and drug targets in diabetes

“…Studies of N-glycosylation changes have demonstrated their potential for identifying individuals at an increased risk of type 2 diabetes development [39], indicating that interindividual variation in protein glycosylation might be a novel risk factor in diabetes. Furthermore, it has been shown that it is possible to distinguish individuals with different types of diabetes based on their N-glycome data, as it is the case for the HNF1A-MODY and its differentiation from other common and rare types of diabetes [38,42]. N-glycan branching on T cells has been implicated in the development of type 1 diabetes, and N-glycan branching on glucose transporter has been implicated in the development of type 2 diabetes [23,43,44,73,105].…”

“…Both antennary fucosylated N‐glycans and hs‐CRP enabled differentiation of individuals with damaging HNF1A alleles; both biomarkers performed better in selecting subjects for genetic testing than classical clinical criteria or the MODY probability calculator . These results imply that it may be possible to identify individuals with a high risk of having damaging HNF1A allele based on glycan biomarkers .…”

“…Overview of implicated N-glycans and glycosyltransferase genes with proposed mechanism for the pathogenesis of different types of diabetes. Risk factor; it was demonstrated that HNF1A inhibits expression of FUT8 and thus formation of core fucosylated N-glycans and activates fucosyltransferases involved in the formation of antennary fucosylated N-glycans (FUT3, -5, -6) which are decreased upon loss-offunction of HNF1A [30,38,42] Gestational diabetes N-glycans with sialic acid, fucose, and mannose…”

Homozygous Hypomorphic HNF1A Alleles Are a Novel Cause of Young-Onset Diabetes and Result in Sulfonylurea-Sensitive Diabetes

“…We assessed predicted pathogenicity using established in silico tools, in line with the American College of Medical Genetics classification (10) and as previously described (11). For structural analysis, we used FoldX (12), introducing variants p.A251T and a nearby MODY-causing mutation, p.V246 L (13), into the structure of the HNF1A DNA binding domain complexed with DNA (Research Collaboratory for Structural Bioinformatics Protein Data Bank identifier 1IC8) (14).…”

“…The impact of p.A251T on HNF1A function was assessed by using a suite of in vitro assays, as described previously (11). This impact on function was compared with that of wild-type HNF1A and two DNA binding domain mutations that cause MODY.…”