Abstract
Aims/hypothesisSystematic studies on the phenotypic consequences of variants causal of HNF1A-MODY are rare. Our aim was to assess the phenotype of carriers of a single HNF1A variant and genetic and clinical factors affecting the clinical spectrum.MethodsWe conducted a family-based multigenerational study by comparing heterozygous carriers of the HNF1A p.(Gly292fs) variant with the non-carrier relatives irrespective of diabetes status. During more than two decades, 145 carriers and 131 non-carriers from 12 families participated in the study, and 208 underwent an OGTT at least once. We assessed the polygenic risk score for type 2 diabetes, age at onset of diabetes and measures of body composition, as well as plasma glucose, serum insulin, proinsulin, C-peptide, glucagon and NEFA response during the OGTT.ResultsHalf of the carriers remained free of diabetes at 23 years, one-third at 33 years and 13% even at 50 years. The median age at diagnosis was 21 years (IQR 17–35). We could not identify clinical factors affecting the age at conversion; sex, BMI, insulin sensitivity or parental carrier status had no significant effect. However, for 1 SD unit increase of a polygenic risk score for type 2 diabetes, the predicted age at diagnosis decreased by 3.2 years. During the OGTT, the carriers had higher levels of plasma glucose and lower levels of serum insulin and C-peptide than the non-carriers. The carriers were also leaner than the non-carriers (by 5.0 kg, p=0.012, and by 2.1 kg/m2 units of BMI, p=2.2 × 10−4, using the first adult measurements) and, possibly as a result of insulin deficiency, demonstrated higher lipolytic activity (with medians of NEFA at fasting 621 vs 441 μmol/l, p=0.0039; at 120 min during an OGTT 117 vs 64 μmol/l, p=3.1 × 10−5).Conclusions/interpretationThe most common causal variant of HNF1A-MODY, p.(Gly292fs), presents not only with hyperglycaemia and insulin deficiency, but also with increased lipolysis and markedly lower adult BMI. Serum insulin was more discriminative than C-peptide between carriers and non-carriers. A considerable proportion of carriers develop diabetes after young adulthood. Even among individuals with a monogenic form of diabetes, polygenic risk of diabetes modifies the age at onset of diabetes.Graphical abstract
Highlights
Subtypes of monogenic diabetes called Maturity-onset diabetes of the young (MODY) result from rare single-gene variants
Since 2014, the FINNMODY study has co-ordinated the study of MODY families from the Botnia Study and recruited individuals with suspected or diagnosed MODY through: (1) advertisements directed at clinicians and patients; (2) directly contacting diabetes clinics and primary care physicians
As hyperglucagonaemia has been reported in individuals with type 1 and 2 diabetes as well as in HNF1A-MODY [32, 56, 57], we evaluated a possible relationship between lipolysis and excess glucagon, despite only vague previous data [58]
Summary
Subtypes of monogenic diabetes called MODY result from rare single-gene variants (reviewed in [1, 2]). MODY was initially defined as an autosomal dominant young-onset nonobese form of non-insulin-dependent diabetes [3, 4]. These features determining patient selection for the first gene discovery studies [5,6,7,8] still guide diagnostic testing [9, 10]. Carriers of pathogenic MODY variants without diabetes or typical phenotype have often not been included in studies. Comparing carriers only with patients with polygenic forms of diabetes can lead to misinterpretations regarding the monogenic variant. Individuals with HNF1AMODY are more sensitive to sulfonylureas than those with type 2 diabetes [17], their beta cell response to sulfonylureas is similar to that in control individuals without diabetes [15, 18], rendering it unlikely that the MODY variant directly affects sulfonylurea sensitivity
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