A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY

Abstract

Aims/hypothesis: Systematic 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.

Methods: We 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.

Results: Half 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/interpretation: The 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.

Keywords: Age at onset; Glucagon; HNF1A-MODY; Insulin deficiency; Lipolysis; MODY3; Maturity-onset diabetes of the young (MODY); Monogenic diabetes; NEFA; Polygenic risk score for type 2 diabetes.

Fig. 1

The survival analysis shows the proportion of carriers (solid red line) and non-carriers (dashed blue line) of HNF1A p.(Gly292fs) not diagnosed with diabetes. As compared with non-carriers, the carriers had an HR of 21 for diabetes (95% CI 12, 37; p<2×10^-16)

Fig. 2

First adult BMI illustrated by a boxplot and overlapping bean plot for female and male carriers and non-carriers of the HNF1A p.(Gly292fs) variant. Each observation is plotted by a short horizontal line (double width symbolises two samples with the same value, etc.); the dashed grey lines represent sex-specific medians. Outliers are marked with 'X'

Fig. 3

First measurements in adult age of NEFA at fasting (a) and at 120 min during an OGTT (b) in carriers and non-carriers of the HNF1A p.(Gly292fs) variant. Each observation is plotted by a short horizontal line (double width symbolises two samples with the same value, etc.); the dashed grey lines represent medians. Also, a sex- and age-adjusted log-transformed linear regression model implied lower NEFA levels among the carriers compared with the non-carriers both at fasting (p=0.00050) and at 120 min (p=2.2×10^-7) after excluding the outliers marked with ‘X’. One non-carrier outlier with fasting NEFA >2000 μmol/l was excluded from the figure

Fig. 4

Fasting glucagon plotted against 120 min glucagon in 43 carriers (red square boxes) and 38 non-carriers (blue circles) of the HNF1A p.(Gly292fs) variant, with a regression line for the combined group (p=4.5×10^-12, r² 0.45). fS-glucagon, fasting serum glucagon; S-glucagon, serum glucagon