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

Kettunen, Jarno L.T. ; Rantala, Elina ; Dwivedi, Om P. ; Isomaa, Bo ; Sarelin, Leena ; Kokko, Paula ; Hakaste, Liisa ; Miettinen, Päivi J. ; Groop, Leif C. LU and Tuomi, Tiinamaija LU orcid (2022) In Diabetologia 65(4). p.632-643
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... (More)

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. Graphical abstract: [Figure not available: see fulltext.].

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Contribution to journal
publication status
published
subject
keywords
Age at onset, Glucagon, HNF1A-MODY, Insulin deficiency, Lipolysis, Maturity-onset diabetes of the young (MODY), MODY3, Monogenic diabetes, NEFA, Polygenic risk score for type 2 diabetes
in
Diabetologia
volume
65
issue
4
pages
12 pages
publisher
Springer
external identifiers
  • scopus:85121576972
  • pmid:34951657
ISSN
0012-186X
DOI
10.1007/s00125-021-05631-z
language
English
LU publication?
yes
id
90d7e8d1-66fa-4bd6-80ec-08f40a56d076
date added to LUP
2022-03-23 12:28:57
date last changed
2024-06-08 21:22:40
@article{90d7e8d1-66fa-4bd6-80ec-08f40a56d076,
  abstract     = {{<p>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/m<sup>2</sup> units of BMI, p=2.2 × 10<sup>−4</sup>, 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<sup>−5</sup>). 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. Graphical abstract: [Figure not available: see fulltext.].</p>}},
  author       = {{Kettunen, Jarno L.T. and Rantala, Elina and Dwivedi, Om P. and Isomaa, Bo and Sarelin, Leena and Kokko, Paula and Hakaste, Liisa and Miettinen, Päivi J. and Groop, Leif C. and Tuomi, Tiinamaija}},
  issn         = {{0012-186X}},
  keywords     = {{Age at onset; Glucagon; HNF1A-MODY; Insulin deficiency; Lipolysis; Maturity-onset diabetes of the young (MODY); MODY3; Monogenic diabetes; NEFA; Polygenic risk score for type 2 diabetes}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{632--643}},
  publisher    = {{Springer}},
  series       = {{Diabetologia}},
  title        = {{A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY}},
  url          = {{http://dx.doi.org/10.1007/s00125-021-05631-z}},
  doi          = {{10.1007/s00125-021-05631-z}},
  volume       = {{65}},
  year         = {{2022}},
}