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A multigenerational...
A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY
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- Kettunen, Jarno L.T. (author)
- Helsinki University Central Hospital,University of Helsinki,Folkhälsan Research Center
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- Rantala, Elina (author)
- Health Care and Social Services, Vantaa
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- Dwivedi, Om P. (author)
- University of Helsinki
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- Isomaa, Bo (author)
- Folkhälsan Research Center
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- Sarelin, Leena (author)
- Folkhälsan Research Center
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- Kokko, Paula (author)
- Folkhälsan Research Center,University of Helsinki
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- Hakaste, Liisa (author)
- Folkhälsan Research Center,University of Helsinki,Helsinki University Central Hospital
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- Miettinen, Päivi J. (author)
- University of Helsinki
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- Groop, Leif C. (author)
- Lund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups,University of Helsinki
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- Tuomi, Tiinamaija (author)
- Lund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups,Folkhälsan Research Center,University of Helsinki,Helsinki University Central Hospital
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(creator_code:org_t)
- 2021-12-24
- 2022
- English 12 s.
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 65:4, s. 632-643
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Abstract
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- 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.].
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Keyword
- 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
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Kettunen, Jarno ...
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Rantala, Elina
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Dwivedi, Om P.
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Isomaa, Bo
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Sarelin, Leena
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Kokko, Paula
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Hakaste, Liisa
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Miettinen, Päivi ...
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Groop, Leif C.
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Tuomi, Tiinamaij ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
- Articles in the publication
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Diabetologia
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Lund University