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A multigenerational...
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Kettunen, Jarno L.T.Folkhälsan Research Center,Helsinki University Central Hospital,University of Helsinki
(author)
A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY
- Article/chapterEnglish2022
Publisher, publication year, extent ...
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2021-12-24
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Springer Science and Business Media LLC,2022
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12 s.
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LIBRIS-ID:oai:lup.lub.lu.se:90d7e8d1-66fa-4bd6-80ec-08f40a56d076
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https://lup.lub.lu.se/record/90d7e8d1-66fa-4bd6-80ec-08f40a56d076URI
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https://doi.org/10.1007/s00125-021-05631-zDOI
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Language:English
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Summary in:English
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Subject category:art swepub-publicationtype
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Subject category:ref swepub-contenttype
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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.].
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Rantala, ElinaHealth Care and Social Services, Vantaa
(author)
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Dwivedi, Om P.University of Helsinki
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Isomaa, BoFolkhälsan Research Center
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Sarelin, LeenaFolkhälsan Research Center
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Kokko, PaulaUniversity of Helsinki,Folkhälsan Research Center
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Hakaste, LiisaUniversity of Helsinki,Helsinki University Central Hospital,Folkhälsan Research Center
(author)
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Miettinen, Päivi J.University of Helsinki
(author)
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Groop, Leif C.Lund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups,University of Helsinki(Swepub:lu)endo-lgr
(author)
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Tuomi, TiinamaijaLund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups,University of Helsinki,Helsinki University Central Hospital,Folkhälsan Research Center(Swepub:lu)ti8736tu
(author)
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Folkhälsan Research CenterHelsinki University Central Hospital
(creator_code:org_t)
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In:Diabetologia: Springer Science and Business Media LLC65:4, s. 632-6430012-186X1432-0428
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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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