ESPEYB21 12. Type 2 Diabetes, Metabolic Syndrome and Lipids Genetics of T2D in Children and Adolescents (1 abstracts)
12.7. Genetic architecture and biology of youth-onset type 2 diabetes
Kwak SH , Srinivasan S , Chen L , Todd J , Mercader JM , Jensen ET , Divers J , Mottl AK , Pihoker C , Gandica RG , Laffel LM , Isganaitis E , Haymond MW , Levitsky LL , Pollin TI , Florez JC & Flannick J
Progress in Diabetes Genetics in Youth (ProDiGY) consortium.
Nat Metab. 2024 Feb;6(2):226-237. doi:10.1038/s42255-023-00970-0.
Brief Summary: Rare forms of diabetes (‘monogenic diabetes’) are caused by a single rare gene variant, while adult-onset T2D is influenced by thousands of common genetic variants. This study reveals that youth-onset T2D shares some genetic features with both monogenic and typical adult-onset T2D, marked by both common and rare genetic variants
Comment: A significant challenge is understanding why the course of T2D in children and teenagers is more aggressive compared to both adult-onset T2D and T1D in adolescents. A possible explanation may lie in the different genetic backgrounds and biological pathways between these conditions. These authors perform detailed genetic characterization of youth-onset T2D by analysing exome sequences and common variant associations in 3,005 individuals with youth-onset T2D and 9,777 adult controls matched for sex and ethnicity.
Firstly, in exome sequence data, 2.4% of those with youth-onset T2D had monogenic diabetes — arising from a single gene variant - including several individuals who carried variants in either MC4R, a gene strongly linked to monogenic obesity, or HNF1A, linked to monogenic diabetes. This suggests that individuals with youth-onset T2D may need screening for monogenic disease, which will inform appropriate medical treatment.
Next, exome sequences were compared between youth-onset and adult-onset T2D. The the combination of common and rare genetic variants exerts a greater influence on youth-onset T2D risk than adult-onset T2D. Individuals with youth-onset T2D were 3-times more likely to harbor common variants, compared with adults with T2D, and 5-times more likely to harbor rare gene variants. These data indicate that genetics plays a greater role in causing youth-onset T2D than it does in the adult-onset form. Genetic risk factors for youth-onset T2D did not overlap with those for lipodystrophies or T1D.
Finally, the specific mix of gene variants correlated with clinical presentation of youth-onset T2D. For example, those with more common variants showed more features of adult-onset T2D, such as high insulin levels, indicative of insulin resistance.
Volume 21
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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