Heja Aga-Barfknecht, Nicole Hallahan, Pascal Gottmann, Markus Jähnert, Sophie Osburg, Gunnar Schulze, Anne Kamitz, Danny Arends, Gudrun Brockmann, Tanja Schallschmidt, Sandra Lebek, Alexandra Chadt, Hadi Al-Hasani, Hans-Georg Joost, Annette Schürmann, Heike Vogel
- Type 2 diabetes (T2D) is a complex metabolic disease regulated by an interaction of genetic predisposition and environmental factors. To understand the genetic contribution in the development of diabetes, mice varying in their disease susceptibility were crossed with the obese and diabetes-prone New Zealand obese (NZO) mouse. Subsequent whole-genome sequence scans revealed one major quantitative trait loci (QTL),Nidd/DBAon chromosome 4, linked to elevated blood glucose and reduced plasma insulin and low levels of pancreatic insulin. Phenotypical characterization of congenic mice carrying 13.6 Mbp of the critical fragment of DBA mice displayed severe hyperglycemia and impaired glucose clearance at week 10, decreased glucose response in week 13, and loss of beta-cells and pancreatic insulin in week 16. To identify the responsible gene variant(s), further congenic mice were generated and phenotyped, which resulted in a fragment of 3.3 Mbp that was sufficient to induce hyperglycemia. By combining transcriptome analysis and haplotypeType 2 diabetes (T2D) is a complex metabolic disease regulated by an interaction of genetic predisposition and environmental factors. To understand the genetic contribution in the development of diabetes, mice varying in their disease susceptibility were crossed with the obese and diabetes-prone New Zealand obese (NZO) mouse. Subsequent whole-genome sequence scans revealed one major quantitative trait loci (QTL),Nidd/DBAon chromosome 4, linked to elevated blood glucose and reduced plasma insulin and low levels of pancreatic insulin. Phenotypical characterization of congenic mice carrying 13.6 Mbp of the critical fragment of DBA mice displayed severe hyperglycemia and impaired glucose clearance at week 10, decreased glucose response in week 13, and loss of beta-cells and pancreatic insulin in week 16. To identify the responsible gene variant(s), further congenic mice were generated and phenotyped, which resulted in a fragment of 3.3 Mbp that was sufficient to induce hyperglycemia. By combining transcriptome analysis and haplotype mapping, the number of putative responsible variant(s) was narrowed from initial 284 to 18 genes, including gene models and non-coding RNAs. Consideration of haplotype blocks reduced the number of candidate genes to four (Kti12,Osbpl9,Ttc39a, andCalr4) as potential T2D candidates as they display a differential expression in pancreatic islets and/or sequence variation. In conclusion, the integration of comparative analysis of multiple inbred populations such as haplotype mapping, transcriptomics, and sequence data substantially improved the mapping resolution of the diabetes QTLNidd/DBA. Future studies are necessary to understand the exact role of the different candidates in beta-cell function and their contribution in maintaining glycemic control.…
MetadatenAuthor details: | Heja Aga-BarfknechtORCiDGND, Nicole Hallahan, Pascal Gottmann, Markus JähnertORCiD, Sophie Osburg, Gunnar Schulze, Anne Kamitz, Danny Arends, Gudrun Brockmann, Tanja Schallschmidt, Sandra Lebek, Alexandra ChadtORCiDGND, Hadi Al-HasaniGND, Hans-Georg Joost, Annette SchürmannORCiDGND, Heike VogelORCiDGND |
---|
DOI: | https://doi.org/10.3389/fgene.2020.567191 |
---|
ISSN: | 1664-8021 |
---|
Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/33133152 |
---|
Title of parent work (English): | Frontiers in genetics |
---|
Publisher: | Frontiers Media |
---|
Place of publishing: | Lausanne |
---|
Publication type: | Article |
---|
Language: | English |
---|
Date of first publication: | 2020/09/30 |
---|
Publication year: | 2020 |
---|
Release date: | 2022/10/04 |
---|
Tag: | beta-cell loss; haplotype; insulin; positional cloning; transcriptomics; type 2 diabetes |
---|
Volume: | 11 |
---|
Article number: | 567191 |
---|
Number of pages: | 11 |
---|
Funding institution: | German Ministry of Education and Research (BMBF: DZD)Federal Ministry of; Education & Research (BMBF) [82DZD00302] |
---|
Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft |
---|
DDC classification: | 5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften |
---|
Peer review: | Referiert |
---|
Publishing method: | Open Access / Gold Open-Access |
---|
License (German): | CC-BY - Namensnennung 4.0 International |
---|