Identification of Novel Potential Type 2 Diabetes Genes Mediating β-Cell Loss and Hyperglycemia Using Positional Cloning.

Heja Aga,Tanja Schallschmidt,Nicole Hallahan,Anne Kamitz,Gudrun Brockmann,Hadi Al-Hasani,Pascal Gottmann,Gunnar Schulze,Markus Jaehnert,Hans-Georg Joost,Sandra Lebek,Alexandra Chadt,Annette Schürmann,Danny Arends,Heike Vogel,Sophie Osburg

doi:10.3389/fgene.2020.567191

Abstract

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/DBA on 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 β-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, and Calr4) 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 QTL Nidd/DBA. Future studies are necessary to understand the exact role of the different candidates in β-cell function and their contribution in maintaining glycemic control.

Highlights

Type 2 diabetes (T2D) arises from a complex interplay of multiple genetic and environmental factors that contribute to inadequate insulin secretion, insulin resistance, or both (American Diabetes Association, 2005; Tallapragada et al, 2015)
Male parental New Zealand obese (NZO) and DBA mice were characterized on a 45% kcal high-fat diet (HFD) until the age of 16 weeks
The mice were phenotyped for metabolic traits relating to obesity and diabetes according to a standardized protocol that was established for the DZD collective diabetes cross (Vogel et al, 2018)

Summary

Introduction

Type 2 diabetes (T2D) arises from a complex interplay of multiple genetic and environmental factors that contribute to inadequate insulin secretion, insulin resistance, or both (American Diabetes Association, 2005; Tallapragada et al, 2015). Genetic predisposition accounts for differences in T2D susceptibility; so called “protective” gene variants mitigate the progression of the disease either through increased insulin sensitivity or secretion, while susceptibility variants can otherwise predispose an individual to β-cell failure and loss (McCarthy and Zeggini, 2009). Genomewide association studies (GWAS) typically utilize genetic variants in the human population in the search for novel pathogenic genes. Despite the enormous numbers of human participants recruited for GWAS, diversity in the genome and environmental influences typically confound datasets, for complex traits such as blood glucose or insulin concentrations. Carefully controlled animal studies which allow for the precise manipulation of both environment and genetic variance remain a critical tool in T2D research

Objectives

Methods

Results

Discussion

Conclusion