Mapping Novel Glucose tolerance specific QTL in the Collaborative Cross mice

Abstract

Abstract A chronic metabolic illness, type 2 diabetes (T2D) is a polygenic and multifactorial complicated disease. With an estimated 463 million persons aged 20 to 79 having diabetes, the number is expected to rise to 700 million by 2045, creating a significant worldwide health burden. Polygenic variants of diabetes are influenced by environmental variables. Diabetes polygenic variants frequently run in families. T2D is regarded as a silent illness that can advance for years before being diagnosed. Numerous metabolic issues are noticed once T2D is diagnosed, either as comorbidities or as side effects. Finding genetic markers for T2D and metabolic syndrome in groups with similar environmental exposure is therefore essential to understanding the mechanism of such complex characteristic illnesses. So herein, we demonstrated the exclusive use of the collaborative cross (CC) mouse reference population to identify novel quantitative trait loci (QTL) and, subsequently, suggested genes associated with host glucose tolerance in response to a high-fat diet. In the current study, we used 539 mice from 60 different CC lines. The diabetogenic effect in response to high-fat dietary challenge was measured by the intraperitoneal glucose tolerance test (IPGTT) after 12 weeks of dietary challenge. Data analysis was performed using a statistical software package IBM SPSS Statistic 23. Using the mouse genome informatics (MGI) database resource enabled us to examine the reported QTL in detail for genetic features related to glucose metabolism. Afterward, the total area under the curve (AUC0-180) of the glucose clearance was computed and utilized as a marker for the presence and severity of diabetes. The observed AUC0-180 averages for males and females were 51267.5 and 36537.5 mg/dL, respectively, representing a 1.4-fold difference in favor of females with lower AUC0-180 indicating adequate glucose clearance. The AUC0-180 mean differences between the sexes within each specific CC line varied widely within the CC population. A total of 46 new QTL, designated as T2DSL and its number, for Type 2 Diabetes Specific Locus and its number, were identified during our study, among which 19 QTL are novel. The interval locations of these novel QTL have not been found in any other previously identified QTL. The remaining 27 QTL observed during our study have been fine mapped. As far as the genome-wide significance is concerned, three sets of QTL were identified during our entire study. The first group is the one which had a 50% of genome-wide significance, the second group is of 90%, and the third group had a 95% of genome-wide significance. Further, our study showed a complex pattern of haplotype effects of the founders, with the wild-derived strains (mainly PWK) playing a significant role in the increase of AUC values.