Diabetic patients have an increased risk of developing atherosclerosis and its complications compared with non-diabetic individuals, and individuals with atherosclerosis frequently have type 2 diabetes mellitus (T2DM). Both diseases have a strong genetic component and show familial clustering. A critical unsolved question is whether there are genetic connections between common forms of atherosclerosis and T2DM? We have found that apolipoprotein E-deficient (Apoe-/-) mice on the C57BL/6 (B6) background develop T2DM when fed a Western diet. In contrast, atherosclerosis- resistant BALB/c (BALB) Apoe-/- mice are resistant to it. We performed quantitative trait locus (QTL) analysis on an intercross derived from B6.Apoe-/- and BALB.Apoe-/- mice and found that the QTL for atherosclerosis coincided with the QTL for hyperglycemia in the middle portion of chromosome 5.
In Aim 1, we will conduct fine mapping for this region by making congenic strains. Speed-congenic lines will be generated by introducing the chromosome 5 region harboring the QTLs from BALB.Apoe-/- into B6.Apoe-/- mice, and the resultant congenic strains will be analyzed for genetic effects on atherosclerosis and T2DM development. Subcongenic strains will be constructed to determine whether atherosclerosis and hyperglycemia are controlled by the same causal gene or two linked but unique genes in the region.
In Aim 2, we will conduct functional study to test Hnf1a as a promising candidate gene for the chromosome 5 QTLs. Polymorphisms in the Hnf1a locus are associated with coronary heart disease and T2DM risk in humans. There are multiple SNPs within the Hnf1a gene between B6 and BALB with one SNP in exon 9 leading to amino acid substitution. Recent genome- wide association studies have identified new loci that are implicated in ?-cell development and function, highlighting insulin secretion in the development of T2DM in humans. B6.Apoe-/- mice exhibit significant defects in ? cell function but have no significant defects in insulin sensitivity. Significant macrophage infiltration in the islets has been observed when T2DM occurs in these animals.
In Aim 3, we will use this unique model to investigate whether inhibition of islet inflammation would prevent diabetes and ameliorate atherosclerosis in B6.Apoe-/- mice. Taken together, this work will uncover genetic connections between the two important diseases.
Atherosclerosis is the primary cause of heart attack, stroke, and peripheral arterial disease, which account for ~40% of all death in the United States, and type 2 diabetes is one of the most common metabolic diseases, affecting over 20 million individuals in the USA. The objective of this proposal is to search for genes and pathways that connect the two disorders. Findings from this work may lead to revelation of new targets for therapeutic intervention and development of new prevention strategies.
|Garrett 3rd, Norman E; Grainger, Andrew T; Li, Jing et al. (2017) Genetic analysis of a mouse cross implicates an anti-inflammatory gene in control of atherosclerosis susceptibility. Mamm Genome 28:90-99|
|Grainger, Andrew T; Jones, Michael B; Chen, Mei-Hua et al. (2017) Polygenic Control of Carotid Atherosclerosis in a BALB/cJ × SM/J Intercross and a Combined Cross Involving Multiple Mouse Strains. G3 (Bethesda) 7:731-739|
|Grainger, Andrew T; Jones, Michael B; Li, Jing et al. (2016) Data on genetic analysis of atherosclerosis identifies a major susceptibility locus in the major histocompatibility complex of mice. Data Brief 9:1067-1069|
|Shi, Weibin; Wang, Qian; Choi, Wonseok et al. (2016) Mapping and Congenic Dissection of Genetic Loci Contributing to Hyperglycemia and Dyslipidemia in Mice. PLoS One 11:e0148462|
|Wang, Qian; Grainger, Andrew T; Manichaikul, Ani et al. (2015) Genetic linkage of hyperglycemia and dyslipidemia in an intercross between BALB/cJ and SM/J Apoe-deficient mouse strains. BMC Genet 16:133|
|Zhang, Yi; Kundu, Bijoy; Zhong, Min et al. (2015) PET imaging detection of macrophages with a formyl peptide receptor antagonist. Nucl Med Biol 42:381-6|
|Liu, Shuiping; Li, Jing; Chen, Mei-Hua et al. (2015) Variation in Type 2 Diabetes-Related Phenotypes among Apolipoprotein E-Deficient Mouse Strains. PLoS One 10:e0120935|
|Zhou, Wei; Chen, Mei-Hua; Shi, Weibin (2015) Influence of phthalates on glucose homeostasis and atherosclerosis in hyperlipidemic mice. BMC Endocr Disord 15:13|
|Banizs, Anna B; Huang, Tao; Dryden, Kelly et al. (2014) In vitro evaluation of endothelial exosomes as carriers for small interfering ribonucleic acid delivery. Int J Nanomedicine 9:4223-30|