Genetic linkage of oxidative stress with cardiometabolic traits in an intercross derived from hyperlipidemic mouse strains

Fuller, Daniela; Grainger, Andrew T.; Manichaikul, Ani; Shi, Weibin

doi:10.1016/j.atherosclerosis.2019.11.034

Cited by 15 publications

(16 citation statements)

References 52 publications

(69 reference statements)

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“…Insulin resistance and associated reductions in cardiac insulin metabolic signaling are major factors for the development of heart failure [ 47 ]. Western diet-induced hyperglycemia and hyperlipidemia are major drivers of oxidative stress and systemic inflammation [ 26 , 48 ], which are major factors contributing to the development of cardiac insulin resistance [ 47 ]. Thus, it is intriguing to speculate that cardiac insulin resistance may act beyond changes in the plasma glycemic state during the development of type 2 diabetes-accelerated atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

“…QTL mapping was performed using R/qtl and Map Manager QTXb17, as reported in [ 26 , 27 , 28 ]. To define genome-wide LOD (logarithm of odds) score thresholds for significant and suggestive linkage with each trait, 1000 permutations were run at a 1-Mb interval across the genome.…”

Section: Methodsmentioning

confidence: 99%

“…When overlapping QTL for two traits were detected, additional analysis was performed to infer causal relationships between the traits, as previously described [ 26 , 31 ]. Briefly, residuals were generated from regression analysis of two affected traits and then subject to genome-wide QTL mapping with the same algorithm previously used for the identification of the overlapped QTL.…”

Section: Methodsmentioning

confidence: 99%

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Genetic Connection between Hyperglycemia and Carotid Atherosclerosis in Hyperlipidemic Mice

Shi

Chagari

et al. 2022

Genes

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Type 2 diabetes (T2D) is a major risk for atherosclerosis and its complications. Apoe-null (Apoe−/−) mouse strains exhibit a wide range of variations in susceptibility to T2D and carotid atherosclerosis, with the latter being a major cause of ischemic stroke. To identify genetic connections between T2D and carotid atherosclerosis, 145 male F2 mice were generated from LP/J and BALB/cJ Apoe−/− mice and fed 12 weeks of a Western diet. Atherosclerotic lesions in the carotid arteries, fasting, and non-fasting plasma glucose levels were measured, and genotyping was performed using miniMUGA arrays. Two significant QTL (quantitative trait loci) on chromosomes (Chr) 6 and 15 were identified for carotid lesions. The Chr15 QTL coincided precisely with QTL Bglu19 for fasting and non-fasting glucose levels. Carotid lesion sizes showed a trend toward correlation with fasting and non-fasting glucose levels in F2 mice. The Chr15 QTL for carotid lesions was suppressed after excluding the influence from fasting or non-fasting glucose. Likely candidate genes for the causal association were Tnfrsf11b, Deptor, and Gsdmc2. These results demonstrate a causative role for hyperglycemia in the development of carotid atherosclerosis in hyperlipidemic mice.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Genetic Connection between Hyperglycemia and Carotid Atherosclerosis in Hyperlipidemic Mice

Shi

Chagari

et al. 2022

Genes

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“…Its positive correlation with plasma glucose levels suggests that HDL lost its anti-diabetic function when the F2 mice developed severe dyslipidemia on the Western diet. Indeed, a high fat diet and subsequent dyslipidemia induce oxidative stress and inflammation [ 48 , 49 ], which can alter the structure and function of HDL, making it dysfunctional [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic Evidence for a Causal Relationship between Hyperlipidemia and Type 2 Diabetes in Mice

Shi

Tang

et al. 2022

IJMS

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Dyslipidemia is considered a risk factor for type 2 diabetes (T2D), yet studies with statins and candidate genes suggest that circulating lipids may protect against T2D development. Apoe-null (Apoe-/-) mouse strains develop spontaneous dyslipidemia and exhibit a wide variation in susceptibility to diet-induced T2D. We thus used Apoe-/- mice to elucidate phenotypic and genetic relationships of circulating lipids with T2D. A male F2 cohort was generated from an intercross between LP/J and BALB/cJ Apoe-/- mice and fed 12 weeks of a Western diet. Fasting, non-fasting plasma glucose, and lipid levels were measured and genotyping was performed using miniMUGA arrays. We uncovered a major QTL near 60 Mb on chromosome 15, Nhdlq18, which affected non-HDL cholesterol and triglyceride levels under both fasting and non-fasting states. This QTL was coincident with Bglu20, a QTL that modulates fasting and non-fasting glucose levels. The plasma levels of non-HDL cholesterol and triglycerides were closely correlated with the plasma glucose levels in F2 mice. Bglu20 disappeared after adjustment for non-HDL cholesterol or triglycerides. These results demonstrate a causative role for dyslipidemia in T2D development in mice.

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“…Statistical Analysis. QTL analysis was performed using R/qtl and Map Manager QTX as previously reported (Fuller et al 2019) , (Grainger et al 2017) (Garrett 3rd et al 2017). One thousand permutations were run to define the genome-wide LOD (logarithm of odds) score threshold for significant or suggestive linkage to a particular trait.…”

Section: Methodsmentioning

confidence: 99%

Regional Variation in Genetic Control of Atherosclerosis in Hyperlipidemic Mice

Jones¹,

An²,

Shi³

et al. 2020

G3 Genes|Genomes|Genetics

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Atherosclerosis is a polygenic disorder that often affects multiple arteries. Carotid arteries are common sites for evaluating subclinical atherosclerosis, and aortic root is the standard site for quantifying atherosclerosis in mice. We compared genetic control of atherosclerosis between the two sites in the same cohort derived from two phenotypically divergent Apoe-null (Apoe-/-) mouse strains. Female F2 mice were generated from C57BL/6 (B6) and C3H/He (C3H) Apoe-/- mice and fed 12 weeks of Western diet. Atherosclerotic lesions in carotid bifurcation and aortic root and plasma levels of fasting lipids and glucose were measured. 153 genetic markers across the genome were typed. All F2 mice developed aortic atherosclerosis, while 1/5 formed no or little carotid lesions. Genome-wide scans revealed 3 significant loci on chromosome (Chr) 1, Chr15, 6 suggestive loci for aortic atherosclerosis, 2 significant loci on Chr6, Chr12, and 6 suggestive loci for carotid atherosclerosis. Only 2 loci for aortic lesions showed colocalization with loci for carotid lesions. Carotid lesion sizes were moderately correlated with aortic lesion sizes (r=0.303; p=4.6E-6), but they showed slight or no association with plasma HDL, non-HDL cholesterol, triglyceride, or glucose levels among F2 mice. Bioinformatics analyses prioritized Cryge as a likely causal gene for Ath30, Cdh6 and Dnah5 as causal genes for Ath22. Our data demonstrate vascular site-specific effects of genetic factors on atherosclerosis in the same animals and highlight the need to extend studies of atherosclerosis to sites beyond aortas of mice.

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Genetic linkage of oxidative stress with cardiometabolic traits in an intercross derived from hyperlipidemic mouse strains

Cited by 15 publications

References 52 publications

Genetic Connection between Hyperglycemia and Carotid Atherosclerosis in Hyperlipidemic Mice

Genetic Connection between Hyperglycemia and Carotid Atherosclerosis in Hyperlipidemic Mice

Genetic Evidence for a Causal Relationship between Hyperlipidemia and Type 2 Diabetes in Mice

Regional Variation in Genetic Control of Atherosclerosis in Hyperlipidemic Mice

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