Polygenic Control of Carotid Atherosclerosis in a BALB/cJ × SM/J Intercross and a Combined Cross Involving Multiple Mouse Strains
Atherosclerosis in the carotid arteries is a major cause of ischemic stroke, which accounts for 85% of all stroke cases. Genetic factors contributing to carotid atherosclerosis remain poorly understood. The aim of this study was to identify chromosomal regions harboring genes contributing to carotid...
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| Format: | Article |
| Language: | English |
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Oxford University Press
2017-02-01
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| Series: | G3: Genes, Genomes, Genetics |
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| Online Access: | http://g3journal.org/lookup/doi/10.1534/g3.116.037879 |
| _version_ | 1818449386358702080 |
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| author | Andrew T. Grainger Michael B. Jones Mei-Hua Chen Weibin Shi |
| author_facet | Andrew T. Grainger Michael B. Jones Mei-Hua Chen Weibin Shi |
| author_sort | Andrew T. Grainger |
| collection | DOAJ |
| description | Atherosclerosis in the carotid arteries is a major cause of ischemic stroke, which accounts for 85% of all stroke cases. Genetic factors contributing to carotid atherosclerosis remain poorly understood. The aim of this study was to identify chromosomal regions harboring genes contributing to carotid atherosclerosis in mice. From an intercross between BALB/cJ (BALB) and SM/J (SM) apolipoprotein E-deficient (Apoe−/−) mice, 228 female F2 mice were generated and fed a “Western” diet for 12 wk. Atherosclerotic lesion sizes in the left carotid artery were quantified. Across the entire genome, 149 genetic markers were genotyped. Quantitative trait locus (QTL) analysis revealed eight loci for carotid lesion sizes, located on chromosomes 1, 5, 12, 13, 15, 16, and 18. Combined cross-linkage analysis using data from this cross, and two previous F2 crosses derived from BALB, C57BL/6J and C3H/HeJ strains, identified five significant QTL on chromosomes 5, 9, 12, and 13, and nine suggestive QTL for carotid atherosclerosis. Of them, the QTL on chromosome 12 had a high LOD score of 9.95. Bioinformatic analysis prioritized Arhgap5, Akap6, Mipol1, Clec14a, Fancm, Nin, Dact1, Rtn1, and Slc38a6 as probable candidate genes for this QTL. Atherosclerotic lesion sizes were significantly correlated with non-HDL cholesterol levels (r = 0.254; p = 0.00016) but inversely correlated with HDL cholesterol levels (r = −0.134; p = 0.049) in the current cross. Thus, we demonstrated the polygenic control of carotid atherosclerosis in mice. The correlations of carotid lesion sizes with non-HDL and HDL suggest that genetic factors exert effects on carotid atherosclerosis partially through modulation of lipoprotein homeostasis. |
| first_indexed | 2024-12-14T20:34:35Z |
| format | Article |
| id | doaj.art-705d2e1cb4fa4f3aafba9e1f301f7a7f |
| institution | Directory Open Access Journal |
| issn | 2160-1836 |
| language | English |
| last_indexed | 2024-12-14T20:34:35Z |
| publishDate | 2017-02-01 |
| publisher | Oxford University Press |
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| series | G3: Genes, Genomes, Genetics |
| spelling | doaj.art-705d2e1cb4fa4f3aafba9e1f301f7a7f2022-12-21T22:48:27ZengOxford University PressG3: Genes, Genomes, Genetics2160-18362017-02-017273173910.1534/g3.116.03787935Polygenic Control of Carotid Atherosclerosis in a BALB/cJ × SM/J Intercross and a Combined Cross Involving Multiple Mouse StrainsAndrew T. GraingerMichael B. JonesMei-Hua ChenWeibin ShiAtherosclerosis in the carotid arteries is a major cause of ischemic stroke, which accounts for 85% of all stroke cases. Genetic factors contributing to carotid atherosclerosis remain poorly understood. The aim of this study was to identify chromosomal regions harboring genes contributing to carotid atherosclerosis in mice. From an intercross between BALB/cJ (BALB) and SM/J (SM) apolipoprotein E-deficient (Apoe−/−) mice, 228 female F2 mice were generated and fed a “Western” diet for 12 wk. Atherosclerotic lesion sizes in the left carotid artery were quantified. Across the entire genome, 149 genetic markers were genotyped. Quantitative trait locus (QTL) analysis revealed eight loci for carotid lesion sizes, located on chromosomes 1, 5, 12, 13, 15, 16, and 18. Combined cross-linkage analysis using data from this cross, and two previous F2 crosses derived from BALB, C57BL/6J and C3H/HeJ strains, identified five significant QTL on chromosomes 5, 9, 12, and 13, and nine suggestive QTL for carotid atherosclerosis. Of them, the QTL on chromosome 12 had a high LOD score of 9.95. Bioinformatic analysis prioritized Arhgap5, Akap6, Mipol1, Clec14a, Fancm, Nin, Dact1, Rtn1, and Slc38a6 as probable candidate genes for this QTL. Atherosclerotic lesion sizes were significantly correlated with non-HDL cholesterol levels (r = 0.254; p = 0.00016) but inversely correlated with HDL cholesterol levels (r = −0.134; p = 0.049) in the current cross. Thus, we demonstrated the polygenic control of carotid atherosclerosis in mice. The correlations of carotid lesion sizes with non-HDL and HDL suggest that genetic factors exert effects on carotid atherosclerosis partially through modulation of lipoprotein homeostasis.http://g3journal.org/lookup/doi/10.1534/g3.116.037879plaquevesselslinkage mappinghaplotype analysisdyslipidemia |
| spellingShingle | Andrew T. Grainger Michael B. Jones Mei-Hua Chen Weibin Shi Polygenic Control of Carotid Atherosclerosis in a BALB/cJ × SM/J Intercross and a Combined Cross Involving Multiple Mouse Strains G3: Genes, Genomes, Genetics plaque vessels linkage mapping haplotype analysis dyslipidemia |
| title | Polygenic Control of Carotid Atherosclerosis in a BALB/cJ × SM/J Intercross and a Combined Cross Involving Multiple Mouse Strains |
| title_full | Polygenic Control of Carotid Atherosclerosis in a BALB/cJ × SM/J Intercross and a Combined Cross Involving Multiple Mouse Strains |
| title_fullStr | Polygenic Control of Carotid Atherosclerosis in a BALB/cJ × SM/J Intercross and a Combined Cross Involving Multiple Mouse Strains |
| title_full_unstemmed | Polygenic Control of Carotid Atherosclerosis in a BALB/cJ × SM/J Intercross and a Combined Cross Involving Multiple Mouse Strains |
| title_short | Polygenic Control of Carotid Atherosclerosis in a BALB/cJ × SM/J Intercross and a Combined Cross Involving Multiple Mouse Strains |
| title_sort | polygenic control of carotid atherosclerosis in a balb cj sm j intercross and a combined cross involving multiple mouse strains |
| topic | plaque vessels linkage mapping haplotype analysis dyslipidemia |
| url | http://g3journal.org/lookup/doi/10.1534/g3.116.037879 |
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