{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:55:00Z","timestamp":1790916900859,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 DK116768"],"award-info":[{"award-number":["R01 DK116768"]}]},{"award":["R01 DK116768"],"award-info":[{"award-number":["R01 DK116768"]}],"id":[{"id":"https:\/\/ror.org\/045016w83","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Overweight and obese individuals often exhibit lower mortality rates or better prognoses than lean or normal-weight individuals with stroke and other diseases, a phenomenon called the \u201cobesity paradox\u201d. Carotid atherosclerosis is a major cause of ischemic stroke, and body weight serves as a reliable surrogate for adiposity in adult mice. Phenotypic and genetic connections of carotid atherosclerosis with body weight were evaluated in 299 F2 mice (154 females, 145 males) derived from BALB\/cJ and LP\/J Apoe knockout (Apoe-\/-) mice. F2 mice were fed a Western diet for 12 weeks. Atherosclerotic lesion sizes in left carotid arteries, body weight, coat color, plasma lipids, glucose, small dense LDL ApoB, and malondialdehyde were measured, and 11,000 single nucleotide polymorphism (SNP) markers were genotyped. Carotid lesion sizes were inversely correlated with body weight in both sexes. Genome-wide scans identified two significant quantitative trait loci (QTLs) for carotid atherosclerosis on chromosomes (Chr) 6 and 15 in an additive sex model, and five QTLs on Chr 6, 7, 12, 13, and 15 in an interactive sex model. Adjusting for body weight variation downgraded Chr 15 QTL (Cath5) in both models, whereas other QTLs upgraded in the additive sex model and downgraded in the interactive sex model. Human syntenic region of Cath5 associated with carotid intima-medial thickness (cIMT) and waist-to-hip ratio (WHR). These findings indicate that the obesity paradox in carotid atherosclerosis is partially driven by shared genetic components that exert opposing effects on adiposity and plaque development and act through sex-independent mechanisms.<\/jats:p>","DOI":"10.3390\/ijms27198762","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:01:19Z","timestamp":1790773279000},"page":"8762","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Dissection of the Obesity Paradox in Carotid Atherosclerosis Using a Hyperlipidemic Mouse Cohort"],"prefix":"10.3390","volume":"27","author":[{"given":"Kiyan","family":"Parvaresh","sequence":"first","affiliation":[{"name":"Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"}]},{"given":"Firas","family":"Dalloul","sequence":"additional","affiliation":[{"name":"Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Mei-Hua","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"}]},{"given":"Lisa J.","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5656-1323","authenticated-orcid":false,"given":"Muhammad Sarfraz","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Hideyuki","family":"Torikai","sequence":"additional","affiliation":[{"name":"Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9155-613X","authenticated-orcid":false,"given":"Weibin","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22908, USA"},{"name":"Biochemistry & Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e93","DOI":"10.1161\/CIR.0000000000001123","article-title":"Heart Disease and Stroke Statistics-2023 Update: A Report From the American Heart Association","volume":"147","author":"Tsao","year":"2023","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1161\/01.STR.31.3.622","article-title":"Low Risk of Ischemic Stroke in Patients with Reduced Internal Carotid Artery Lumen Diameter Distal to Severe Symptomatic Carotid Stenosis: Cerebral Protection Due to Low Poststenotic Flow? On Behalf of the European Carotid Surgery Trialists\u2019 Collaborative Group","volume":"31","author":"Rothwell","year":"2000","journal-title":"Stroke J. Cereb. Circ."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1093\/brain\/124.3.457","article-title":"Severely Impaired Cerebrovascular Reactivity Predicts Stroke and TIA Risk in Patients with Carotid Artery Stenosis and Occlusion","volume":"124","author":"Markus","year":"2001","journal-title":"Brain J. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1161\/01.STR.0000048214.56981.6F","article-title":"Framingham Heart Study Genetic and Environmental Contributions to Atherosclerosis Phenotypes in Men and Women: Heritability of Carotid Intima-Media Thickness in the Framingham Heart Study","volume":"34","author":"Fox","year":"2003","journal-title":"Stroke"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1161\/STROKEAHA.109.554121","article-title":"Heritability and Linkage Analysis for Carotid Intima-Media Thickness: The Family Study of Stroke Risk and Carotid Atherosclerosis","volume":"40","author":"Sacco","year":"2009","journal-title":"Stroke"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1161\/01.STR.0000155746.65185.4e","article-title":"A Genome-Wide Scan for Carotid Artery Intima-Media Thickness: The Mexican-American Coronary Artery Disease Family Study","volume":"36","author":"Wang","year":"2005","journal-title":"Stroke"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Meena, D., Huang, J., Zare, M., Hasbani, N.R., Romuald, B.P., Mustafa, R., van der Laan, S.W., Xu, H., Terry, J.G., and Bis, J.C. (2025). Genome-Wide Association Study and Multi-Ancestry Meta-Analysis Identify Common Variants Associated with Carotid Artery Intima-Media Thickness. medRxiv.","DOI":"10.1101\/2025.04.11.25325582"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Liu, S., Li, J., Chen, M.H., Liu, Z., and Shi, W. (2015). Variation in Type 2 Diabetes-Related Phenotypes among Apolipoprotein E-Deficient Mouse Strains. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0120935"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1161\/STROKEAHA.107.492165","article-title":"Quantitative Trait Locus Analysis of Carotid Atherosclerosis in an Intercross between C57BL\/6 and C3H Apolipoprotein E-Deficient Mice","volume":"39","author":"Li","year":"2008","journal-title":"Stroke J. Cereb. Circ."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1152\/physiolgenomics.00099.2012","article-title":"New Quantitative Trait Loci for Carotid Atherosclerosis Identified in an Intercross Derived from Apolipoprotein E-Deficient Mouse Strains","volume":"45","author":"Rowlan","year":"2013","journal-title":"Physiol. Genom."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1534\/g3.116.037879","article-title":"Polygenic Control of Carotid Atherosclerosis in a BALB\/cJ \u00d7 SM\/J Intercross and a Combined Cross Involving Multiple Mouse Strains","volume":"7","author":"Grainger","year":"2017","journal-title":"G3 Genes Genomes Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1161\/ATVBAHA.108.176685","article-title":"Genetic Regulation of Atherosclerotic Plaque Size and Morphology in the Innominate Artery of Hyperlipidemic Mice","volume":"29","author":"Bennett","year":"2009","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Shi, L.J., Chagari, B., An, A., Chen, M.-H., Bao, Y., and Shi, W. (2022). Genetic Connection between Hyperglycemia and Carotid Atherosclerosis in Hyperlipidemic Mice. Genes, 13.","DOI":"10.3390\/genes13030510"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.atherosclerosis.2019.11.034","article-title":"Genetic Linkage of Oxidative Stress with Cardiometabolic Traits in an Intercross Derived from Hyperlipidemic Mouse Strains","volume":"293","author":"Fuller","year":"2019","journal-title":"Atherosclerosis"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Chen, M.-H., Chagari, B., Abramson, A.M., Shi, L.J., He, J., and Shi, W. (2025). The Genetic Elements of the Obesity Paradox in Atherosclerosis Identified in an Intercross Between Hyperlipidemic Mouse Strains. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26094241"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1152\/physiolgenomics.00006.2022","article-title":"Genetic Connection of Carotid Atherosclerosis with Coat Color and Body Weight in an Intercross between Hyperlipidemic Mouse Strains","volume":"54","author":"Chagari","year":"2022","journal-title":"Physiol. Genom."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1159\/000118945","article-title":"Body Mass Index and Poststroke Mortality","volume":"30","author":"Olsen","year":"2008","journal-title":"Neuroepidemiology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1212\/WNL.0b013e31820b7667","article-title":"Paradoxical Longevity in Obese Patients with Intracerebral Hemorrhage","volume":"76","author":"Kim","year":"2011","journal-title":"Neurology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1093\/eurheartj\/ehs340","article-title":"Overweight and Obesity Are Associated with Improved Survival, Functional Outcome, and Stroke Recurrence after Acute Stroke or Transient Ischaemic Attack: Observations from the TEMPiS Trial","volume":"34","author":"Doehner","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/ijs.12016","article-title":"The Obesity Paradox in Stroke: Lower Mortality and Lower Risk of Readmission for Recurrent Stroke in Obese Stroke Patients","volume":"10","author":"Andersen","year":"2015","journal-title":"Int. J. Stroke"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1161\/STROKEAHA.110.593434","article-title":"Association between Obesity and Mortality after Acute First-Ever Stroke: The Obesity-Stroke Paradox","volume":"42","author":"Vemmos","year":"2011","journal-title":"Stroke"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1161\/CIRCOUTCOMES.113.000129","article-title":"Association of Body Mass Index and Mortality after Acute Ischemic Stroke","volume":"7","author":"Skolarus","year":"2014","journal-title":"Circ. Cardiovasc. Qual. Outcomes"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e201","DOI":"10.1016\/j.jstrokecerebrovasdis.2013.10.002","article-title":"Favorable Functional Recovery in Overweight Ischemic Stroke Survivors: Findings from the China National Stroke Registry","volume":"23","author":"Zhao","year":"2014","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4679","DOI":"10.1534\/g3.120.401856","article-title":"Regional Variation in Genetic Control of Atherosclerosis in Hyperlipidemic Mice","volume":"10","author":"Jones","year":"2020","journal-title":"G3 Genes Genomes Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1161\/CIRCGENETICS.108.829747","article-title":"Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of Prospective Meta-Analyses of Genome-Wide Association Studies from Five Cohorts","volume":"2","author":"Psaty","year":"2009","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.1161\/CIRCRESAHA.107.152975","article-title":"Identification of Pathways for Atherosclerosis in Mice: Integration of Quantitative Trait Locus Analysis and Global Gene Expression Data","volume":"101","author":"Wang","year":"2007","journal-title":"Circ. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Bennett, B.J., Davis, R.C., Civelek, M., Orozco, L., Wu, J., Qi, H., Pan, C., Packard, R.R., Eskin, E., and Yan, M. (2015). Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains. PLoS Genet., 11, Erratum in PLoS Genet. 2016, 12, e1005913. https:\/\/doi.org\/10.1371\/journal.pgen.1005913.","DOI":"10.1371\/journal.pgen.1005913"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1161\/01.ATV.0000201044.33220.5c","article-title":"Atherosclerosis Susceptibility Loci Identified from a Strain Intercross of Apolipoprotein E-Deficient Mice via a High-Density Genome Scan","volume":"26","author":"Smith","year":"2006","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9475","DOI":"10.1038\/s41598-023-35917-8","article-title":"Integrative Analysis of Hepatic Transcriptional Profiles Reveals Genetic Regulation of Atherosclerosis in Hyperlipidemic Diversity Outbred-F1 Mice","volume":"13","author":"Kim","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1161\/ATVBAHA.121.317007","article-title":"Twenty-Five Novel Loci for Carotid Intima-Media Thickness: A Genome-Wide Association Study in >45 000 Individuals and Meta-Analysis of >100 000 Individuals","volume":"42","author":"Yeung","year":"2022","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5141","DOI":"10.1038\/s41467-018-07340-5","article-title":"GWAS and Colocalization Analyses Implicate Carotid Intima-Media Thickness and Carotid Plaque Loci in Cardiovascular Outcomes","volume":"9","author":"Franceschini","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1038\/ng.920","article-title":"Meta-Analysis of Genome-Wide Association Studies from the CHARGE Consortium Identifies Common Variants Associated with Carotid Intima Media Thickness and Plaque","volume":"43","author":"Bis","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1089\/met.2013.0151","article-title":"The Relation between Carotid Intima Media Thickness and Serum Osteoprotegerin Levels in Nonalcoholic Fatty Liver Disease","volume":"12","author":"Ayaz","year":"2014","journal-title":"Metab. Syndr. Relat. Disord."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1161\/CIRCGENETICS.109.902320","article-title":"Quantitative Trait Locus Mapping and Identification of Zhx2 as a Novel Regulator of Plasma Lipid Metabolism","volume":"3","author":"Gargalovic","year":"2010","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2587","DOI":"10.1161\/01.ATV.20.12.2587","article-title":"Advanced Atherosclerotic Lesions in the Innominate Artery of the ApoE Knockout Mouse","volume":"20","author":"Rosenfeld","year":"2000","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1159\/000502691","article-title":"Atherogenesis in the Carotid Artery with and without Interrupted Blood Flow of Two Hyperlipidemic Mouse Strains","volume":"56","author":"Zhao","year":"2019","journal-title":"J. Vasc. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e14829","DOI":"10.14814\/phy2.14829","article-title":"Inflammation and Enhanced Atherogenesis in the Carotid Artery with Altered Blood Flow in an Atherosclerosis-Resistant Mouse Strain","volume":"9","author":"Zhao","year":"2021","journal-title":"Physiol. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"iyab160","DOI":"10.1093\/genetics\/iyab160","article-title":"Identification of Mep1a as a Susceptibility Gene for Atherosclerosis in Mice","volume":"219","author":"Grainger","year":"2021","journal-title":"Genetics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.amjms.2021.06.014","article-title":"Hyperlipidemia Influences the Accuracy of Glucometer-Measured Blood Glucose Concentrations in Genetically Diverse Mice","volume":"362","author":"Shi","year":"2021","journal-title":"Am. J. Med. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Torikai, H., Chen, M.-H., Jin, L., He, J., Angle, J.F., and Shi, W. (2023). Atherogenesis in Apoe-\/- and Ldlr-\/- Mice with a Genetically Resistant Background. Cells, 12.","DOI":"10.3390\/cells12091255"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Abramson, A.M., Shi, L.J., Lee, R.N., Chen, M.-H., and Shi, W. (2022). Phenotypic and Genetic Evidence for a More Prominent Role of Blood Glucose than Cholesterol in Atherosclerosis of Hyperlipidemic Mice. Cells, 11.","DOI":"10.3390\/cells11172669"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1534\/genetics.106.061176","article-title":"The X Chromosome in Quantitative Trait Locus Mapping","volume":"174","author":"Broman","year":"2006","journal-title":"Genetics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1194\/jlr.M011130","article-title":"Integration of QTL and Bioinformatic Tools to Identify Candidate Genes for Triglycerides in Mice","volume":"52","author":"Leduc","year":"2011","journal-title":"J. Lipid Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.tig.2010.09.002","article-title":"Critical Reasoning on Causal Inference in Genome-Wide Linkage and Association Studies","volume":"26","author":"Li","year":"2010","journal-title":"Trends Genet. 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