Genetic Dissection of the Obesity Paradox in Carotid Atherosclerosis Using a Hyperlipidemic Mouse Cohort
- 1Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22908, USA
- 2Biochemistry & Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA
Abstract
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 “obesity paradox”. 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.
Related
- Haplotype-resolved genetic mapping using selfed progeny enables simultaneous genome assembly validation and trait dissection in a heterozygous plant
- Genetic dissection of a Solanum elaeagnifolium tertiary genepool introgression associated with 4-O-caffeoylquinic acid accumulation in eggplant
- Genetic dissection of soybean cyst nematode HG type 2.5.7 resistance reveals a multilocus architecture and favorable alleles from both parents
- Genomic and genetic dissection of drought tolerance in a resilient wheat germplasm JIN50
- Multi-omic dissection of reversible and persistent molecular alterations in diet-induced obesity
BibTeX
@article{parvaresh2026genetic,
title = {{Genetic Dissection of the Obesity Paradox in Carotid Atherosclerosis Using a Hyperlipidemic Mouse Cohort}},
author = {Kiyan Parvaresh and Firas Dalloul and Mei-Hua Chen and Lisa J. Shi and Muhammad Sarfraz Ali and Hideyuki Torikai and Weibin Shi},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27198762},
url = {https://www.mdpi.com/1422-0067/27/19/8762},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Genetic Dissection of the Obesity Paradox in Carotid Atherosclerosis Using a Hyperlipidemic Mouse Cohort
AU - Kiyan Parvaresh
AU - Firas Dalloul
AU - Mei-Hua Chen
AU - Lisa J. Shi
AU - Muhammad Sarfraz Ali
AU - Hideyuki Torikai
AU - Weibin Shi
PY - 2026
DA - 2026/09/30
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27198762
UR - https://www.mdpi.com/1422-0067/27/19/8762
AB - 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 “obesity paradox”. 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.
SN - 1422-0067
ER -