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bioRxiv · 10.64898/2026.08.13.744610

Genetic dissection of the obesity paradox in carotid atherosclerosis using a hyperlipidemic mouse cohort

Parvaresh, K.·Dalloul, F.·Chen, M.-H.·Shi, L. J.·Ali, M. S.·Torikai, H.·Shi, W.
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Abstract

BackgroundOverweight 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 the primary cause of ischemic stroke, and body weight serves as a reliable surrogate for adiposity in mice. MethodsPhenotypic and genetic connections of carotid atherosclerosis with body weight were evaluated in 299 F2 mice 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. ResultsCarotid lesion sizes 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). ConclusionsThese 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-dependent mechanisms.

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Parvaresh, K., Dalloul, F., Chen, M.-H., Shi, L. J., Ali, M. S., Torikai, H., Shi, W.. 2026-08-21. Genetic dissection of the obesity paradox in carotid atherosclerosis using a hyperlipidemic mouse cohort. https://doi.org/10.64898/2026.08.13.744610

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