# The Genetic Elements of the Obesity Paradox in Atherosclerosis Identified in an Intercross Between Hyperlipidemic Mouse Strains

## TL;DR

This study finds that the obesity paradox in atherosclerosis is partly due to shared genetic factors that affect body weight and atherosclerosis in opposite ways.

## Contribution

The study identifies genetic loci that link body weight and atherosclerosis, explaining part of the obesity paradox in mice.

## Key findings

- Four QTLs for atherosclerosis and three for body weight were identified in F2 mice.
- Body weight inversely correlates with atherosclerotic lesion size and explains more variance than other risk factors.
- Genetic overlap on Chr15 suggests shared components influencing both traits in opposite directions.

## Abstract

Overweight and obese individuals show lower mortality rates or better prognoses than those of normal weight in a variety of diseases, a phenomenon called the “obesity paradox”. An inverse association of adiposity with atherosclerosis has been observed in both humans and mice. To dissect phenotypic and genetic connections between the traits, 154 female and 145 male F2 mice were generated from an intercross between BALB/cJ and LP/J apolipoprotein E-deficient mice and fed a Western diet for 12 weeks. Atherosclerotic lesion size in the aortic root, body weight, plasma lipids, and glucose were measured, and genotyping was performed on miniMUGA SNP arrays. Quantitative trait locus (QTL) analyses on all F2 mice with sex as a covariate revealed four significant QTLs on chromosomes (Chr) 3, 6, 13, and 15 for atherosclerosis and three significant QTLs on Chr2, 7, and 15 for body weight. Chr15 QTL for atherosclerosis overlapped with one for body weight near 36 Mb. After adjusting for variation in body weight, Chr15 atherosclerosis QTL was downgraded from significant to suggestive linkage. Body weight was inversely correlated with atherosclerotic lesion sizes and accounted for more variance than a single other risk factor for atherosclerosis among F2 mice. Analysis of public data collected from two backcross cohorts revealed strong correlations between body weight and fat mass in adult mice (r ≥ 0.93; p ≤ 1.6 × 10−136). Thus, the obesity paradox in atherosclerosis is partially attributable to shared genetic components that have an opposite effect on adiposity and atherosclerosis.