Atherosclerosis Susceptibility Loci Identified in an Extremely Atherosclerosis-Resistant Mouse Strain

Background-C3H/HeJ (C3H) mice are extremely resistant to atherosclerosis, especially males. To understand the underlying genetic basis, we performed quantitative trait locus (QTL) analysis on a male F-2 (the second generation from an intercross between 2 inbred strains) cohort derived from an intercross between C3H and C57BL/6 (B6) apolipoprotein E-deficient (Apoe(-/-)) mice. Methods and Results-Two hundred forty-six male F2 mice were started on a Western diet at 8 weeks of age and kept on the diet for 5 weeks. Atherosclerotic lesions in the aortic root and fasting plasma lipid levels were measured. One hundred thirty-four microsatellite markers across the entire genome were genotyped. Four significant QTLs on chromosomes (Chr) 2, 4, 9, and 15 and 4 suggestive loci on Chr1, Chr4, and Chr7 were identified for atherosclerotic lesions. Unexpectedly, the C3H allele was associated with increased lesion formation for 2 of the 4 significant QTLs. Six loci for high-density lipoprotein (HDL), 6 for non-HDL cholesterol, and 3 for triglycerides were also identified. The QTL for atherosclerosis on Chr9 replicated Ath29, originally mapped in a female F-2 cohort derived from B6 and C3H Apoe(-/-) mice. This locus coincided with a QTL for HDL, and there was a moderate, but statistically significant, correlation between atherosclerotic lesion sizes and plasma HDL cholesterol levels in F-2 mice. Conclusions-These data indicate that most atherosclerosis susceptibility loci are distinct from those for plasma lipids except for the Chr9 locus, which exerts effect through interactions with HDL.