Genetic architecture of atherosclerosis dissected by QTL analyses in three F2 intercrosses of apolipoprotein E-null mice on C57BL6/J, DBA/2J and 129S6/SvEvTac backgrounds.

Natalia Makhanova,Yukako Kayashima,Svetlana Zhilicheva,Longquan Xu,Nobuyo Maeda,Sylvia Hiller,Andrew P Morgan,Andrei Makhanov,Fernando Pardo-Manuel De Villena,Xianwu Cheng

doi:10.1371/journal.pone.0182882

Natalia Makhanova, Yukako Kayashima + Show 8 more

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https://doi.org/10.1371/journal.pone.0182882

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Abstract

Quantitative trait locus (QTL) analyses of intercross populations between widely used mouse inbred strains provide a powerful approach for uncovering genetic factors that influence susceptibility to atherosclerosis. Epistatic interactions are common in complex phenotypes and depend on genetic backgrounds. To dissect genetic architecture of atherosclerosis, we analyzed F2 progeny from a cross between apolipoprotein E-null mice on DBA/2J (DBA-apoE) and C57BL/6J (B6-apoE) genetic backgrounds and compared the results with those from two previous F2 crosses of apolipoprotein E-null mice on 129S6/SvEvTac (129-apoE) and DBA-apoE backgrounds, and B6-apoE and 129-apoE backgrounds. In these round-robin crosses, in which each parental strain was crossed with two others, large-effect QTLs are expected to be detectable at least in two crosses. On the other hand, observation of QTLs in one cross only may indicate epistasis and/or absence of statistical power. For atherosclerosis at the aortic arch, Aath4 on chromosome (Chr)2:66 cM follows the first pattern, with significant QTL peaks in (DBAx129)F2 and (B6xDBA)F2 mice but not in (B6x129)F2 mice. We conclude that genetic variants unique to DBA/2J at Aath4 confer susceptibility to atherosclerosis at the aortic arch. A similar pattern was observed for Aath5 on chr10:35 cM, verifying that the variants unique to DBA/2J at this locus protect against arch plaque development. However, multiple loci, including Aath1 (Chr1:49 cM), and Aath2 (Chr1:70 cM) follow the second type of pattern, showing significant peaks in only one of the three crosses (B6-apoE x 129-apoE). As for atherosclerosis at aortic root, the majority of QTLs, including Ath29 (Chr9:33 cM), Ath44 (Chr1:68 cM) and Ath45 (Chr2:83 cM), was also inconsistent, being significant in only one of the three crosses. Only the QTL on Chr7:37 cM was consistently suggestive in two of the three crosses. Thus QTL analysis of round-robin crosses revealed the genetic architecture of atherosclerosis.

Highlights

Atherosclerosis is the major cause of morbidity and mortality in North America
To determine the genetic factors that affect susceptibility to atherosclerosis in a vascular location-dependent manner, we performed genome wide scans for Quantitative trait locus (QTL) in F2 progeny from an intercross of Apoe-null mice on B6 and DBA backgrounds
Our study revealed a significant QTL on Chr2 and a suggestive QTL on Chr10 that influence aortic arch lesion

Summary

Introduction

Atherosclerosis is the major cause of morbidity and mortality in North America It is an inflammatory disease of arteries, characterized by the development of lipid-laden plaques affecting multiple vascular beds. The precise role of these loci is not fully understood, with the exception of a few genes such as Ldlr (low-density lipoprotein receptor) and Apoe (apolipoprotein E). This is because atherogenesis is a highly complex process on which each gene often has only small effects, and certain lifestyle characteristics, such as smoking, diet, and stress, have an impact on the development of this disease. A large number of genetic loci affecting plaque development have yielded results utilizing hyperlipidemic Apoe-null mice, Ldlr-null mice or atherogenic diet-fed wild type mice [2], defining causative variants/gene(s) within any QTL regions remains a challenge

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