Complex inheritance of the 5-lipoxygenase locus influencing atherosclerosis in mice.
We previously mapped a locus on chromosome 6 with a large effect (LOD > 6) on aortic lesion size in a (C57BL/6J x CAST/Ei) F(2) cross and identified arachidonate 5-lipoxygenase (5LO) as a candidate gene in this region. Subsequent studies with the 5LO knockout model showed effects on atherosclerosis and aortic aneurysms. We now report detailed genetic analysis of the chromosome 6 locus. We created a panel of overlapping and reciprocal subcongenic lines from the B6.CAST Ldlr(-/-) chromosome 6 congenic strain (CON6.Ldlr(-/-)) and analyzed aortic lesion size in different subcongenic lines. Our results revealed that there are at least two subregions, designated as Ath37 and Ath38 that affect the size of aortic lesions independently of 5LO. We also showed that homozygote 5LO null mice develop smaller atherosclerotic lesions. We conclude that the relation between the mouse chromosome 6 locus and atherosclerosis is complex and is due to at least two genes with large effects within this region. This complexity should be considered when interpreting results of knockout studies.
Ghazalpour
Anatole
A
Department of Microbiology Immunology and Molecular Genetics, University of California, Los Angeles, California 90095-1679, USA.
Wang
Xuping
X
Lusis
Aldons J
AJ
Mehrabian
Margarete
M
D000818:Animals; D001011:Aorta / Q000473:pathology; D001014:Aortic Aneurysm / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency / Q000235:genetics*; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics; D005260:Female; D006720:Homozygote; D008126:Lod Score; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics
D011973:Receptors, LDL; D004247:DNA; D001094:Arachidonate 5-Lipoxygenase