Locating Ath8, a locus for murine atherosclerosis susceptibility and testing several of its candidate genes in mice and humans

A previous study revealed that the difference in susceptibility to atherosclerotic lesions between inbred mouse strains SM/J and NZB/B1NJ was determined by one major locus (Ath8). In this study a (SM/J x NZB/BINJ) F-1 x SM/J backcross localized Ath8 by quantitative trait locus mapping to chromosome 4 with a suggestive LOD score of 2.7. This quantitative trait locus (QTL) was confirmed using an (SM/J x NZB/B1NJ) intercross; Ath8 mapped to a 23 cM region with a significant LOD score of 3.6. The genes for toll-like receptor 4 (T1r4), arachidonic acid epoxygenase (Cyp2j5), and angiopoietin-like protein 3 (Angpt13) map to this region. These candidate genes were analyzed for expression and sequence differences in the mouse and for associations with cardiovascular traits in human. Sequence analysis of Angpt13 shows a base pair substitution in SM, the susceptible strain, giving rise to an amino acid change in the fibrinogen homology domain of the protein. We found a significant association between ANGPTL3 and atherosclerotic lesions (P < 0.05) in human. These results suggest that Angpt13 is involved in atherosclerosis susceptibility in both mouse and human. (C) 2004 Elsevier Ireland Ltd. All rights reserved.