Increased ADAM17 mRNA expression and activity is associated with atherosclerosis resistance in LDL-receptor deficient mice.

BACKGROUND We have previously identified an atherosclerosis quantitative trait locus (QTL) on mouse chromosome (Chr) 12 in an F2-intercross of atherosclerosis-resistant FVB and atherosclerosis-susceptible C57BL/6 (B6) mice on the LDL-receptor deficient (LDL-/-) background. The aim of the present study was to identify potentially causative genes at this locus. METHODS AND RESULTS Expression QTL (eQTL) analysis of candidate genes in livers of F2-mice revealed that a disintegrin and metalloproteinase 17 (ADAM17) mRNA expression mapped to the physical position of ADAM17 on proximal Chr12 (21.6 Mb, LOD 3.3) and colocalized with the atherosclerosis QTL. The FVB allele was associated with significantly higher ADAM17 mRNA expression (39%) than the B6 allele. Likewise, ADAM17 mRNA levels in the parental strains were significantly elevated in FVB.LDLR-/- compared to B6.LDLR-/- mice in liver, macrophages, and aorta (68%, 58%, and 32%, respectively). Reporter gene assays revealed a genetic variant that might explain these expression differences. Moreover, FVB.LDLR-/- macrophages showed 5-fold increased PMA-induced shedding of tumor necrosis factor (TNF)-alpha and 32% increased release of TNF-receptor I compared to B6.LDLR-/-. The atherosclerosis locus and expression differences were confirmed in Chr12 interval-specific congenic mice. CONCLUSIONS Our data provide functional evidence for ADAM17 as a candidate gene of atherosclerosis susceptibility at the murine Chr12 QTL.