Abstract 442: Loss of Kiaa1462 , a Coronary Artery Disease Associated Gene, Decreases Atherosclerosis

Abstract

Introduction: KIAA1462 is the only coding gene in a chromosome 10 genomic locus consistently associated with Coronary Artery Disease (CAD) in Genome Wide Association Studies. KIAA1462 has no recognizable functional domains and little homology to other protein families, but has been previously implicated in endothelial cell proliferation and angiogenesis. We used a murine knock out (KO) model to investigate the role of Kiaa1462 in the development of atherosclerosis. Methods and Results: Kiaa1462 global KO mice were generated by replacing exon 3 with a reporter/selection cassette harbouring LacZ. Kiaa1462 KO mice bred normally with offspring born in the expected Mendelian ratio. X-gal staining of aortas showed Kiaa1462 expression in vascular smooth muscle cells (VSMC) and endothelial cells. This was confirmed by qRT-PCR with expression of Kiaa1462 observed in both isolated endothelial cells and VSMC from WT but not KO mice. Loss of Kiaa1462 did not alter blood pressure or heart rate. Furthermore, no difference in vascular contractile function, or either endothelial cell dependent or independent dilation in the aorta was observed between WT and KO mice. To assess the role of Kiaa1462 in the development of atherosclerosis we crossed Kiaa1462 KO mice with hyperlipidaemic ApoE -/- mice. Heterozygous breeding pairs were used to generate matched WT, heterozygous and homozygous KO mice. On an ApoE -/- background Kiaa1462 KO mice were no longer born at the expected Mendelian ratio with a significant (~50%) decrease in KO mice alive 21 days after birth. Surviving KO mice were indistinguishable from their littermates with no difference in body or organ weight observed. Atherosclerosis was assessed after high fat feeding for 10 weeks (6 to 16wk of age). Loss of Kiaa1462 caused a significant decrease in plaque burden in the aortic root of both male and female KO mice vs. WT mice, with no difference observed between WT and heterozygous KO mice. Despite the decrease in plaque size there was no significant difference in macrophage or collagen content between genotypes. Conclusions: Our findings support that Kiaa1462 a GWAS gene candidate plays a critical role in the development of atherosclerosis.