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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 38; no. Suppl_1
• Main Authors: Douglas, Gillian, Kyriakou, Theodosios, Rashbrook, Victoria S, Al Haj Zen, Ayman, Trelfa, Lucy, Mehta, Vedanta, Tzima, Ellie, Watkins, Hugh, Channon, Keith
• Format: Journal Article
• Language: English
• Published: 01-05-2018
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/atvb.38.suppl_1.442

Abstract only
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.