Coronary artery disease (CAD), characterized by the narrowing of coronary
arteries through the complex manifestation and development of atherosclerosis, is a
complex disease and one of the leading causes of death worldwide. Both genetic
and environmental factors are believed to contribute equally to the risk of CAD.
Recently, a study identified a non-synonymous coding variant, rs11556924, (MAF,
0.38) in ZC3HC1 associated with protection against CAD (p= 9.8x10-18; OR= 0.90).
NIPA, encoded by ZC3HC1, is a characterized F-Box protein and regulator of cell
cycle. Since the amino acid change (Arg363His) is in a conserved region of NIPA
and is predicted to have functional effects (Polyphen-2), this study aimed at
understanding the functional implications of this amino acid change on NIPA and cell
cycle regulation. Here we are able to effectively show a) allele specific differences in
mRNA expression in whole blood, b) a slight structural difference between
NIPA363Arg and NIPA363His variants, c) proliferation rates of NIPA363Arg
expressing cells were significantly increased, and d) phosphorylation of a critical
serine residue in close proximity to aa.363 is not statistically different between the
two variants. These results suggest that rs11556924 plays a direct role in
development of CAD through its disruption of cell cycle regulation and NIPA mRNA
availability. This study is the first to identify a molecular basis for the association of
rs11556924 to CAD development.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/34329 |
| Date | January 2016 |
| Creators | Linseman, Tara |
| Contributors | McPherson, Ruth |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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