P324Circadian genes in the regulation of lipids in coronary artery disease

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Background/Aims. Cholesterol takes part in atherogenesis and is therefore a crucial risk factor of coronary artery disease (CAD). Lipid metabolism is regulated by a number of genes, including circadian ones. Circadian genes participate in the regulation of vessel function and are associated with CAD, although their exact role in CAD pathogenesis remains unknown. The study was aimed to reveal the connection of circadian genes with various lipids of blood plasma.

Methods. The study included Russian patients with CAD (N=250) confirmed by coronary angiography, and healthy donors without such lesions (N=137). All patients underwent thorough cardiologic examination due to suspected CAD. Genotyping of single nucleotide polymorphisms (SNP) was performed using MALDI-TOF minisequencing. We analyzed CLOCK (rs1801260), PER1 (rs2735611), PER2 (rs2304672), CRY1 (rs8192440), NPAS2 (rs11123857, AGT-3 (rs699), AGT-4 (rs4762), AGTR (rs5186), LIPC4 (rs1800588), MTHFR (rs1801133), PAI (rs1799889), CRP (rs1205) and some other genes. Pink software was used to analyze the associations.

Results. We have found significant associations of atherosclerotic lesion of coronary arteries with polymorphisms of CRY1 (rs8192440), AGT-3 (rs699), AGT-4 (rs4762), LIPC4 (rs1800588), MTHFR (rs1801133), CRP (rs1205) with p-value <0.05, and strongest association of total plasma cholesterol level with CLOCK (rs1801260) gene polymorphism (p=0.003); low density lipoprotein (LDL) level with CLOCK (rs1801260, p=0.0006), PAI (rs1799889, p=0.01), CRP (rs1205, p=0.003); very low density lipoprotein (VLDL) level with AGTR (rs5186, p=0.006). We produced decision tree from variants associated with different cholesterol fractions using coronary defense as outcome, and area under ROC curve is 0.67±0.1.

Conclusions. The obtained data suggest a complex role of circadian genes in CAD pathogenesis in respect of their involvement in lipid metabolism. CLOCK gene is associated with LDL and total cholesterol, but not with CAD, and may therefore indirectly influence the process of coronary atherosclerosis. Other noncircadian genes that connected with various lipid fractions also do not seem to have significant association with coronary atherosclerosis. The exception is CRP (rs1205), which is associated both with CAD and lipids. This finding requires further study.

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