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Coronary artery disease (CAD) remains one of the leading causes of cardiovascular morbidity and mortality worldwide. The maintenance of endothelial homeostasis and vitamin D metabolism play an important role in CAD pathogenesis. This study aimed to determine the association of endothelial homeostasis and vitamin D metabolism gene polymorphism with CAD severity. A total of 224 low-risk patients (SYNTAX score ≤ 31) and 36 high-risk patients (SYNTAX score > 31) were recruited for this study. The serum level of E-, L- and P-selectins; endothelin; eNOS; 25OH; and 1.25-dihydroxy vitamin D was measured using an enzyme-linked immunosorbent assay (ELISA). Polymorphic variants in <i>SELE</i>, <i>SELP</i>, <i>SELPLG</i>, <i>END1</i>, <i>NOS3</i>, <i>VDR</i> and <i>GC</i> were analyzed using a polymerase chain reaction (PCR). We found no differences in the serum levels of the studied markers between high- and low-risk patients. Three polymorphic variants associated with CAD severity were discovered: <i>END1</i> rs3087459, <i>END1</i> rs5370 and <i>GC</i> rs2298849 in the log-additive model. Moreover, we discovered a significantly decreased serum level of 1.25-dihydroxy vitamin D in high-risk CAD patients with the A/A–A/G genotypes of the rs2228570 polymorphism of the <i>VDR</i> gene, the A/A genotype of the rs7041 polymorphism of the <i>GC</i> gene and the A/A genotype of the rs2298849 polymorphism of the <i>GC</i> gene.