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To investigate the cAMP-regulated transcriptional co-activator 3 (CRTC3) polymorphism and its significance in the acute coronary syndrome patients.In total, 248 patients with acute coronary syndrome admitted to Taizhou People's Hospital between March 2016 and October 2016 were included in this study. Eighty-eight age- and gender-matched healthy individuals received physical examination in our hospital served as normal control. Single nucleotide polymorphism (SNP) analysis of CRTC3 (rs3862434 and rs11635252) was evaluated using PCR amplification.For the SNP of CRTC3, significant differences were identified in rs3862434 (AA/AG) and rs11635252 (TT/CT/CC) between the 2 groups (P < .05). Statistical increase was noticed in the high density lipoprotein cholesterol (HDL-C) in those with AG phenotype compared with those with AA phenotype in those with rs3862434. Significant decrease was identified in the total cholesterol (TC), triglyceride (TG), and weight in those with CC phenotype compared with those with CT phenotype among the cases with rs11635252 (P < .05).CRTC3 polymorphism was associated with the onset of acute coronary syndrome in Han Chinese patients, which may be related to the imbalance of the lipid metabolism.