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Background: Loss‐of‐function (LOF) variants of the angiopoietin‐like 3 (ANGPTL3) gene are reported to be associated with serum triglyceride (TG) and high‐density lipoprotein cholesterol (HDL‐C) concentrations and thereby affect the risk of cardiovascular disease (CVD). Objective: In the present study, we examined the association of rs10789117 in the ANGPTL 3 gene locus and the risk of CVD in the group of people who were part of the Mashhad‐Stroke and Heart‐Atherosclerotic‐Disorders (MASHAD) cohort. Methods: One thousand and two healthy individuals enrolled in this study of whom 849 subjects were healthy and 153 subjects developed CVD outcomes after 6 years of follow‐up. After a 12‐h overnight fasting, 20 mL of blood samples were collected for the measurement of fasting blood glucose and lipid profile. DNA was extracted, and the Tetra‐ARMS PCR (amplification refractory mutation system) was used for genotyping of rs10789117 in the ANGPTL3 gene. The genotype frequencies of the variant of rs10789117 in the ANGPTL3 gene were estimated using χ2 tests. Eventually, the statistical analysis was done by SPSS version 20. Results: Individuals with AC/CC genotypes (rs10789117) were found to have to greater risk of CVD events compared to AA genotype (OR = 1.43, 95%CI = 1.01–2.02, p = 0.041). There was a 1.3‐fold increase in cardiovascular events in individuals carrying the C allele of rs10789117 variant compared to non‐carriers (OR = 1.32, 95%CI = 1.06–1.72, p value = 0.038). There were significant differences between different genotypes for serum triglyceride levels within the control group, but this difference was not significant in the group with CVD. Moreover, there was a significant association between CC genotype and CVD risk in the individuals with a normal serum HDL‐C. Conclusion: We have found that a rs10789117 C>A in ANGPTL3 gene polymorphism was associated with incident CVD events, and this may be of value as a risk stratification biomarker in CVD in the Iranian population. [ABSTRACT FROM AUTHOR]