PCSK9 plays an important role in low-density lipoprotein cholesterol (LDL-C) homeostasis by enhancing the low-density lipoprotein receptor (LDLR) clearance of the cell surface through a posttranscriptional mechanism independent of its enzymatic activity (Chen et al., 2014). We aimed to study the association between single-nucleotide polymorphisms (SNPs) of PCSK9 E670G (rs505151) and CAD.
Patients with CAD are known to be elderly (Nose et al., 2019). In agreement with our results, Peng et al. (2020) found that the mean age of the CAD population was
57.8 ± 10.1 years, and 833 (68%) participants were male. Furthermore, Namordizadeh and Nasiri (2021) also found that the mean age of CAD patients was significantly higher than that of controls.
In the present study, we found that CAD cases were significantly associated with a higher frequency of a positive family history of hypertension, as well as smoking (P = 0.009; P < 0.001). In agreement with our results, Lin et al. (2011) and Namordizadeh and Nasiri (2021) showed that CAD patients had higher frequencies of smoking, which might be an important risk factor for CAD. Additionally, Chiang et al. (2019) showed that significantly higher proportions of smokers were seen in the CAD group than in the control group (P = 0.05).
Furthermore, we found that CAD cases were significantly associated with a higher frequency of hypertension, while no significant difference was found regarding DM among the studied groups. This may be explained by the absence of the GG genotype in our study. It is noteworthy that patients with DM present a significantly higher frequency of the G allele than patients without DM (Slimani et al., 2014; Mohamed et al., 2021). Additionally, the small sample size (13 DM cases with CAD vs. 18 DM cases without CAD) limits the power of this analysis to only some risk factors. Namordizadeh and Nasiri. (2021) found that both DM and hypertension showed higher frequencies in patients than in controls.
In the present study, the CAD group was significantly associated with higher total cholesterol, LDL-C, non-HDL-C, and TG and lower HDL-C than the control group (P < 0.001). In agreement with our results, Lin et al. (2011) and Manochehri and
Moghadam (2016) showed that there were significant differences in triglycerides between CAD patients and individuals in the control group (P = 0.05). Manochehri and Moghadam (2016) conducted an observational case‒control study that contained 80 male participants. Half of these participants had proven CAD by angiography test, and the other participants were healthy as a control group. They found that fasting TG and postprandial TG levels were significantly higher in CAD patients (P value = 0.001). Furthermore, Namordizadeh and Nasiri (2021) concluded that higher TC, LDL-C, and TG and lower HDL were found in CAD patients than in controls.
Regarding the PCSK9 E670G polymorphism, we found that all studied control groups had the AA genotype (100%), while 79% of cases had the AA genotype and 21% had the AG genotype. None of the cases or controls had the GG genotype. There was a significant association of the AG genotype and G allele with the CAD group (P
< 0.001). In agreement with our results, Salazar et al. (2007) (110 patient vs. 108 control), Meng and Le (2011) (165 patient vs. 181 control), and Yang et al. (2015) (160 patient vs. 182 control) reported the absence of the GG genotype among cases or controls, and Reddy et al. (2018) found that the homozygous mutant (GG) genotype was completely absent from the studied population. Zibaeenezhad et al. (2020) performed a study to assess the rs505151 polymorphism of the PCSK9 gene in two Iranian ethnic groups (Turk and Lur) with coronary artery disease (CAD) in Fars Province. They concluded that the PCSK9 polymorphism rs505151 was correlated with LDL-C levels in Turk ethnicity CAD patients; therefore, it could be used as a predictive factor for hypercholesterolemia and CAD.
Namordizadeh and Nasiri (2021) reported in another study that the homozygote rs505151 GG genotype and GG + AG genotypes (dominant model) have higher MI risk in Iranian populations. An Indonesian study by Santoso et al. (2021) showed that major adverse cardio-cerebrovascular events (MACCEs) in ST-segment elevation myocardial infarction (STEMI) patients are associated with the E670G polymorphism of PCSK9.
On the other hand, a Chinese study conducted in a Southern Han population showed that PCSK9 levels, but not PCSK9 polymorphisms, are associated with CAD risk in the Southern Chinese Han population and that serum PCSK9 levels are positively associated with the atherogenic index of plasma (AIP) (Cai et al., 2018). In contrast to the current results and Slimani et al. (2014) results of G carriers, Chinese CAD patients in Taiwan had less frequent G carriers than controls (HSU et al., 2009). Furthermore, Reddy et al. (2018) found that a more prevalent (57.
wild homozygous genotype (AA) among cases in comparison to controls (42%) and a more prevalent heterozygous genotype (AG) among controls (58.0%) in comparison to cases (42.8%). The discrepant results between studies may be partly due to differences in patient characteristics.
In the present study, no significant association was found between demographic data, family history of DM and PCSK9 genotypes or alleles in the CAD group. In agreement with our results, Chen et al. (2005) showed that there were no significant associations between single nucleotide polymorphisms and baseline demographic variables or clinical variables, including age, sex, ethnic background, BMI, history of diabetes, and smoking.
Regarding the association between PCSK9 genotypes and lipid profiles, we found that the AG genotype and G allele were significantly associated with higher TG than the AA genotype among the CAD group, while TC, HDL-C, LDL-C and non-HDL-C did not differ significantly between either genotypes or alleles among the studied CAD cases. This was in agreement with HSU et al. (2009), who failed to find a significant association between G allele carriers and the plasma level of LDL. Additionally, this was in agreement with Qiu et al. (2017), who found an association between G allele carriers of PCSK9 and high TG levels in CAD patients.
On the other hand, previous studies have shown that the E670G variant was associated with increased plasma total cholesterol (Chen et al., 2005; Scartezini et al., 2007). Additionally, Evans and Beil (2006) found that males with GG or AG genotypes had higher plasma LDL-C than those with AA genotypes.
In the present study, logistic regression analysis was conducted for the prediction of CAD susceptibility. Smoking, hypertension, higher TC, TG, LDL-C, non-HDL-C, lower HDL-C, PCSK9 AG genotype and G allele were associated with risk of CAD susceptibility in univariate analysis. However, in multivariate analysis, smoking, hypertension, higher TC, LDL-C, non-HDL-C, presence of PCSK9 AG genotype and G allele were suggested to be independent predictors of CAD susceptibility.
A meta-analysis previously indicated that the E670G polymorphism in PCSK9 might be correlated with the risk of CAD (Adi et al., 2015). In addition, Lin et al. (2011) found that AG and GG alleles were significantly correlated with CAD morbidity. After adjusting for age, sex, BMI, smoking and drinking habits, a significant association of the GG genotype with CAD was still observed, whereas no significant difference was observed for the AG genotype. This disparity in the results of these studies could be
due to the sample size, genotyping method, study design and the different environmental and risk factors.