To the best of our knowledge, this is the first study exploring the value of a genetic variant ANGPTL3 rs10789117 in a large and cohort-based program for evaluating its value as a risk stratification biomarker. Our data showed a significant relationship between ANGPTL3 rs10789117 and increased risk of CVD event, which is in line with recent GWASs [2, 15]. The results of the correlational analysis specified that individuals with CC genotype had higher serum TG level compared to AA/AC. Also, the prior clinical and genetic studies have established that loss-of-function variants in ANGPTL3 are related to decreased plasma TGs, LDL-C, HDL-C, which leads to a significant decline in cardiovascular risk [7, 8, 16, 17]. However, the mentioned variant has previously been examined in few other studies but, the findings of this study were confirmed by GWASs with respect to the ANGPTL3 gene [18]. Our study also showed that the frequency of C alleles in rs10789117 was 34.5% as the risk allele for CVD. These results are consistent with the minor allele frequency of other studies like the 1000 Genomes project (C = 0.435/2182) and in East Asian population (C = 0.233/235). Our result was indicating that, there was a significant association between genotypes of rs10789117 and sex so that females are more likely to have genotype CC compared to AA/AC in the healthy group (p = 0.006). This finding is in agreement with Asselbergs’s (2012) findings which showed a statistical difference between genders, with SNP rs10789117 in DOCK7 being significant only in females[19].
To our knowledge, the association of ANGPTL3 variant and CVD event and HDL-C level has not been simultaneously assessed in a cohort study with available clinical fallow up of CVD. Another important finding was that, there was a positive association between rs10789117 CC genotype and, CVD risk ( in the group of individuals with normal HDL-C serum levels). Furthermore, The C allele of rs10789117 variant confirmed a significant association with the incidence of a CVD event (inthe low and normal HDL-C groups). It can be hypothesized that the association between CVD and the rs10789117 polymorphism of the ANGPTL3 gene in addition to dependent on levels of HDL-C, may additionally rely on its function as showed through preceding research [20]. Hence, it could conceivably be suggested that the functionality of HDL plays an important role as a predictor for clinical CVD risk [21]. This finding supports previous clinical research that has demonstrated the efficacy of increasing HDL-C concentration to decrease cardiovascular risk has been failed [22, 23].
Furthermore, structure evaluation of the ANGPTL3 gene confirmed that this protein has coiled-coil, signal peptide, and FBG domains. The cleavage site of the signal peptide sequence is between pos. 16 and 17 amino acid which helps to secretion ANGPTL3 into extracellular space [7]. Consequently, ANGPTL3 inhibits LPL potency to release phospholipids from HDL-C and free fatty acid (FFA) from VLDL via binding LPL with its coiled-coil domain [24]. This process can enhance TG levels and cause atherosclerotic plaque [10]. Also, analysis tools indicated ANGPTL3 has physical interactions with some proteins such as integrin subunit beta 3 (ITGB3) and integrin subunit alpha V(ITGAV) [3, 25]. ITGB3 and ITGAV have regulations on lipid storage and transport. According to this, defecting in ANGPTL3 can cause problems for storing and transporting lipid through ITGB3 and ITGAV [3].