The present study indicated a significant interaction between ApoB Ins/Del SNP and HEI-2015 on serum IL-18 level. In subjects with Ins/Ins genotype, there were higher IL-18 levels in tertile 2 than those in tertiles 1 and 3 of HEI-2015. While the trend of the IL-18 level seemed to be inversed in Del-allele carries (i.e. subjects had higher IL-18 in the tertiles 1 and 3 of HEI-2015 than tertile 2). The most important conclusion from this observation was that, Del allele carriers could respond to healthy diet with higher IL-18 only when HEI-2015 score is moderate. It has been reported that high blood IL-18 levels rise CVDs risk (28). HEI-2015 focuses on main elements of a healthy diet such as limited consumption of SFA and added sugar as well as high intake of fruits, vegetables, nuts and whole grains which have inflammation reducing properties (29, 30). Moreover, HEI-2015 score has been shown to have significant negative relationships with inflammation and risk of CVDs (31). There is currently evidence that Ins/Del SNP is related to deletion of 3 amino acids (Ala-Leu-Ala) from ApoB gene which alters the normal formation of recognition sit of ApoB for LDL recipient (32). Del allele in this SNP may lead to dyslipidemia especially hypercholesterolemia (33). Some evidence indicates that hypercholesterolemia people like Del-allele carriers are more responsive to beneficial dietary changes than subjects with normal blood cholesterol level (34). The present study also provided the evidence that Del allele carriers of ApoB Ins/Del SNP had significantly higher TC level than Ins/Ins genotype. On the other hand, the scoring systems in indices such as HEI-2015 and DQI-I does not consider over-consumption of energy and some food groups such as refined grains (20, 21) which might explain the higher IL-18 level in tertile 3 of HEI-2015 than tertile 2 in Del allele carriers. According to our best knowledge to date, there is no research that has investigated the interaction between ApoB SNPs and dietary factors on IL-18 levels and other inflammatory cytokines. There are some interaction studies between lipid, SFA and cholesterol intakes and ApoB Ins/Del polymorphism on lipid profile that reported insignificant results on TC (35, 36). However, there was not significant interaction between Ins/Del and dietary indices on TC in our study. This inconsistency might be due to differences in study population and the interaction of other food parameters in dietary indices in this study with ApoB Ins/Del SNP. In our study, we also represented a significant interaction between DQI-I and Ins/Del variants on serum leptin concentration in both crude and adjusted models. It was observed that, serum leptin in individuals with Ins/Ins genotype was lower in tertile 3 and 1 of DQI-I than tertile 2. Although in those with Del allele, leptin level was not very different within DQI-I tertiles. A dietary pattern with high DQI-I and HEI-2015 scores is rich in MUFAs, PUFAs and fiber, poor in SFA and sugar and has a suitable proportion of total fat intake which can inhibit hypertriglyceridemia (37–39). Low blood TG level can protect against leptin resistance via change in receptor signaling or metabolism of leptin (40). Secondarily, we explored a borderline significant interaction between HEI-2015 and EcoR1 SNP on leptin level which disappeared after controlling of confounding factors. There was a reducing trend in leptin concentration from tertile 1 toward tertile 3 of HEI-2015 in E- allele carriers, while there was only a mild increasing trend in subjects with E + E + homozygous. EcoR1 SNP is related to the substitution of lysine for glutamic acid that alters the formation and tendency of recognition site for LDL receptor that might lead to hypercholesterolemia (41). It appears that subjects with Del allele in Ins/Del SNP and E- allele in EcoR1 SNP are more beneficially responsive to healthier diet than those with Ins/Ins and E + E + homozygous. Leptin is an adipokine which plays important roles in energy homeostasis and satiety. But hyperleptinemia and leptin resistance might be predictive factors of CVDs risk (42). To our knowledge, only a study by Rafiee et al assessed the interaction between dietary components and ApoB SNP on blood leptin levels in patients with T2DM. In their study, in Del allele carriers with T2DM, higher intake of MUFA, PUFA, SFA and protein and lower intake of carbohydrates were related to lower serum leptin concentration. However there was not any significant difference in subjects with Ins/Ins genotype (43). Another finding of our study was the significant interaction between ApoB EcoR1 polymorphism and DPI on serum TC concentrations in both crude and adjusted models. Based on our analysis, during tertiles of DPI in E + E + homozygous and E- allele carriers, TC levels had decreasing and increasing trends, respectively, indicating that phytochemical components may reduce cholesterol level in diabetic patients homozygous for E + allele through their anti-oxidative and anti-inflammatory characteristics (19, 44). Currently, there is no experimental or human study on the interaction between genetic profile and DPI on cardio metabolic parameters. However, some researched have demonstrated the reducing effect of DPI on inflammation, obesity and pre-diabetes (19, 45). Furthermore, the interaction between dietary patterns or components and ApoB SNPs on oxidative stress and anti-oxidative markers has not been investigated, yet. Present study indicated significant interaction between ApoB Ins/Del polymorphism and DQI-I on 8-iso-PGF2α in both crude and adjusted models. In fact, in Ins/Ins homozygous, moderate DQI-I score (tertile 2) was associated with benefits for oxidative stress shown by lower 8-iso-PGF2α levels compared to high (tertile 3) and low (tertile 1) DQI-I scores. On the other hand, there was increasing trend in 8-iso-PGF2α level from tertile 1 and 3 toward tertile 2 in Del allele carriers. Puchau B revealed a possible protective role of high DQI-I scores against oxidative stress in healthy subjects (46). Therefore, in diabetic patients carrying Del allele, DQI-I appeared to have the strongest impact on reducing the serum 8-iso-PGF2α level, when it has the highest score due to high intake of antioxidant nutrients such as vitamin E, C, selenium, fiber (47, 48). While, it seems that only a moderate score of DQI-I is enough to reduce 8-iso-PGF2α level in subjects with Ins/Ins homozygous. Additionally, in subjects with Ins/Ins homozygous, high intakes of energy, refined grains and fruits in tertile 3 of DQI-I may have contributed to higher 8-iso-PGF2α compared to tertile 2. The change of tendency of ApoB to LDL recipients might explain variability in plasma 8-iso-PGF2α associations with DQI-I values between genotypes of Ins/Del polymorphism. In crude models, we also observed borderline significant interactions between ApoB EcoR1 SNP and DQI-I on TAC level and between ApoB EcoR1 SNP and HEI-2015 on SOD level. There was an elevating impact of high DQI-I scores in serum TAC in E- allele carriers. However, our results indicated that the response of SOD level as a main marker of antioxidant defense system to HEI-2015 was inversed and its concentrations decreased within HEI-2015 tertiles in E- allele carriers in crude model. But these borderline significant interactions on TAC and SOD disappeared after adjusting for confounding variables including BMI, age and smoking or alcohol uses. Findings of the relationship between HEI and oxidative stress are very limited. Tow investigation have demonstrated that the HEI-2015 had a positive association with TAC and HEI-2010 had an insignificant association with SOD (49, 50). We further indicated that greater adherence to the HEI-2015 had favorable effects on serum HDL level and LDL/HDL ratio, respectively, which can be due to high intake of cardio protective micro-nutrients irrespective of differences in genotypes of ApoB SNPs (45). In addition, serum HDL concentration was significantly higher in E- allele carriers in ApoB EcoR1 SNP than E + E + homozygous. It should be noted that, high HDL level in E + E + homozygous in the current study can’t be interpreted as a cardio protective factor because some studies have indicated that genetic mutations that increase blood HDL level do not necessarily protects against CVDs (51). In this study, lack of causal interpretation due to cross-sectional design and measuring of ApoB serum level due to limited budget must be taken into consideration as limitations. However, our research is unique, because for the first time, we assessed the interaction between DQI-I, DPI and HEI-2015 with ApoB Ins/Del and EcoR1 SNPs on cardio-metabolic risk factors in patients with T2DM.