4. Discussion
LDL-C reduction, hyperlipidemia, diabetes mellitus, Diabetes mellitus, atherosclerotic, CAD, dyslipidemia, metabolic syndrome, diabetes
ELEVATED CHOLESTEROL, HYPERLIPIDEMIA, CARDIOVASCULAR DISEASES, CVD, DIABETES MELLITUS, DIABETES MELLITUS, HYPERGLYCEMIA, DIABETES, SECONDARY, INSULIN RESISTANCE, DYSLIPIDEMIA, ELEVATED GLUCOSE, METABOLIC SYNDROME, INSULIN SENSITIVITY, CAD, CORONARY ARTERY DISEASE
In the present study, we successfully replicated the interaction of genetic variants at PPARG with omega-3 fatty acids on blood lipids. The principal outcomes of this randomized, double-blind, parallel-group clinical trial include: (1) among patients with PPARG polymorphisms, elevated cholesterol levels, and low-to-moderate cardiovascular risk, the intake of omega-3 fatty acids significantly reduced LDL-C and serum triglycerides by the end of 3 months; and (2) patients with PPARG polymorphisms exhibited a more pronounced reduction in LDL-C, and serum triglycerides in response to omega-3 fatty acid supplementation compared to similar patients without the PPARG polymorphisms.The results of this study provide compelling evidence for the differential impact of omega-3 fatty acid supplementation on lipid profiles in the context of PPARG polymorphisms. Consistent with previous research indicating the role of PPARG in lipid metabolism, our findings suggest a modulatory effect of genetic variation on the efficacy of dietary interventions [PPARG genes have been extensively studied for their role in glucose homeostasis and insulin sensitivity. Specifically, PPAR-gamma activation, a result of PPARG gene expression, enhances glucose tolerance and insulin sensitivity in both diabetes mellitus patients and animal models of insulin resistance. This activation leads to marked improvements in insulin and glucose parameters due to enhanced whole-body insulin sensitivity, though the precise mechanisms are not fully understood [Subsequent studies have identified specific polymorphisms in the PPARG promoter, notably rs10865710 and rs3856806, which are significantly associated with glucose levels in diabetes mellitus patients. The rs10865710 polymorphism is also correlated with the severity of coronary artery disease (CAD), potentially influenced by hyperlipidemia and hyperglycemia. Diabetes mellitus patients with the G allele of rs10865710 demonstrate higher levels of glucose, triglycerides, and other markers compared to non-carriers. Similarly, T allele carriers of rs3856806 show elevated glucose levels. Notably, the rs10865710 polymorphism is significantly related to CAD severity, likely due to its effects on lipid and glucose metabolism [Thus, the broader implications of PPARG polymorphisms on metabolic health are not limited to lipid metabolism but also include significant roles in glucose regulation and insulin sensitivity. Understanding these relationships is crucial for developing tailored dietary and therapeutic strategies for individuals with specific genetic profiles, especially in managing metabolic syndrome and diabetes.In our cohort, the substantial decrease in LDL-C levels by 15.4% among those with PPARG polymorphisms receiving omega-3 fatty acids is significantly higher than the 2.6% reduction observed in the placebo group. This effect size is comparable to outcomes observed in earlier trials involving omega-3 supplementation for dyslipidemia management [The lack of significant LDL-C reduction in patients without PPARG polymorphisms receiving omega-3 fatty acids underscores the necessity of genetic screening before dietary interventions. This observation is in line with the personalized medicine approach, which has been gaining traction in the management of cardiovascular diseases (CVD) and highlights the importance of individual genetic makeup in treatment response [The secondary endpoint analysis revealed that omega-3 fatty acids also led to a marked reduction in serum triglycerides by 13.3% in the genetically predisposed group, which supports the lipid-lowering capacity of omega-3 fatty acids as documented in a meta-analysis by Eslick et al. [The absence of significant differences in hsCRP levels indicates that the anti-inflammatory effects of omega-3 fatty acids may not be as pronounced in a short-term intervention or may require a longer duration to manifest, as suggested by other long-term studies [Furthermore, the differential response to omega-3 fatty acids in our study raises questions about the potential role of other genetic factors in lipid metabolism. For example, polymorphisms in other genes related to lipid transport and metabolism, such as APOE, LDLR, and PCSK9, might also influence the response to dietary interventions. Previous studies have indicated that variations in these genes can significantly affect lipid levels and cardiovascular risk [Another aspect that warrants further exploration is the role of dietary patterns and lifestyle factors in conjunction with genetic predispositions. While our study focused on the supplementation of omega-3 fatty acids, the interaction of these supplements with overall dietary habits, physical activity, and other lifestyle choices could significantly influence lipid profiles and cardiovascular health. Studies have shown that dietary patterns, such as the Mediterranean diet, which is rich in natural sources of omega-3, along with regular physical activity, have a synergistic effect in improving cardiovascular health [In addition to the outcomes observed in this study, the inclusion of biomarkers for pre-inflammatory and preclinical atherosclerotic states, such as intima-media-thickness of carotid arteries, IL-6, TGF-b1, FGF, and ox-LDL, presents a compelling avenue for future research [The strengths of our study include its randomized, double-blind, placebo-controlled design and stringent adherence monitoring, which reinforce the validity of our findings. However, limitations exist, including the relatively short duration of the study and the specific genetic focus, which may not be generalizable to all populations with different genetic backgrounds.Future research should explore the long-term effects of omega-3 fatty acid supplementation across diverse genetic landscapes to establish broader implications for CVD risk management. Additionally, investigations into the molecular mechanisms by which PPARG polymorphisms modulate lipid metabolism could offer insights into the development of targeted therapies [