Association of genetic polymorphisms in SOD2, SOD3, GPX3, and GSTT1 with hypertriglyceridemia and low HDL-C level in subjects with high risk of coronary artery disease

Abstract

Background Oxidative stress modulates insulin resistant-related atherogenic dyslipidemia: hypertriglyceridemia (HTG) and low high-density lipoprotein cholesterol (HDL-C) level. Gene polymorphisms in superoxide dismutase (SOD2 and SOD3), glutathione peroxidase-3 (GPX3), and glutathione S-transferase theta-1 (GSTT1) may enable oxidative stress-related lipid abnormalities and severity of coronary atherosclerosis. The present study investigated the associations of antioxidant-related gene polymorphisms with atherogenic dyslipidemia and atherosclerotic severity in subjects with high risk of coronary artery disease (CAD). Methods Study population comprises of 396 subjects with high risk of CAD. Gene polymorphisms: SOD2 rs4880, SOD3 rs2536512 and rs2855262, GPX rs3828599, and GSTT1 (deletion) were evaluated the associations with HTG, low HDL-C, high TG/HDL-C ratio, and severity of coronary atherosclerosis. Results SOD2 rs4880-CC, SOD3 rs2536512-AA, rs2855262-CC, and GPX3 rs3828599-AA, but not GSTT1-/- individually increased risk of HTG combined with low HDL-C level. With a combination of five risk-genotypes as a genetic risk score (GRS), GRS ≥ 6 increased risks of low HDL-C, high TG/HDL-C ratio, and HTG combined with low HDL-C, comparing with GRS 0–2 [respective adjusted ORs (95% CI) = 2.70 (1.24–5.85), 3.11 (1.55–6.23), and 5.73 (2.22–14.77)]. Gene polymorphisms, though, were not directly associated with severity of coronary atherosclerosis; high TG/HDL-C ratio was associated with coronary atherosclerotic severity [OR = 2.26 (95% CI [1.17–4.34])]. Conclusion Combined polymorphisms in antioxidant-related genes increased the risk of dyslipidemia related to atherosclerotic severity, suggesting the combined antioxidant-related gene polymorphisms as predictor of atherogenic dyslipidemia.

Glutathione S-Transferase (GSTT1 rs17856199) and Nitric Oxide Synthase (NOS2 rs2297518) Genotype Combination as Potential Oxidative Stress-Related Molecular Markers for Type 2 Diabetes Mellitus

“…57,58 Risk alleles interaction in these antioxidant-related gene variants might impact the overall antioxidant activities, thus allowing more susceptibility to oxidative stress and increasing the overall disease risk as proposed by Decharatchakul and colleagues. 59 The SOD2 rs4880 GG, and SOD3 rs2536512 AA genotypes, though they did not show a significant association with T2DM risk in the present cohort, they showed significant association with BMI and/or hyperlipidemia (Table 5), and the former variant also showed an association with blood glucose levels (Table S2). Interestingly, these results are consistent with a recent study that identified the same genotypes' association with increased hypertriglyceridemia risk combined with low high-density lipoprotein cholesterol levels.…”

“…Interestingly, these results are consistent with a recent study that identified the same genotypes’ association with increased hypertriglyceridemia risk combined with low high-density lipoprotein cholesterol levels. 59 SOD2 rs4880 variant causes valine substitution of alanine in “mitochondrial targeting sequence” as mentioned previously, affecting the normal importing process of the enzyme into the mitochondrial matrix with a partial halt of the precursor within the inner mitochondrial membrane and decline in active SOD2 enzyme formation with concomitant lower enzyme activity. 60 Also, other studies suggested that this variant might not be associated with T2DM pathogenesis but could be related to diabetic microangiopathy in terms of microalbuminuria 61 or macular edema.…”

“…These findings are consistent with the previous observations, which reported that the “combined or additive effect of multiple gene variants from distinct loci might account for a greater proportion of the disease risk.” 57 , 58 Risk alleles interaction in these antioxidant-related gene variants might impact the overall antioxidant activities, thus allowing more susceptibility to oxidative stress and increasing the overall disease risk as proposed by Decharatchakul and colleagues. 59 …”

Antioxidants-Related Superoxide Dismutase (SOD), Catalase (CAT), Glutathione Peroxidase (GPX), Glutathione-S-Transferase (GST), and Nitric Oxide Synthase (NOS) Gene Variants Analysis in an Obese Population: A Preliminary Case-Control Study

“…This could explain the protective role this allele displays in the present obese cohort. Although, to the authors’ knowledge, no previous study related this variant to the increased/decreased odds of obesity development, other studies have explored the role of this polymorphism with type 2 diabetes mellitus [ 75 ] and altered serum TG/HDL-C levels [ 71 ]. Originally SOD family was related to obesity due to “its protective role as an antioxidant”, and high SOD3 concentration/activity is expected to neutralize the high levels of the superoxide anion (O 2 •− ) effectively [ 29 , 71 ].…”

“…Although, to the authors’ knowledge, no previous study related this variant to the increased/decreased odds of obesity development, other studies have explored the role of this polymorphism with type 2 diabetes mellitus [ 75 ] and altered serum TG/HDL-C levels [ 71 ]. Originally SOD family was related to obesity due to “its protective role as an antioxidant”, and high SOD3 concentration/activity is expected to neutralize the high levels of the superoxide anion (O 2 •− ) effectively [ 29 , 71 ]. This isozyme’s availability on the extracellular compartment and the endothelial cells add advantage to its action to neutralize (O 2 •− ) generated in the extracellular matrix and discontinue the peroxynitrite generation [ 76 ].…”