The Role of rs713041 Glutathione Peroxidase 4 (GPX4) Single Nucleotide Polymorphism on Disease Susceptibility in Humans: A Systematic Review and Meta-Analysis

Abstract

Aim: The single-nucleotide polymorphism (SNP) rs713041, located in the regulatory region, is required to incorporate selenium into the selenoprotein glutathione peroxidase 4 (GPX4) and has been found to have functional consequences. This systematic review aimed to conduct a meta-analysis to determine whether there is an association between GPX4 (rs713041) SNP and the risk of diseases in humans and its correlation with selenium status. Material and methods: A systematic search for English-language manuscripts published between January 1990 and November 2022 was carried out using six databases: CINAHL, Cochrane, Medline, PubMed, Scopus and Web of Science. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to assess a relationship between GPX4 (rs713041) SNP and the risk of different diseases based on three genetic models. Review Manager 5.4 and Comprehensive Meta-Analysis 4 software were used to perform the meta-analysis and carry out Egger’s test for publication bias. Results: Data from 21 articles were included in the systematic review. Diseases were clustered according to the physiological system affected to understand better the role of GPX4 (rs713041) SNP in developing different diseases. Carriers of the GPX4 (rs173041) T allele were associated with an increased risk of developing colorectal cancer in additive and dominant models (p = 0.02 and p = 0.004, respectively). In addition, carriers of the T allele were associated with an increased risk of developing stroke and hypertension in the additive, dominant and recessive models (p = 0.002, p = 0.004 and p = 0.01, respectively). On the other hand, the GPX4 (rs713041) T allele was associated with a decreased risk of developing pre-eclampsia in the additive, dominant and recessive models (p < 0.0001, p = 0.002 and p = 0.0005, respectively). Moreover, selenium levels presented lower mean values in cancer patients relative to control groups (SMD = −0.39 µg/L; 95% CI: −0.64, −0.14; p = 0.002, I2 = 85%). Conclusion: GPX4 (rs713041) T allele may influence colorectal cancer risk, stroke, hypertension and pre-eclampsia. In addition, low selenium levels may play a role in the increased risk of cancer.

Distinct Roles of SELENOF in Different Human Cancers

“…Some selenoproteins have been investigated in this regard due to altered levels in cancers compared to normal tissues, their molecular function, or the association of genetic variations in the corresponding genes to cancer risk or outcome [ 25 , 26 ]. For example, polymorphisms in the genes for members of the glutathione peroxidase family of antioxidant selenoproteins have been associated with the risk of several cancers, although epidemiological studies have often resulted in conflicting results [ 27 , 28 ]. Possible reasons for studies yielding different conclusions include the impact of selenium status or ethnicity of study participants [ 29 , 30 ].…”

Glutathione peroxidase 4 suppresses manganese-dependent oxidative stress to reduce colorectal tumorigenesis.

“…An earlier study reported no significant overall association with colorectal adenoma risk for GPX4 ( Peters et al, 2008 ). However, a recent systematic review showed that carriers of the GPX4 (rs173041) T allele were associated with an increased risk of developing colorectal cancer ( Barbosa et al, 2022 ). Another most recent study reports that high expression of GPX4, which suppresses ferroptosis, was associated with poorer 5-year overall survival only in KRAS mutant tumors from male colorectal cancer patients ( Yan et al, 2023 ).…”

Ferroptosis in Cardiovascular Disease and Cardiomyopathies: Therapeutic Implications of Glutathione and Iron Chelating Agents

“…Ultimately, exhausting the glutathione levels would decrease GPX4 activity and intensify its propensity for ferroptosis [ 17 ] ( Figure 1 ). Glutathione peroxidase 4, also known as phospholipid hydroperoxide glutathione peroxidase (GPX4), possesses a unique capability to reduce hydroperoxides found in intricate lipids like phospholipids, cholesterol, and cholesterolester hydroperoxides, even when they are incorporated into biomembranes or lipoproteins [ 18 ]. This ability is crucial for preventing the iron (Fe 2+ )-dependent formation of harmful lipid reactive oxygen species (ROS) [ 18 ].…”

“…Glutathione peroxidase 4, also known as phospholipid hydroperoxide glutathione peroxidase (GPX4), possesses a unique capability to reduce hydroperoxides found in intricate lipids like phospholipids, cholesterol, and cholesterolester hydroperoxides, even when they are incorporated into biomembranes or lipoproteins [ 18 ]. This ability is crucial for preventing the iron (Fe 2+ )-dependent formation of harmful lipid reactive oxygen species (ROS) [ 18 ]. The significance of GPX4 extends to normal physiology, as its absence is incompatible with life due to its pivotal role in preserving mitochondrial function, inflammation, differentiation, immunity, and cell death [ 18 ].…”

“…This ability is crucial for preventing the iron (Fe 2+ )-dependent formation of harmful lipid reactive oxygen species (ROS) [ 18 ]. The significance of GPX4 extends to normal physiology, as its absence is incompatible with life due to its pivotal role in preserving mitochondrial function, inflammation, differentiation, immunity, and cell death [ 18 ]. The inhibition of GPX4 function results in lipid peroxidation and can trigger ferroptosis, an iron-dependent, non-apoptotic form of cell death [ 18 ].…”