rs1050450 — GPX1 Pro198Leu

GPX1 Pro198Leu — Your Selenium-Powered Antioxidant Shield

Glutathione peroxidase 1 (GPX1) is the most abundant member of the selenoprotein family¹¹ selenoprotein family
Proteins that incorporate the amino acid selenocysteine at their active site, requiring dietary selenium for synthesis, a group of enzymes that depend on dietary selenium for their activity. GPX1 serves as a frontline defense against oxidative damage by converting hydrogen peroxide (H2O2) and organic hydroperoxides into harmless water and alcohols, using glutathione²² glutathione
A tripeptide (glutamate-cysteine-glycine) that serves as the cell's primary antioxidant and detoxification molecule as its reducing substrate. The Pro198Leu variant (rs1050450) changes a proline to leucine in the enzyme, reducing its catalytic activity and -- critically -- diminishing its responsiveness to selenium. This makes it one of the most actionable variants in the antioxidant pathway: adequate selenium intake can partially compensate for the genetic reduction.

The Mechanism

GPX1 contains a selenocysteine residue³³ selenocysteine residue
The 21st amino acid, encoded by a UGA codon that is recoded by a selenocysteine insertion sequence (SECIS) in the mRNA's 3' UTR at its active site, which is essential for catalysis. The enzyme reduces H2O2 to water in a two-step reaction: selenocysteine is first oxidized by the peroxide substrate, then reduced back to its active form by two molecules of glutathione. This cycle occurs millions of times per second in every cell.

The Pro198Leu substitution (C>T at codon 198, reported as G>A on the plus strand) does not directly disrupt the active site but alters the enzyme's tertiary structure in a way that reduces catalytic efficiency. In vitro studies⁴⁴ In vitro studies
Hu YJ and Diamond AM demonstrated in breast carcinoma cell lines that the Leu variant shows significantly lower enzyme activity and reduced responsiveness to selenium supplementation in cell lines showed the Leu allele produces an enzyme with approximately 40% lower activity than the Pro allele. Perhaps more importantly, the Leu variant shows a blunted response to selenium supplementation -- the enzyme fails to upregulate as effectively when selenium levels rise.

A study of 405 healthy individuals⁵⁵ study of 405 healthy individuals
Jablonska E et al. Association between GPx1 Pro198Leu polymorphism, GPx1 activity and plasma selenium concentration in humans. Eur J Nutr, 2009 quantified this genotype-selenium interaction precisely. The correlation between plasma selenium and red blood cell GPx1 activity was strong for Pro/Pro carriers (r = 0.44, p < 0.001), intermediate for Pro/Leu (r = 0.35, p < 0.001), and essentially absent for Leu/Leu (r = 0.25, p = 0.45). In other words, Leu/Leu carriers derive substantially less antioxidant benefit from a given selenium intake compared to Pro/Pro carriers.

The Evidence

The clinical consequences of reduced GPX1 activity have been examined across multiple disease domains.

Cancer risk. A comprehensive meta-analysis of 60 studies⁶⁶ comprehensive meta-analysis of 60 studies
Xie Y et al. Association between GPX1 rs1050450 polymorphisms and cancer risk. Int J Clin Exp Pathol, 2020 (21,296 cancer cases, 30,346 controls) found the TT (Leu/Leu) genotype associated with modestly increased overall cancer susceptibility (OR 1.15, 95% CI 1.00-1.31). Subgroup analyses revealed particularly strong associations with bladder cancer (OR 3.56, 95% CI 1.42-8.94), head and neck cancer (OR 2.19, 95% CI 1.39-3.46), and brain tumors (OR 1.19, 95% CI 1.03-1.37).

Cardiovascular disease. A meta-analysis of 10 studies⁷⁷ meta-analysis of 10 studies
Bao Y et al. Association of GPx-1 rs1050450 Pro198Leu and Pro197Leu polymorphisms with cardiovascular risk. J Geriatr Cardiol, 2014 (1,430 cases, 3,767 controls) found the variant associated with cardiovascular disease risk under a co-dominant model (OR 1.36, 95% CI 1.08-1.70), with a particularly strong effect in East Asian populations (OR 1.84, 95% CI 1.39-2.43). A Japanese study of type 2 diabetic patients found the Leu allele associated with increased carotid intima-media thickness⁸⁸ increased carotid intima-media thickness
Hamanishi T et al. Functional variants in GPx-1 gene associated with increased intima-media thickness and macrovascular disease in Japanese type 2 diabetic patients. Diabetes, 2004, a marker of subclinical atherosclerosis.

Diabetic neuropathy. The TT genotype was significantly associated with diabetic peripheral neuropathy⁹⁹ diabetic peripheral neuropathy
Tang TS et al. Pro198Leu polymorphism in GPX1 contributes to diabetic peripheral neuropathy in type 2 diabetes patients. NeuroMolecular Medicine, 2016 in type 2 diabetes patients (OR 1.89, 95% CI 1.30-2.74), likely through increased oxidative damage to peripheral nerves.

Practical Implications

GPX1 Pro198Leu is unusually actionable because the enzyme's activity is directly dependent on selenium availability. The recommended dietary allowance (RDA)¹⁰¹⁰ recommended dietary allowance (RDA)
55 mcg/day for adults, set by the US Institute of Medicine based on the amount needed to maximize plasma GPx activity for selenium is 55 mcg per day, but this was calibrated for an average population. Individuals with the Leu allele likely need higher selenium intake to achieve the same level of GPX1 activity. Good dietary sources include Brazil nuts (one nut contains roughly 70-90 mcg selenium), seafood, organ meats, and whole grains.

Selenium supplementation in the range of 100-200 mcg/day (total from diet plus supplements) appears safe and may partially compensate for the genetic reduction in enzyme activity. The tolerable upper limit is 400 mcg/day; exceeding this risks selenosis (hair loss, nail changes, neurological symptoms). Selenomethionine is the preferred supplemental form due to superior bioavailability.

Beyond selenium, maintaining adequate glutathione levels supports GPX1 function. N-acetylcysteine (NAC), a glutathione precursor, and dietary sources rich in cysteine (cruciferous vegetables, allium family) help sustain the glutathione pool that GPX1 requires as its co-substrate.

Interactions

GPX1 functions in a critical two-step antioxidant relay with SOD2¹¹¹¹ SOD2
Superoxide dismutase 2 (rs4880), the mitochondrial enzyme that converts superoxide radicals to hydrogen peroxide (manganese superoxide dismutase, rs4880). SOD2 converts superoxide radicals into hydrogen peroxide, which GPX1 then neutralizes to water. When GPX1 activity is reduced by the Pro198Leu variant, hydrogen peroxide generated by SOD2 accumulates, increasing oxidative damage. This effect is compounded when SOD2 itself carries the Val16Ala variant (rs4880 T allele), which alters its mitochondrial import efficiency. Studies have shown that the combination of variant alleles in both SOD2 and GPX1 is associated with significantly higher oxidative stress markers and increased bladder cancer risk compared to either variant alone. This SOD2-GPX1 interaction represents a biologically plausible compound effect: SOD2 feeds H2O2 into GPX1, so deficiency at either step -- or both -- disrupts the entire antioxidant relay. A compound implication should be created for the combination of GPX1 rs1050450 AA (or AG) with SOD2 rs4880 TT, recommending enhanced antioxidant support including selenium, CoQ10, and mitochondria-targeted antioxidants like MitoQ.