Current Understanding of Human Polymorphism in Selenoprotein Genes: A Review of Its Significance as a Risk Biomarker

International Journal of Molecular Sciences · 7 authors, 2 centres

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This review summarizes how polymorphisms in selenoprotein genes (e.g., GPX1, GPX4, SelP, DIO2) can alter protein function and selenium status, thereby influencing susceptibility to diseases such as cancer, cardiovascular disease, diabetes, and thyroid disorders. The paper highlights that specific variants, like the Pro198Leu (rs1050450) polymorphism in GPX1, are associated with increased risk for several cancers and other conditions, while some variants may offer protection. Understanding these genetic variations could lead to personalized risk assessment and targeted prevention strategies.

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**Background:** Selenium (Se) is an essential trace element incorporated into 25 selenoproteins in humans, including glutathione peroxidases (GPXs), thioredoxin reductases (TXNRDs), iodothyronine deiodinases (DIOs), and selenoproteins P, F, S, and others. These proteins play critical roles in antioxidant defense, thyroid hormone metabolism, immune function, and fertility. Se deficiency affects over 500 million people worldwide and is linked to increased mortality and disease risk. Recent evidence indicates that single nucleotide polymorphisms (SNPs) in selenoprotein genes can affect protein expression, activity, and selenium status, thereby modulating disease susceptibility. This narrative review aims to describe the role of selenoprotein gene polymorphisms as potential risk biomarkers for various diseases.

**Methods:** The authors conducted a narrative review of the literature, summarizing findings from multiple studies (primarily case-control and cohort designs) that investigated associations between selenoprotein polymorphisms and disease risk or progression. The review focuses on the most studied polymorphisms in GPX1 (rs1050450, alanine repetition, rs1800668), GPX3 (rs8177409, rs3805435, rs8177412), GPX4 (rs713041, rs4965814, rs9874), SelP (rs7579, rs3877899, rs11959466, rs13168440), SelF (rs5845, rs5859), SelS (-105G>A, rs34713741), TXNRD1 (rs35009941), TXNRD2 (rs4485648), and DIO1/DIO2/DIO3 (rs11206244, rs12885300, rs225014, rs945006). The review includes studies from diverse populations across multiple countries.

**Key Results:** The most extensively studied polymorphism is GPX1 rs1050450 (Pro198Leu), a C to T substitution resulting in a proline-to-leucine change that reduces enzyme activity. This variant was associated with: increased risk of breast cancer (1.9-fold for non-ductal, 1.43-fold for T allele carriers in Danish cohorts), lung cancer (higher risk in South Korean and Finnish smokers), bladder cancer (3.8-fold increased probability in Ecuadorian population, association with advanced stage in Japanese and Serbian cohorts), prostate cancer (higher risk in Turkish population, protective in North Macedonian), keratoconus (higher risk in Egyptian, Iranian, and Turkish populations), open-angle glaucoma (increased risk in Polish cohort), diabetic peripheral neuropathy (increased risk in Polish and Turkish patients), Kashin-Beck disease (increased risk in Chinese), and restenosis after coronary stenting (74% increased risk in carriers). Conversely, the T allele was associated with decreased mortality and higher Activity of Daily Living scores in a Danish longevity cohort. The alanine repetition polymorphism (Ala5/Ala6/Ala7) in GPX1 was linked to autism spectrum disorder (Ala5 more frequent in patients) and head and neck cancer progression (Ala7 associated with second primary tumors). The GPX4 rs713041 (T to C substitution in 3'UTR) was associated with increased risk of cerebral stroke in Russian hypertensive patients, acute pancreatitis recurrence in Polish patients, preeclampsia in Chinese women, and endometriosis in Taiwanese women. The SelP rs7579 (G to A) was associated with increased risk of prostate cancer in German men and metabolic syndrome in a Chinese cohort. The SelP rs3877899 (Ala234Thr) was associated with a 3.8-fold higher risk of breast cancer in Iranian women and treatment failure in prostate cancer in African-American men. The SelF rs5859 (G to A) was associated with increased risk of Kashin-Beck disease in Chinese, shorter progression to AIDS in HIV-positive patients, and 2.8-fold higher risk of breast cancer in Iranian women. The SelS -105G>A polymorphism was associated with increased risk of gastric cancer in Japanese, spontaneous preterm birth in Chinese, and Hashimoto's thyroiditis in Portuguese (3.94-fold increased risk in males). The TXNRD2 rs4485648 was associated with a 4.6-fold increased risk of type 2 diabetes in Slovenian patients. The DIO2 Thr92Ala (rs225014) polymorphism was associated with a 47% reduced risk of intrahospital mortality in Brazilian COVID-19 patients and lower bone mineral density in Korean women. The DIO3 rs945006 minor G allele was associated with poor outcome after ischemic stroke in Lithuanian patients.

**Clinical Implications:** This review underscores the potential of selenoprotein polymorphisms as risk biomarkers for a wide range of diseases, including cancers, cardiovascular diseases, metabolic disorders, thyroid diseases, and neurodegenerative conditions. The findings suggest that genetic variations in selenoprotein genes can modulate selenium metabolism and antioxidant capacity, thereby influencing disease susceptibility and progression. For example, the GPX1 Pro198Leu polymorphism, which reduces enzyme activity by up to 30-40%, may increase oxidative stress and contribute to carcinogenesis and cardiovascular pathology. Similarly, polymorphisms in SelP, which is the primary selenium transporter, can affect selenium distribution to tissues and impact diseases like prostate cancer and metabolic syndrome. The review highlights the potential for personalized medicine approaches, where individuals carrying specific polymorphisms could be identified as at-risk and offered targeted interventions, such as selenium supplementation or enhanced monitoring. However, the authors note that many studies show conflicting results across populations, likely due to differences in selenium status, dietary habits, genetic background, and environmental factors. The review also identifies gaps in knowledge, particularly for less-studied selenoproteins like SelH, SelN, SelW, SelV, SelT, SelI, SelK, SelM, SelR, and SelO, whose functions and polymorphisms remain poorly characterized. Future research should focus on large-scale, multi-ethnic studies with standardized selenium status assessment to clarify these associations and translate them into clinical practice.

STUDY TYPE

narrative_review

SPECIALTY

nutrition

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AI pipeline

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80% · B

ORIGINAL PAPER

PMC10855570

Current Understanding of Human Polymorphism in Selenoprotein Genes: A Review of Its Significance as a Risk Biomarker

International Journal of Molecular Sciences

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ABSTRACT

Abstract Selenium has been proven to influence several biological functions, showing to be an essential micronutrient. The functional studies demonstrated the benefits of a balanced selenium diet and how its deficiency is associated with diverse diseases, especially cancer and viral diseases. Selenium is an antioxidant, protecting the cells from damage, enhancing the immune system response, preventing cardiovascular diseases, and decreasing inflammation. Selenium can be found in its inorganic and organic forms, and its main form in the cells is the selenocysteine incorporated into selenoproteins. Twenty-five selenoproteins are currently known in the human genome: glutathione peroxidases, iodothyronine deiodinases, thioredoxin reductases, selenophosphate synthetase, and other selenoproteins. These proteins lead to the transport of selenium in the tissues, protect against oxidative damage, contribute to the stress of the endoplasmic reticulum, and control inflammation. Due to these functions, there has been growing interest in the influence of polymorphisms in selenoproteins in the last two decades. Selenoproteins’ gene polymorphisms may influence protein structure and selenium concentration in plasma and its absorption and even impact the development and progression of certain diseases. This review aims to elucidate the role of selenoproteins and understand how their gene polymorphisms can influence the balance of physiological conditions. In this polymorphism review, we focused on the PubMed database, with only articles published in English between 2003 and 2023. The keywords used were “selenoprotein” and “polymorphism”. Articles that did not approach the theme subject were excluded. Selenium and selenoproteins still have a long way to go in molecular studies, and several works demonstrated the importance of their polymorphisms as a risk biomarker for some diseases, especially cardiovascular and thyroid diseases, diabetes, and cancer. Keywords: selenium, selenoprotein, biomarker, polymorphism

CITATION EXPORT

Roberto Rodrigues Ferreira, Regina Vieira Carvalho, Laura Lacerda Coelho et al.. Current Understanding of Human Polymorphism in Selenoprotein Genes: A Review of Its Significance as a Risk Biomarker. International Journal of Molecular Sciences. (2024). https://doi.org/10.3390/ijms25031402

AUTHORS

7 · 2 CENTRES

Roberto Rodrigues Ferreira, Regina Vieira Carvalho, Laura Lacerda Coelho, Beatriz Matheus de Souza Gonzaga, Maria da Gloria Bonecini-Almeida, Luciana Ribeiro Garzoni, Tania C Araujo-Jorge

1Laboratory of Innovations in Therapies, Education and Bioproducts, Oswaldo Cruz Institute (LITEB-IOC/Fiocruz), Oswaldo Cruz Foundation (Fiocruz), Avenida Brasil 4365, Manguinhos, Pav. Cardoso Fontes, Sala 64, Rio de Janeiro 21040-360, Brazil; [email protected] (R.V.C.); [email protected] (L.L.C.); [email protected] (B.M.d.S.G.); [email protected] (L.R.G.)
2Laboratory of Immunology and Immunogenetics, Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Avenida Brasil 4365, Manguinhos, Rio de Janeiro 21040-360, Brazil; [email protected]