Association of Selenoprotein and Selenium Pathway Genotypes with Risk of Colorectal Cancer and Interaction with Selenium Status

• Main Authors: Veronika Fedirko, Mazda Jenab, Catherine Méplan, Jeb S. Jones, Wanzhe Zhu, Lutz Schomburg, Afshan Siddiq, Sandra Hybsier, Kim Overvad, Anne Tjønneland, Hanane Omichessan, Vittorio Perduca, Marie-Christine Boutron-Ruault, Tilman Kühn, Verena Katzke, Krasimira Aleksandrova, Antonia Trichopoulou, Anna Karakatsani, Anastasia Kotanidou, Rosario Tumino, Salvatore Panico, Giovanna Masala, Claudia Agnoli, Alessio Naccarati, Bas Bueno-de-Mesquita, Roel C.H. Vermeulen, Elisabete Weiderpass, Guri Skeie, Therese Haugdahl Nøst, Leila Lujan-Barroso, J. Ramón Quirós, José María Huerta, Miguel Rodríguez-Barranco, Aurelio Barricarte, Björn Gylling, Sophia Harlid, Kathryn E. Bradbury, Nick Wareham, Kay-Tee Khaw, Marc Gunter, Neil Murphy, Heinz Freisling, Kostas Tsilidis, Dagfinn Aune, Elio Riboli, John E. Hesketh, David J. Hughes
• Format: Article
• Language: English
• Published: MDPI AG 2019-04-01
• Series: Nutrients
• Subjects: selenium; selenium status; selenoprotein gene variation; selenium pathway; colorectal neoplasms; selenoprotein P; prospective cohort; colorectal cancer risk; genetic epidemiology; biomarkers
• Online Access: https://www.mdpi.com/2072-6643/11/4/935

Selenoprotein genetic variations and suboptimal selenium (Se) levels may contribute to the risk of colorectal cancer (CRC) development. We examined the association between CRC risk and genotype for single nucleotide polymorphisms (SNPs) in selenoprotein and Se metabolic pathway genes. <i>Illumina Goldengate</i> assays were designed and resulted in the genotyping of 1040 variants in 154 genes from 1420 cases and 1421 controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Multivariable logistic regression revealed an association of 144 individual SNPs from 63 Se pathway genes with CRC risk. However, regarding the selenoprotein genes, only <i>TXNRD1</i> rs11111979 retained borderline statistical significance after adjustment for correlated tests (<i>P</i>_ACT = 0.10; <i>P</i>_ACT significance threshold was <i>P</i> &lt; 0.1). SNPs in Wingless/Integrated (Wnt) and Transforming growth factor (TGF) beta-signaling genes (<i>FRZB</i>, <i>SMAD3</i>, <i>SMAD7</i>) from pathways affected by Se intake were also associated with CRC risk after multiple testing adjustments. Interactions with Se status (using existing serum Se and Selenoprotein P data) were tested at the SNP, gene, and pathway levels. Pathway analyses using the modified Adaptive Rank Truncated Product method suggested that genes and gene x Se status interactions in antioxidant, apoptosis, and TGF-beta signaling pathways may be associated with CRC risk. This study suggests that SNPs in the Se pathway alone or in combination with suboptimal Se status may contribute to CRC development.