Abstract
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. Illumina Goldengate 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 TXNRD1 rs11111979 retained borderline statistical significance after adjustment for correlated tests (PACT = 0.10; PACT significance threshold was P < 0.1). SNPs in Wingless/Integrated (Wnt) and Transforming growth factor (TGF) beta-signaling genes (FRZB, SMAD3, SMAD7) 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.
Highlights
In Europe, colorectal cancer (CRC) is the cancer type with both the second highest incidence and mortality rate [1]
Considering nominal significance for association with disease risk by pathway of P < 0.05, these analyses suggest that Transforming growth factor (TGF)-beta signaling (P < 0.001) is the sole pathway highly associated with CRC risk independent of Se status interaction
Selenoprotein genes nominally associated with CRC risk included several with limited or no prior evidence (DIO1, GPX6, SELENOM, SELENON, SELENOT, SELENOV) and those reported in several studies (GPX1, GPX4, SELENOF, TXNRD1, TXNRD2, TXNRD3) for an association with CRC risk
Summary
In Europe, colorectal cancer (CRC) is the cancer type with both the second highest incidence and mortality rate [1]. Experimental and observational evidence suggests that suboptimal dietary intakes of the micronutrient selenium (Se) contribute to greater risk for the development of cancers at several anatomical sites, including the colorectum [4,5,6]. Adequate Se intake and selenoprotein expression have been shown to prevent colon cancer while selenoprotein dysregulation may increase colon cancer risk [14,15,16]. Data from nutritional intervention trials and epidemiological studies suggest implications for Se intake regarding CRC risk could potentially be more important in individuals with particular selenoprotein genotypes and/or in populations with low Se status, such as in Western Europe where the present study was conducted [4,5,17,18]. Risk modification by sex has been observed for CRC risk associations with selenoprotein genotypes [19,20] and Se status [5,17]
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