Selenium Pathway Genotypes Are Associated With Colorectal Cancer Risk And Modified By Selenium Status

David HUGHES, Royal College of Surgeons in Ireland, Ireland
FEDIRKO V. 2 , JONES J. 2 , MÉPLAN C. 3 , SCHOMBURG L. 4 , HYBSIER S. 4 , RIBOLI E. 5 , JENAB M. 6

1 Centre for Systems Medicine & Department of Physiology, Royal College of Surgeons in Ireland, Dublin 2, Ireland
2 Rollins School of Public Health, Emory University, Atlanta GA, USA
3 Institute for Cell and Molecular Biosciences & Human Nutrition Research Centre, Newcastle University, Newcastle-upon-Tyne, UK
4 Institute for Experimental Endocrinology, University Medical School Berlin, Germany
5 School of Public Health, Imperial College London, UK
6 Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France

Purpose: Suboptimal intakes of the micronutrient selenium (Se) and selenoprotein genetic variation may contribute to colorectal cancer (CRC). We recently reported the association of higher Se status with lower CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (Hughes et al. 2015; PMID 25042282). In this study, we examine the association of Se pathway genotypes with CRC risk, including the interaction of SNP-Se status in disease risk modification.
Methods: Tagging SNPs (N=1050) in the Se pathway (153 selected genes comprising 159 variants in 24 of 25 selenoprotein genes plus 891 variants in 129 genes in pathways sensitive to Se intake) were successfully assayed by Illumina GoldengateTM genotyping in DNA samples from 1478 CRC case-control pairs matched within EPIC (a further 99 SNPs with at least 20% missing data were excluded from analysis). Multivariate logistic regression was used to assess the influence of Se pathway genetic variation on CRC risk. In pathway analyses, genes were sorted into at least one known functional pathway and gene and pathway p-values were computed using the PIGE package Adaptive Rank Truncated test.
Results: Genetic variations in 20 of 41 selenoprotein and Se biosynthesis genes, plus variations in several other Se pathway genes, are associated with CRC risk (not adjusted for multiple testing). Additionally, genetic variation can interact with Se status (as assessed by our existing data on serum Se and Selenoprotein P) to decrease or increase CRC risk. Pathway analyses suggest that gene only and gene-Se interactions in selenoprotein, anti-oxidant and apoptosis pathways may alter CRC susceptibility risk.
Conclusions: Individuals of particular risk Se pathway genotypes and / or those with suboptimal Se status may especially benefit from an increased dietary Se intake for CRC prevention. 
 
Funding: The Irish Health Research Board (grant HRA_PHS/2013/397; PI: D. Hughes) and various EPIC funders.