In a nested case-control study published in JAMA Network Open, researchers from South Korea investigated the genetic variants that modify the association between diet and colorectal cancer (CRC) risk.
They found that single-nucleotide polymorphisms (SNPs) in the EPDR1 gene can modify the impact of fish intake on the risk of CRC.
Further, they highlighted the potential pathways underlying the link between the consumption of tea, milk, cheese, and alcohol and the development of CRC.
Study: Genome-Wide Interaction Study of Dietary Intake and Colorectal Cancer Risk in the UK Biobank. Image Credit: BlurryMe/Shutterstock.com
Background
CRC is the second most prevalent cancer in Europe (12.9%) and stands among the top three most-diagnosed cancers in both men and women in the United Kingdom (UK). Evidence suggests that the consumption of meat and alcohol is associated with an increased risk of CRC.
On the other hand, the intake of fish, milk, fruits, and vegetables shows an inverse association with CRC-risk. Genetic factors, accounting for 3.5% to 10.5% of variations, may influence dietary habits and CRC-risk.
For example, specific genes impact the metabolism of carcinogens in cooked meat and modify associations. Similarly, cruciferous vegetables are found to be inversely linked to CRC in individuals with certain enzyme deficiencies.
Advances in technology have enabled genome-wide association studies that reveal genetic susceptibility loci and facilitate the assessment of gene-diet interactions across the genome.
Dietary factors may influence CRC pathogenesis by modulating gene expression through metabolites or activating complex metabolic pathways.
Previous studies explored the role of nutrition in various carcinogenesis pathways, including deoxyribonucleic acid (DNA) synthesis, epigenetic control via one-carbon metabolism, DNA damage, phase 1 and 2 enzymes, tumor promotion, and polynucleotide repair.
Although potential mechanisms suggesting the association between dietary intake and CRC have been proposed, the specific genes and pathways involved in this association have not been extensively documented.
Therefore, researchers in the present study conducted a gene-diet interaction analysis using genetic data and CRC cases to identify genetic variants that influence the association between diet and CRC-risk.
About the study
Data was obtained from the UK Biobank of participants enrolled between 2006 and 2010. Individuals with sex mismatches, putative sex chromosome aneuploidy, non-White racial background, and prevalent cancer at recruitment were excluded.
A total of 4,686 participants (mean age 60.7 years) and 14,058 matched controls (mean age 60.4 years) were included in the study. In both the cohorts, 57.8% of participants were male.
Dietary intake information, including milk, cheese, poultry, red meat, processed meat, fish, coffee, tea, alcohol, and total fruit and vegetables, was collected through a touchscreen food frequency questionnaire.
Although the median follow-up was 12.4 years, only 10.2% of participants had data from more than one follow-up visit. Imputed genotyping data underwent quality control, resulting in 4,122,345 variants for the genome-wide interaction (GWI) analysis.
CRC cases were identified based on the International Statistical Classification of Diseases and Related Health Problems (revision 10).
Gene-based and gene-enrichment analyses were conducted. Statistical analysis involved the Cochran-Mantel-Haenszel χ2 test, conditional logistic model, principal component analysis, and p-values for gene or gene-set levels interactions.
Results and discussion
As compared to controls, the cases had a higher proportion of smokers, higher frequency of alcohol consumption, and higher prevalence of obesity.
Individuals consuming red meat ≥3 times per week and processed meat ≥2 times per week showed a higher CRC-risk (odds ratio 1.16) after adjusting for confounding factors.
Additionally, those who consumed alcohol more than thrice a week showed an increased CRC-risk compared to those with alcohol intake less than once a week. Notably, a protective association against CRC was found for participants consuming ≥4 servings of fruit daily compared to those with ≤ 2 servings daily.
324 SNPs were suggested to interact with dietary intake without statistical significance. Genes EPDR1 and ZNRF2 were identified in the gene-based analysis, with EPDR1 showing significance with fish consumption through multiple SNPs.
Further, gene-set enrichment analysis revealed overrepresented pathways (OR, ART, KRT, PRM, and TNP) for genes interacting with cheese, milk, tea, and alcohol consumption, respectively.
The study’s findings could contribute to personalized preventive strategies and interventions for CRC.
However, the study is limited by the analysis of CRC-risk based on dietary information from a single time point, limited availability of dietary data at multiple follow-up visits, potential instability in certain nutritional factors, inability to confirm specific SNPs modifying diet-CRC associations, and a lack of validation in non-European populations.
Conclusion
In conclusion, the study reveals several SNPs showing suggestive interactions with dietary intake, particularly significant interactions between EPDR1 and total fish consumption affecting CRC- risk.
The findings point to various biological and functional pathways potentially underlying the association and highlight the need for further investigation through experimental studies.
