Colorectal cancer (CRC) stands as a significant global health concern, ranking as the third most common cancer worldwide and the second leading cause of cancer-related deaths in 2020 [1]. The intricate relationship between human diet and CRC risk has been a focus of extensive research, with particular attention given to the multifaceted role of folate [2].
Folate’s Crucial Role in CRC
Folate, a B-vitamin, plays a pivotal role in DNA biosynthesis, repair, and methylation, influencing key cellular processes and maintaining cellular homeostasis. This has led to a surge in interest regarding its potential impact on carcinogenesis, with experimental evidence supporting its preventive effects on colorectal tumorigenesis [3]. However, a paradoxical hypothesis has been proposed, suggesting a dual role of folic acid, where excess folate may enhance the progression of existing premalignant and malignant lesions [4, 5, 6, 7].
Epidemiological Puzzle
Epidemiological studies investigating the relationship between folate intake and CRC risk present a complex picture. While many studies report inverse associations between folate intake and CRC, findings from studies on circulating folate concentrations yield mixed results [[8], [9], [10], [11], [12], [13], [14]]. Additionally, the concept of a latency period for folate intake, beyond which no protective benefit is observed, has been proposed [15].
Genetic Landscape of CRC
Recent advances in genetic research have identified over 200 common genetic variants associated with CRC risk through genome-wide association studies (GWASs) [16, 17, 18, 19, 20]. However, the total contribution of these common variants to familial risk is estimated to be around 20%. Exploring the interaction between these genetic variants and environmental factors, such as diet, may unveil novel genetic loci and shed light on the missing heritability [21].
Limitations of Previous Studies
Previous investigations into the interplay between genetic variants and folate intake have been restricted to a handful of single nucleotide polymorphisms (SNPs) in candidate genes within the folate-mediated one-carbon metabolism (FOCM) pathway. However, these studies have often yielded inconsistent results, hampering a comprehensive understanding of the complex relationship [[22], [23], [24], [25], [26], [27], [28]].
Advancing the Field: Genome-Wide Interaction Analysis
To address the gaps in existing research, we conducted a groundbreaking genome-wide interaction analysis. This comprehensive study aimed to identify SNPs that might modify the effects of dietary and total folate, as well as folic acid supplementation, on CRC risk. By pooling data from 51 studies, representing the largest sample to date, our analysis promises to provide the most robust estimate of the marginal associations between folate and CRC risk.
Discussion: Unraveling the Complex Interactions of Folate, Genetics, and CRC Risk
Our study delved into the intricate interplay between folate and common genetic variants across the genome, representing the most extensive sample to date. The identification of novel interactions, particularly with folic acid supplement use near the 3p25.2 locus and a secondary interaction near the 6p22.3 locus, opens new avenues for understanding colorectal cancer (CRC) risk modulation. Furthermore, our pooled analyses, encompassing over 30,000 CRC cases and 40,000 controls, reinforce the evidence supporting an inverse association between folate and CRC risk.
Confirmation of Inverse Association
Consistent with previous research, our pooled analysis affirms an inverse association between folate (total, dietary, and supplement) and overall CRC risk, including subtypes such as proximal colon, distal colon, and rectal cancer [8,15]. Notably, similar estimates for dietary and total folate underscore the efficacy of folate in CRC prevention even at levels achievable through a regular diet [3]. Despite variations in folate intake due to mandatory fortification policies, our analysis reveals largely consistent study-specific estimates across different countries, emphasizing the robustness of the observed associations [60].
Latency Period and Protective Effect
Our findings support the proposition of a latency period for the protective effect of folate, with observational studies aligning with the hypothesis that the benefit may manifest 12 to 24 years before CRC diagnosis [15]. In contrast, randomized controlled trials with shorter follow-up periods often reported null results or benefits limited to individuals with low folate at baseline [8,10,63].
Genetic Modulation of Folic Acid Supplementation
The identification of two interaction loci, particularly rs150924902 near SYN2 and rs1291413 near the 6p22.3 locus, provides novel insights into the potential mechanisms underlying the interplay between genetics and folic acid supplementation in CRC risk modulation. SYN2’s involvement in neurotransmitter synthesis and its association with glioblastoma and prostate cancer warrant further exploration in the context of CRC [64,65,69,70]. Additionally, the interaction of TIMP4, located within SYN2’s intron, with folic acid supplementation introduces a new dimension, connecting folate availability, homocysteine levels, and extracellular matrix modulation in CRC [71,72,73,74,75,76].
Advancements in Gene-by-Folate Interaction Studies
Our study stands as the first to explore gene-by-folate interactions on a genome-wide scale, overcoming the limitations of previous small-scale investigations focused on specific genetic loci within the folate-mediated one-carbon metabolism pathway [22,23,24,25,26]. The failure to replicate previous associations, such as those with MTHFR variants, highlights the challenges of candidate gene studies and emphasizes the need for large-scale, comprehensive approaches.
Study Strengths and Limitations
The strength of our study lies in its large sample size, sophisticated statistical methods, and comprehensive analyses across overall CRC and subtypes. However, inherent limitations include potential measurement errors in self-reported exposures and the use of a single measurement for folate intake across studies, neglecting changes over participants’ lifecourse. The exclusive focus on European ancestry populations limits generalizability, and potential interactions with other exposure variables or genetic loci warrant further exploration.
Future Directions
Our findings propose that genetic variation in the 3p25.2 region may modify the association between folate and CRC risk. To validate these findings, experimental studies and investigations incorporating omics data are imperative. The complexity of the interplay between folate, genetics, and CRC risk underscores the need for continued exploration, fostering a deeper understanding that can inform personalized prevention and intervention strategies.
reference link : https://www.sciencedirect.com/science/article/pii/S0002916523661088#sec4
