| Authors: |
Bouras, E.; Kim, A. E.; Lin, Y.; Morrison, J.; Du, M.; Albanes, D.; Barry, E. L.; Baurley, J. W.; Berndt, S. I.; Bien, S. A.; Bishop, T. D.; Brenner, H.; Budiarto, A.; Burnett-Hartman, A.; Campbell, P. T.; Carreras-Torres, R.; Casey, G.; Cenggoro, T. W.; Chan, A. T.; Chang-Claude, J.; Conti, D. V.; Cotterchio, M.; Devall, M.; Diez-Obrero, V.; Dimou, N.; Drew, D. A.; Figueiredo, J. C.; Giles, G. G.; Gruber, S. B.; Gunter, M. J.; Harrison, T. A.; Hidaka, A.; Hoffmeister, M.; Huyghe, J. R.; Joshi, A. D.; Kawaguchi, E. S.; Keku, T. O.; Kundaje, A.; Le Marchand, L.; Lewinger, J. P.; Li, L.; Lynch, B. M.; Mahesworo, B.; Männistö, S.; Moreno, V.; Murphy, N.; Newcomb, P. A.; Obón-Santacana, M.; Ose, J.; Palmer, J. R.; Papadimitriou, N.; Pardamean, B.; Pellatt, A. J.; Peoples, A. R.; Platz, E. A.; Potter, J. D.; Qi, L.; Qu, C.; Rennert, G.; Ruiz-Narvaez, E.; Sakoda, L. C.; Schmit, S. L.; Shcherbina, A.; Stern, M. C.; Su, Y. R.; Tangen, C. M.; Thomas, D. C.; Tian, Y.; Um, C. Y.; van Duijnhoven, F. J. B.; Van Guelpen, B.; Visvanathan, K.; Wang, J.; White, E.; Wolk, A.; Woods, M. O.; Ulrich, C. M.; Hsu, L.; Gauderman, W. J.; Peters, U.; Tsilidis, K. K. |
| Article Title: |
Genome-wide interaction analysis of folate for colorectal cancer risk |
| Abstract: |
Background: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC. Objectives: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. Methods: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). Results: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. Conclusions: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding. © 2023 The Author(s) |
| Keywords: |
controlled study; human tissue; major clinical study; single nucleotide polymorphism; case control study; genetics; case-control studies; cancer localization; cancer risk; colorectal cancer; metabolism; allele; gene expression; genetic variability; genotype; gene frequency; genetic variation; genome-wide association study; risk factors; risk factor; colorectal neoplasms; body mass; colorectal tumor; genetic susceptibility; vitamin supplementation; interaction; dietary supplements; folic acid; alcohol consumption; dna methyltransferase; dietary supplement; 5 methyltetrahydrofolate homocysteine methyltransferase; 5,10 methylenetetrahydrofolate reductase (fadh2); gene linkage disequilibrium; folate; genome-wide; european; folate metabolism; synapsin; folate intake; humans; human; male; female; article; crc; colon tissue; people by smoking status; anatomical location; gwis; syn2; timp4; tissue inhibitor of metalloproteinase 4; synapsin ii
|
| Journal Title: |
American Journal of Clinical Nutrition
|
| Volume: |
118 |
| Issue: |
5 |
| ISSN: |
0002-9165 |
| Publisher: |
American Society for Nutrition
|
| Date Published: |
2023-11-01 |
| Start Page: |
881 |
| End Page: |
891 |
| Language: |
English |
| DOI: |
10.1016/j.ajcnut.2023.08.010
|
| PUBMED: |
37640106
|
| PROVIDER: |
scopus
|
| PMCID: |
PMC10636229
|
| DOI/URL: |
|
| Notes: |
The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Scopus |
