Abstract 815: Genome-wide gene-calcium interaction in relation to colorectal cancer risk
Authors: Díez-Obrero Virginia , van Duijnhoven Fränzel , Kim Andre E. , Baurley James , Campbell Peter T. , Carreras-Torres Robert , Chang-Claude Jenny , Conti David V. , Jenab Mazda , Hsu Li , Jordahl Kristina M. , Lewinger Juan Pablo , Lin Yi , Newcomb Polly A. , Obón-Santacana Mireia , Bens Pardamean , Anita Peoples , Qu Conghui , Ruiz-Narvaez Edward , Tian Yu , Tsilidis Kostas , Casey Graham , Peters Ulrike , Gauderman James W. , Moreno Victor 
Published: July 2021

Abstract
Calcium intake has been associated with a decreased risk of colorectal cancer (CRC). However, the role of germline genetics and the molecular mechanisms underlying this association have not been fully elucidated. In previous gene-environment studies, several single nucleotide polymorphisms (SNPs), including some associated with genes involved in calcium reabsorption, have been identified but with limited statistical power. In this study, we aimed to investigate SNP interactions with calcium intake in relation to CRC risk in the largest study to date.
We performed a genome-wide interaction study (GWIS) using genotype and self-reported calcium intake information from 31,007 CRC cases and 41,683 controls (n=72,690) of European ancestry from 46 studies within the GECCO study. We ran the analysis with the GxEScanR package and adjusted the models by sex, age, study, total energy intake, and genetic ancestry (3 principal components).
Higher total calcium (dietary and supplemental) intake was associated with reduced CRC risk (OR per quartile, 0.83; 95% CI, 0.78-0.89). Similar results were found for dietary calcium intake and for stratified analyses by sex and anatomic location (proximal, distal and rectum). Total calcium intake was strongly associated with SNPs near the MCM6 gene, related to lactose intolerance. In the GWIS results, we found 60 and 82 SNPs (suggestive hits, P values &lt; 5e-6) interacting with total and dietary calcium intake, respectively, in relation to CRC risk, some located in genes such as CNTNAP2, SHFM1, PEBP4, NRDE2, PLA2G4D, SLC26A11, ZNF45, and PLA2G4D. No variants reached the 10-8 threshold. Finally, we performed annotation in open chromatin regions, expression quantitative trait loci (eQTLs) and genes differentially expressed according to calcium intake in colon tissue.
In conclusion, our preliminary results provide suggestive loci for gene-calcium interaction in relation to CRC risk, which may give insights into the molecular mechanisms underlying the preventive role of calcium in this type of cancer. Further analyses will include joint association tests, two-step methods and additive and multiplicative polygenic risk score analyses.
Citation Format: Virginia Díez-Obrero, Fränzel van Duijnhoven, Andre E. Kim, James Baurley, Peter T. Campbell, Robert Carreras-Torres, Jenny Chang-Claude, David V. Conti, Mazda Jenab, Li Hsu, Kristina M. Jordahl, Juan Pablo Lewinger, Yi Lin, Polly A. Newcomb, Mireia Obón-Santacana, Pardamean Bens, Peoples Anita, Conghui Qu, Edward Ruiz-Narvaez, Yu Tian, Kostas Tsilidis, Graham Casey, Ulrike Peters, James W. Gauderman, Victor Moreno. Genome-wide gene-calcium interaction in relation to colorectal cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 815.