TY - JOUR
T1 - Interaction between polymorphisms in aspirin metabolic pathways, regular aspirin use and colorectal cancer risk
T2 - A case-control study in unselected white European populations
AU - Sheth, Harsh
AU - Northwood, Emma
AU - Ulrich, Cornelia M.
AU - Scherer, Dominique
AU - Elliott, Faye
AU - Barrett, Jennifer H.
AU - Forman, David
AU - Wolf, C. Roland
AU - Smith, Gillian
AU - Jackson, Michael S.
AU - Santibanez-Koref, Mauro
AU - Haile, Robert
AU - Casey, Graham
AU - Jenkins, Mark
AU - Win, Aung Ko
AU - Hopper, John L
AU - Marchand, Loic Le
AU - Lindor, Noralane M.
AU - Thibodeau, Stephen N.
AU - Potter, John D.
AU - Burn, John
AU - Bishop, D. Timothy
N1 - The UK-CCSG study was supported by the Cancer Research UK grant C588/A19167. The NIH-CCFR study was supported by grant UM1 CA167551 from the National Cancer Institute and through cooperative agreements with the following CCFR centers: Australasian Colorectal Cancer Family Registry (U01 CA074778 and U01/U24 CA097735), Ontario Familial Colorectal Cancer Registry (U01/U24 CA074783) and Seattle Colorectal Cancer Family Registry (U01/U24 CA074794). The Colon CFR Illumina GWAS was supported by funding from the National Cancer Institute, National Institutes of Health (U01 CA122839 and R01 CA143237 to Graham Casey). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Colon Cancer Family Registry (CCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CCFR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PY - 2018/2/9
Y1 - 2018/2/9
N2 - Regular aspirin use is associated with reduced risk of colorectal cancer (CRC). Variation in aspirin's chemoprevention efficacy has been attributed to the presence of single nucleotide polymorphisms (SNPs). We conducted a meta-analysis using two large population-based case-control datasets, the UK-Leeds Colorectal Cancer Study Group and the NIH-Colon Cancer Family Registry, having a combined total of 3325 cases and 2262 controls. The aim was to assess 42 candidate SNPs in 15 genes whose association with colorectal cancer risk was putatively modified by aspirin use, in the literature. Log odds ratios (ORs) and standard errors were estimated for each dataset separately using logistic regression adjusting for age, sex and study site, and dataset-specific results were combined using random effects meta-analysis. Meta-analysis showed association between SNPs rs6983267, rs11694911 and rs2302615 with CRC risk reduction (All P<0.05). Association for SNP rs6983267 in the CCAT2 gene only was noteworthy after multiple test correction (P = 0.001). Site-specific analysis showed association between SNPs rs1799853 and rs2302615 with reduced colon cancer risk only (P = 0.01 and P = 0.004, respectively), however neither reached significance threshold following multiple test correction. Meta-analysis of SNPs rs2070959 and rs1105879 in UGT1A6 gene showed interaction between aspirin use and CRC risk (Pinteraction = 0.01 and 0.02, respectively); stratification by aspirin use showed an association for decreased CRC risk for aspirin users having a wild-type genotype (rs2070959 OR = 0.77, 95% CI = 0.68-0.86; rs1105879 OR = 0.77 95% CI = 0.69-0.86) compared to variant allele cariers. The direction of the interaction however is in contrast to that published in studies on colorectal adenomas. Both SNPs showed potential site-specific interaction with aspirin use and colon cancer risk only (Pinteraction = 0.006 and 0.008, respectively), with the direction of association similar to that observed for CRC. Additionally, they showed interaction between any non-steroidal anti-inflammatory drugs (including aspirin) use and CRC risk (Pinteraction = 0.01 for both). All gene x environment (GxE) interactions however were not significant after multiple test correction. Candidate gene investigation indicated no evidence of GxE interaction between genetic variants in genes involved in aspirin pathways, regular aspirin use and colorectal cancer risk.
AB - Regular aspirin use is associated with reduced risk of colorectal cancer (CRC). Variation in aspirin's chemoprevention efficacy has been attributed to the presence of single nucleotide polymorphisms (SNPs). We conducted a meta-analysis using two large population-based case-control datasets, the UK-Leeds Colorectal Cancer Study Group and the NIH-Colon Cancer Family Registry, having a combined total of 3325 cases and 2262 controls. The aim was to assess 42 candidate SNPs in 15 genes whose association with colorectal cancer risk was putatively modified by aspirin use, in the literature. Log odds ratios (ORs) and standard errors were estimated for each dataset separately using logistic regression adjusting for age, sex and study site, and dataset-specific results were combined using random effects meta-analysis. Meta-analysis showed association between SNPs rs6983267, rs11694911 and rs2302615 with CRC risk reduction (All P<0.05). Association for SNP rs6983267 in the CCAT2 gene only was noteworthy after multiple test correction (P = 0.001). Site-specific analysis showed association between SNPs rs1799853 and rs2302615 with reduced colon cancer risk only (P = 0.01 and P = 0.004, respectively), however neither reached significance threshold following multiple test correction. Meta-analysis of SNPs rs2070959 and rs1105879 in UGT1A6 gene showed interaction between aspirin use and CRC risk (Pinteraction = 0.01 and 0.02, respectively); stratification by aspirin use showed an association for decreased CRC risk for aspirin users having a wild-type genotype (rs2070959 OR = 0.77, 95% CI = 0.68-0.86; rs1105879 OR = 0.77 95% CI = 0.69-0.86) compared to variant allele cariers. The direction of the interaction however is in contrast to that published in studies on colorectal adenomas. Both SNPs showed potential site-specific interaction with aspirin use and colon cancer risk only (Pinteraction = 0.006 and 0.008, respectively), with the direction of association similar to that observed for CRC. Additionally, they showed interaction between any non-steroidal anti-inflammatory drugs (including aspirin) use and CRC risk (Pinteraction = 0.01 for both). All gene x environment (GxE) interactions however were not significant after multiple test correction. Candidate gene investigation indicated no evidence of GxE interaction between genetic variants in genes involved in aspirin pathways, regular aspirin use and colorectal cancer risk.
UR - http://www.scopus.com/inward/record.url?scp=85041919787&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0192223
DO - 10.1371/journal.pone.0192223
M3 - Article
C2 - 29425227
SN - 1932-6203
VL - 13
SP - 1
EP - 17
JO - PLoS ONE
JF - PLoS ONE
IS - 2
M1 - e0192223
ER -