Interaction between polymorphisms in aspirin metabolic pathways, regular aspirin use and colorectal cancer risk

A case-control study in unselected white European populations

Harsh Sheth (Lead / Corresponding author), Emma Northwood, Cornelia M. Ulrich, Dominique Scherer, Faye Elliott, Jennifer H. Barrett, David Forman, C. Roland Wolf, Gillian Smith, Michael S. Jackson, Mauro Santibanez-Koref, Robert Haile, Graham Casey, Mark Jenkins, Aung Ko Win, John L Hopper, Loic Le Marchand, Noralane M. Lindor, Stephen N. Thibodeau, John D. Potter & 2 others John Burn, D. Timothy Bishop

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    Abstract

    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.

    Original languageEnglish
    Article numbere0192223
    Pages (from-to)1-17
    Number of pages17
    JournalPLoS ONE
    Volume13
    Issue number2
    DOIs
    Publication statusPublished - 9 Feb 2018

    Fingerprint

    aspirin
    Metabolic Networks and Pathways
    case-control studies
    Polymorphism
    colorectal neoplasms
    Aspirin
    biochemical pathways
    Case-Control Studies
    Colorectal Neoplasms
    genetic polymorphism
    Single Nucleotide Polymorphism
    Nucleotides
    Genes
    single nucleotide polymorphism
    Population
    Association reactions
    Meta-Analysis
    meta-analysis
    Colonic Neoplasms
    Gene-Environment Interaction

    Cite this

    Sheth, Harsh ; Northwood, Emma ; Ulrich, Cornelia M. ; Scherer, Dominique ; Elliott, Faye ; Barrett, Jennifer H. ; Forman, David ; Wolf, C. Roland ; Smith, Gillian ; Jackson, Michael S. ; Santibanez-Koref, Mauro ; Haile, Robert ; Casey, Graham ; Jenkins, Mark ; Win, Aung Ko ; Hopper, John L ; Marchand, Loic Le ; Lindor, Noralane M. ; Thibodeau, Stephen N. ; Potter, John D. ; Burn, John ; Bishop, D. Timothy. / Interaction between polymorphisms in aspirin metabolic pathways, regular aspirin use and colorectal cancer risk : A case-control study in unselected white European populations. In: PLoS ONE. 2018 ; Vol. 13, No. 2. pp. 1-17.
    @article{1210baab6b5d4408adc7a56914194a8d,
    title = "Interaction between polymorphisms in aspirin metabolic pathways, regular aspirin use and colorectal cancer risk: A case-control study in unselected white European populations",
    abstract = "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.",
    author = "Harsh Sheth and Emma Northwood and Ulrich, {Cornelia M.} and Dominique Scherer and Faye Elliott and Barrett, {Jennifer H.} and David Forman and Wolf, {C. Roland} and Gillian Smith and Jackson, {Michael S.} and Mauro Santibanez-Koref and Robert Haile and Graham Casey and Mark Jenkins and Win, {Aung Ko} and Hopper, {John L} and Marchand, {Loic Le} and Lindor, {Noralane M.} and Thibodeau, {Stephen N.} and Potter, {John D.} and John Burn and Bishop, {D. Timothy}",
    note = "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.",
    year = "2018",
    month = "2",
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    doi = "10.1371/journal.pone.0192223",
    language = "English",
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    Sheth, H, Northwood, E, Ulrich, CM, Scherer, D, Elliott, F, Barrett, JH, Forman, D, Wolf, CR, Smith, G, Jackson, MS, Santibanez-Koref, M, Haile, R, Casey, G, Jenkins, M, Win, AK, Hopper, JL, Marchand, LL, Lindor, NM, Thibodeau, SN, Potter, JD, Burn, J & Bishop, DT 2018, 'Interaction between polymorphisms in aspirin metabolic pathways, regular aspirin use and colorectal cancer risk: A case-control study in unselected white European populations', PLoS ONE, vol. 13, no. 2, e0192223, pp. 1-17. https://doi.org/10.1371/journal.pone.0192223

    Interaction between polymorphisms in aspirin metabolic pathways, regular aspirin use and colorectal cancer risk : A case-control study in unselected white European populations. / Sheth, Harsh (Lead / Corresponding author); Northwood, Emma; Ulrich, Cornelia M.; Scherer, Dominique; Elliott, Faye; Barrett, Jennifer H.; Forman, David; Wolf, C. Roland; Smith, Gillian; Jackson, Michael S.; Santibanez-Koref, Mauro; Haile, Robert; Casey, Graham; Jenkins, Mark; Win, Aung Ko; Hopper, John L; Marchand, Loic Le; Lindor, Noralane M.; Thibodeau, Stephen N.; Potter, John D.; Burn, John; Bishop, D. Timothy (Lead / Corresponding author).

    In: PLoS ONE, Vol. 13, No. 2, e0192223, 09.02.2018, p. 1-17.

    Research output: Contribution to journalArticle

    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.

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    DO - 10.1371/journal.pone.0192223

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