Browsing by Author "Papadimitriou N"

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    A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk.
    (American Association for Cancer Research, 2023-08-01) Aglago EK; Kim A; Lin Y; Qu C; Evangelou M; Ren Y; Morrison J; Albanes D; Arndt V; Barry EL; Baurley JW; Berndt SI; Bien SA; Bishop DT; Bouras E; Brenner H; Buchanan DD; Budiarto A; Carreras-Torres R; Casey G; Cenggoro TW; Chan AT; Chang-Claude J; Chen X; Conti DV; Devall M; Diez-Obrero V; Dimou N; Drew D; Figueiredo JC; Gallinger S; Giles GG; Gruber SB; Gsur A; Gunter MJ; Hampel H; Harlid S; Hidaka A; Harrison TA; Hoffmeister M; Huyghe JR; Jenkins MA; Jordahl K; Joshi AD; Kawaguchi ES; Keku TO; Kundaje A; Larsson SC; Marchand LL; Lewinger JP; Li L; Lynch BM; Mahesworo B; Mandic M; Obón-Santacana M; Moreno V; Murphy N; Nan H; Nassir R; Newcomb PA; Ogino S; Ose J; Pai RK; Palmer JR; Papadimitriou N; Pardamean B; Peoples AR; Platz EA; Potter JD; Prentice RL; Rennert G; Ruiz-Narvaez E; Sakoda LC; Scacheri PC; Schmit SL; Schoen RE; Shcherbina A; Slattery ML; Stern MC; Su Y-R; Tangen CM; Thibodeau SN; Thomas DC; Tian Y; Ulrich CM; van Duijnhoven FJ; Van Guelpen B; Visvanathan K; Vodicka P; Wang J; White E; Wolk A; Woods MO; Wu AH; Zemlianskaia N; Hsu L; Gauderman WJ; Peters U; Tsilidis KK; Campbell PT
    Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
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    Genome-wide interaction analysis of folate for colorectal cancer risk.
    (Elsevier B.V., 2023-11) Bouras E; Kim AE; Lin Y; Morrison J; Du M; Albanes D; Barry EL; Baurley JW; Berndt SI; Bien SA; Bishop TD; Brenner H; Budiarto A; Burnett-Hartman A; Campbell PT; Carreras-Torres R; Casey G; Cenggoro TW; Chan AT; Chang-Claude J; Conti DV; Cotterchio M; Devall M; Diez-Obrero V; Dimou N; Drew DA; Figueiredo JC; Giles GG; Gruber SB; Gunter MJ; Harrison TA; Hidaka A; Hoffmeister M; Huyghe JR; Joshi AD; Kawaguchi ES; Keku TO; Kundaje A; Le Marchand L; Lewinger JP; Li L; Lynch BM; Mahesworo B; Männistö S; Moreno V; Murphy N; Newcomb PA; Obón-Santacana M; Ose J; Palmer JR; Papadimitriou N; Pardamean B; Pellatt AJ; Peoples AR; Platz EA; Potter JD; Qi L; Qu C; Rennert G; Ruiz-Narvaez E; Sakoda LC; Schmit SL; Shcherbina A; Stern MC; Su Y-R; Tangen CM; Thomas DC; Tian Y; Um CY; van Duijnhoven FJ; Van Guelpen B; Visvanathan K; Wang J; White E; Wolk A; Woods MO; Ulrich CM; Hsu L; Gauderman WJ; Peters U; Tsilidis KK
    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.
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    Probing the diabetes and colorectal cancer relationship using gene - environment interaction analyses.
    (Springer Nature, 2023-06-26) Dimou N; Kim AE; Flanagan O; Murphy N; Diez-Obrero V; Shcherbina A; Aglago EK; Bouras E; Campbell PT; Casey G; Gallinger S; Gruber SB; Jenkins MA; Lin Y; Moreno V; Ruiz-Narvaez E; Stern MC; Tian Y; Tsilidis KK; Arndt V; Barry EL; Baurley JW; Berndt SI; Bézieau S; Bien SA; Bishop DT; Brenner H; Budiarto A; Carreras-Torres R; Cenggoro TW; Chan AT; Chang-Claude J; Chanock SJ; Chen X; Conti DV; Dampier CH; Devall M; Drew DA; Figueiredo JC; Giles GG; Gsur A; Harrison TA; Hidaka A; Hoffmeister M; Huyghe JR; Jordahl K; Kawaguchi E; Keku TO; Larsson SC; Le Marchand L; Lewinger JP; Li L; Mahesworo B; Morrison J; Newcomb PA; Newton CC; Obon-Santacana M; Ose J; Pai RK; Palmer JR; Papadimitriou N; Pardamean B; Peoples AR; Pharoah PDP; Platz EA; Potter JD; Rennert G; Scacheri PC; Schoen RE; Su Y-R; Tangen CM; Thibodeau SN; Thomas DC; Ulrich CM; Um CY; van Duijnhoven FJB; Visvanathan K; Vodicka P; Vodickova L; White E; Wolk A; Woods MO; Qu C; Kundaje A; Hsu L; Gauderman WJ; Gunter MJ; Peters U
    BACKGROUND: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis. METHODS: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test). RESULTS: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - ORAA: 1.62, 95% CI: 1.34-1.96; ORAG: 1.41, 95% CI: 1.30-1.54; ORGG: 1.22, 95% CI: 1.13-1.31; p-value3-d.f.: 5.46 × 10-11) and 13q14.13 (rs9526201, LRCH1 - ORGG: 2.11, 95% CI: 1.56-2.83; ORGA: 1.52, 95% CI: 1.38-1.68; ORAA: 1.13, 95% CI: 1.06-1.21; p-value2-d.f.: 7.84 × 10-09). DISCUSSION: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.
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    Prospective and Mendelian randomization analyses on the association of circulating fatty acid binding protein 4 (FABP-4) and risk of colorectal cancer.
    (BioMed Central, 2023-10-13) Nimptsch K; Aleksandrova K; Pham TT; Papadimitriou N; Janke J; Christakoudi S; Heath A; Olsen A; Tjønneland A; Schulze MB; Katzke V; Kaaks R; van Guelpen B; Harbs J; Palli D; Macciotta A; Pasanisi F; Yohar SMC; Guevara M; Amiano P; Grioni S; Jakszyn PG; Figueiredo JC; Samadder NJ; Li CI; Moreno V; Potter JD; Schoen RE; Um CY; Weiderpass E; Jenab M; Gunter MJ; Pischon T
    BACKGROUND: Fatty acid binding protein 4 (FABP-4) is a lipid-binding adipokine upregulated in obesity, which may facilitate fatty acid supply for tumor growth and promote insulin resistance and inflammation and may thus play a role in colorectal cancer (CRC) development. We aimed to investigate the association between circulating FABP-4 and CRC and to assess potential causality using a Mendelian randomization (MR) approach. METHODS: The association between pre-diagnostic plasma measurements of FABP-4 and CRC risk was investigated in a nested case-control study in 1324 CRC cases and the same number of matched controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A two-sample Mendelian randomization study was conducted based on three genetic variants (1 cis, 2 trans) associated with circulating FABP-4 identified in a published genome-wide association study (discovery n = 20,436) and data from 58,131 CRC cases and 67,347 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. RESULTS: In conditional logistic regression models adjusted for potential confounders including body size, the estimated relative risk, RR (95% confidence interval, CI) per one standard deviation, SD (8.9 ng/mL) higher FABP-4 concentration was 1.01 (0.92, 1.12) overall, 0.95 (0.80, 1.13) in men and 1.09 (0.95, 1.25) in women. Genetically determined higher FABP-4 was not associated with colorectal cancer risk (RR per FABP-4 SD was 1.10 (0.95, 1.27) overall, 1.03 (0.84, 1.26) in men and 1.21 (0.98, 1.48) in women). However, in a cis-MR approach, a statistically significant association was observed in women (RR 1.56, 1.09, 2.23) but not overall (RR 1.23, 0.97, 1.57) or in men (0.99, 0.71, 1.37). CONCLUSIONS: Taken together, these analyses provide no support for a causal role of circulating FABP-4 in the development of CRC, although the cis-MR provides some evidence for a positive association in women, which may deserve to be investigated further.
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    Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.
    (American Association for the Advancement of Science, 2024-05-29) Drew DA; Kim AE; Lin Y; Qu C; Morrison J; Lewinger JP; Kawaguchi E; Wang J; Fu Y; Zemlianskaia N; Díez-Obrero V; Bien SA; Dimou N; Albanes D; Baurley JW; Wu AH; Buchanan DD; Potter JD; Prentice RL; Harlid S; Arndt V; Barry EL; Berndt SI; Bouras E; Brenner H; Budiarto A; Burnett-Hartman A; Campbell PT; Carreras-Torres R; Casey G; Chang-Claude J; Conti DV; Devall MAM; Figueiredo JC; Gruber SB; Gsur A; Gunter MJ; Harrison TA; Hidaka A; Hoffmeister M; Huyghe JR; Jenkins MA; Jordahl KM; Kundaje A; Le Marchand L; Li L; Lynch BM; Murphy N; Nassir R; Newcomb PA; Newton CC; Obón-Santacana M; Ogino S; Ose J; Pai RK; Palmer JR; Papadimitriou N; Pardamean B; Pellatt AJ; Peoples AR; Platz EA; Rennert G; Ruiz-Narvaez E; Sakoda LC; Scacheri PC; Schmit SL; Schoen RE; Stern MC; Su Y-R; Thomas DC; Tian Y; Tsilidis KK; Ulrich CM; Um CY; van Duijnhoven FJB; Van Guelpen B; White E; Hsu L; Moreno V; Peters U; Chan AT; Gauderman WJ
    Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.