Browsing by Author "Diez-Obrero V"

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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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    Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations.
    (Springer Nature, 2023-10-02) Thomas M; Su Y-R; Rosenthal EA; Sakoda LC; Schmit SL; Timofeeva MN; Chen Z; Fernandez-Rozadilla C; Law PJ; Murphy N; Carreras-Torres R; Diez-Obrero V; van Duijnhoven FJB; Jiang S; Shin A; Wolk A; Phipps AI; Burnett-Hartman A; Gsur A; Chan AT; Zauber AG; Wu AH; Lindblom A; Um CY; Tangen CM; Gignoux C; Newton C; Haiman CA; Qu C; Bishop DT; Buchanan DD; Crosslin DR; Conti DV; Kim D-H; Hauser E; White E; Siegel E; Schumacher FR; Rennert G; Giles GG; Hampel H; Brenner H; Oze I; Oh JH; Lee JK; Schneider JL; Chang-Claude J; Kim J; Huyghe JR; Zheng J; Hampe J; Greenson J; Hopper JL; Palmer JR; Visvanathan K; Matsuo K; Matsuda K; Jung KJ; Li L; Le Marchand L; Vodickova L; Bujanda L; Gunter MJ; Matejcic M; Jenkins MA; Slattery ML; D'Amato M; Wang M; Hoffmeister M; Woods MO; Kim M; Song M; Iwasaki M; Du M; Udaltsova N; Sawada N; Vodicka P; Campbell PT; Newcomb PA; Cai Q; Pearlman R; Pai RK; Schoen RE; Steinfelder RS; Haile RW; Vandenputtelaar R; Prentice RL; Küry S; Castellví-Bel S; Tsugane S; Berndt SI; Lee SC; Brezina S; Weinstein SJ; Chanock SJ; Jee SH; Kweon S-S; Vadaparampil S; Harrison TA; Yamaji T; Keku TO; Vymetalkova V; Arndt V; Jia W-H; Shu X-O; Lin Y; Ahn Y-O; Stadler ZK; Van Guelpen B; Ulrich CM; Platz EA; Potter JD; Li CI; Meester R; Moreno V; Figueiredo JC; Casey G; Lansdorp Vogelaar I; Dunlop MG; Gruber SB; Hayes RB; Pharoah PDP; Houlston RS; Jarvik GP; Tomlinson IP; Zheng W; Corley DA; Peters U; Hsu L
    Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.
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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.