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114 results on '"Carreras-Torres R"'

1. Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk

Author: Tian, Y, Lin, Y, Qu, C, Arndt, V, Baurley, JW, Berndt, SI, Bien, SA, Bishop, DT, Brenner, H, Buchanan, DD, Budiarto, A, Campbell, PT, Carreras-Torres, R, Casey, G, Chan, AT, Chen, R, Chen, X, Conti, DV, Diez-Obrero, V, Dimou, N, Drew, DA, Figueiredo, JC, Gallinger, S, Giles, GG, Gruber, SB, Gunter, MJ, Harlid, S, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jenkins, MA, Jordahl, KM, Joshi, AD, Keku, TO, Kawaguchi, E, Kim, AE, Kundaje, A, Larsson, SC, Marchand, LL, Lewinger, JP, Li, L, Moreno, V, Morrison, J, Murphy, N, Nan, H, Nassir, R, Newcomb, PA, Obon-Santacana, M, Ogino, S, Ose, J, Pardamean, B, Pellatt, AJ, Peoples, AR, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Ruiz-Narvaez, EA, Sakoda, LC, Schoen, RE, Shcherbina, A, Stern, MC, Su, Y-R, Thibodeau, SN, Thomas, DC, Tsilidis, KK, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, White, E, Wolk, A, Woods, MO, Wu, AH, Peters, U, Gauderman, WJ, Hsu, L, Chang-Claude, J, Tian, Y, Lin, Y, Qu, C, Arndt, V, Baurley, JW, Berndt, SI, Bien, SA, Bishop, DT, Brenner, H, Buchanan, DD, Budiarto, A, Campbell, PT, Carreras-Torres, R, Casey, G, Chan, AT, Chen, R, Chen, X, Conti, DV, Diez-Obrero, V, Dimou, N, Drew, DA, Figueiredo, JC, Gallinger, S, Giles, GG, Gruber, SB, Gunter, MJ, Harlid, S, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jenkins, MA, Jordahl, KM, Joshi, AD, Keku, TO, Kawaguchi, E, Kim, AE, Kundaje, A, Larsson, SC, Marchand, LL, Lewinger, JP, Li, L, Moreno, V, Morrison, J, Murphy, N, Nan, H, Nassir, R, Newcomb, PA, Obon-Santacana, M, Ogino, S, Ose, J, Pardamean, B, Pellatt, AJ, Peoples, AR, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Ruiz-Narvaez, EA, Sakoda, LC, Schoen, RE, Shcherbina, A, Stern, MC, Su, Y-R, Thibodeau, SN, Thomas, DC, Tsilidis, KK, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, White, E, Wolk, A, Woods, MO, Wu, AH, Peters, U, Gauderman, WJ, Hsu, L, and Chang-Claude, J
Abstract: BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.
Published: 2024

2. A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Author: Aglago, EK, Kim, A, Lin, Y, Qu, C, Evangelou, M, Ren, Y, Morrison, J, Albanes, D, Arndt, V, Barry, EL, Baurley, JW, Berndt, S, Bien, SA, Bishop, DT, Bouras, E, Brenner, H, Buchanan, DD, Budiarto, A, Carreras-Torres, R, Casey, G, Cenggoro, TW, Chen, AT, Chang-Claude, J, Chen, X, Conti, D, 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, Le Marchand, L, Lewinger, JP, Li, L, Lynch, BM, Mahesworo, B, Mandic, M, Obon-Santacana, M, Morento, V, Murphy, N, Men, 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, FJB, 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, Aglago, EK, Kim, A, Lin, Y, Qu, C, Evangelou, M, Ren, Y, Morrison, J, Albanes, D, Arndt, V, Barry, EL, Baurley, JW, Berndt, S, Bien, SA, Bishop, DT, Bouras, E, Brenner, H, Buchanan, DD, Budiarto, A, Carreras-Torres, R, Casey, G, Cenggoro, TW, Chen, AT, Chang-Claude, J, Chen, X, Conti, D, 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, Le Marchand, L, Lewinger, JP, Li, L, Lynch, BM, Mahesworo, B, Mandic, M, Obon-Santacana, M, Morento, V, Murphy, N, Men, 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, FJB, 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, and Campbell, PT
Abstract: UNLABELLED: 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.
Published: 2023

3. Genetic Predictors for Fecal Propionate and Butyrate-Producing Microbiome Pathway Are Not Associated with Colorectal Cancer Risk: A Mendelian Randomization Analysis.

Author: Lu, Y, Zhao, YC, Chang-Claude, J, Gruber, SB, Gsur, A, Offit, K, Vodickova, L, Woods, MO, Nguyen, LH, Wade, KH, Carreras-Torres, R, Moreno, V, Buchanan, DD, Cotterchio, M, Chan, AT, Phipps, AI, Peters, U, Song, M, Lu, Y, Zhao, YC, Chang-Claude, J, Gruber, SB, Gsur, A, Offit, K, Vodickova, L, Woods, MO, Nguyen, LH, Wade, KH, Carreras-Torres, R, Moreno, V, Buchanan, DD, Cotterchio, M, Chan, AT, Phipps, AI, Peters, U, and Song, M
Abstract: BACKGROUND: Mechanistic data indicate the benefit of short-chain fatty acids (SCFA) produced by gut microbial fermentation of fiber on colorectal cancer, but direct epidemiologic evidence is limited. A recent study identified SNPs for two SCFA traits (fecal propionate and butyrate-producing microbiome pathway PWY-5022) in Europeans and showed metabolic benefits. METHODS: We conducted a two-sample Mendelian randomization analysis of the genetic instruments for the two SCFA traits (three SNPs for fecal propionate and nine for PWY-5022) in relation to colorectal cancer risk in three large European genetic consortia of 58,131 colorectal cancer cases and 67,347 controls. We estimated the risk of overall colorectal cancer and conducted subgroup analyses by sex, age, and anatomic subsites of colorectal cancer. RESULTS: We did not observe strong evidence for an association of the genetic predictors for fecal propionate levels and the abundance of PWY-5022 with the risk of overall colorectal cancer, colorectal cancer by sex, or early-onset colorectal cancer (diagnosed at <50 years), with no evidence of heterogeneity or pleiotropy. When assessed by tumor subsites, we found weak evidence for an association between PWY-5022 and risk of rectal cancer (OR per 1-SD, 0.95; 95% confidence intervals, 0.91-0.99; P = 0.03) but it did not surpass multiple testing of subgroup analysis. CONCLUSIONS: Genetic instruments for fecal propionate levels and the abundance of PWY-5022 were not associated with colorectal cancer risk. IMPACT: Fecal propionate and PWY-5022 may not have a substantial influence on colorectal cancer risk. Future research is warranted to comprehensively investigate the effects of SCFA-producing bacteria and SCFAs on colorectal cancer risk.
Published: 2023

4. Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response

Author: Carreras-Torres, R, Kim, AE, Lin, Y, Diez-Obrero, V, Bien, SA, Qu, C, Wang, J, Dimou, N, Aglago, EK, Albanes, D, Arndt, V, Baurley, JW, Berndt, SI, Bezieau, S, Bishop, DT, Bouras, E, Brenner, H, Budiarto, A, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Chen, X, Conti, D, Dampier, CH, Devall, MAM, Drew, DA, Figueiredo, JC, Gallinger, S, Giles, GG, Gruber, SB, Gsur, A, Gunter, MJ, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jenkins, MA, Jordahl, KM, Kawaguchi, E, Keku, TO, Kundaje, A, Le Marchand, L, Lewinger, JP, Li, L, Mahesworo, B, Morrison, JL, Murphy, N, Nan, H, Nassir, R, Newcomb, PA, Obon-Santacana, M, Ogino, S, Ose, J, Pai, RK, Palmer, JR, Papadimitriou, N, Pardamean, B, Peoples, AR, Pharoah, PDP, Platz, EA, Rennert, G, Ruiz-Narvaez, E, Sakoda, LC, Scacheri, PC, Schmit, SL, Schoen, RE, Shcherbina, A, Slattery, ML, Stern, MC, Su, Y-R, Tangen, CM, Thomas, DC, Tian, Y, Tsilidis, KK, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Vodicka, P, Cenggoro, TW, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Hsu, L, Peters, U, Moreno, V, Gauderman, WJ, Carreras-Torres, R, Kim, AE, Lin, Y, Diez-Obrero, V, Bien, SA, Qu, C, Wang, J, Dimou, N, Aglago, EK, Albanes, D, Arndt, V, Baurley, JW, Berndt, SI, Bezieau, S, Bishop, DT, Bouras, E, Brenner, H, Budiarto, A, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Chen, X, Conti, D, Dampier, CH, Devall, MAM, Drew, DA, Figueiredo, JC, Gallinger, S, Giles, GG, Gruber, SB, Gsur, A, Gunter, MJ, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jenkins, MA, Jordahl, KM, Kawaguchi, E, Keku, TO, Kundaje, A, Le Marchand, L, Lewinger, JP, Li, L, Mahesworo, B, Morrison, JL, Murphy, N, Nan, H, Nassir, R, Newcomb, PA, Obon-Santacana, M, Ogino, S, Ose, J, Pai, RK, Palmer, JR, Papadimitriou, N, Pardamean, B, Peoples, AR, Pharoah, PDP, Platz, EA, Rennert, G, Ruiz-Narvaez, E, Sakoda, LC, Scacheri, PC, Schmit, SL, Schoen, RE, Shcherbina, A, Slattery, ML, Stern, MC, Su, Y-R, Tangen, CM, Thomas, DC, Tian, Y, Tsilidis, KK, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Vodicka, P, Cenggoro, TW, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Hsu, L, Peters, U, Moreno, V, and Gauderman, WJ
Abstract: BACKGROUND: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer. METHODS: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia. RESULTS: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33). CONCLUSIONS: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response. IMPACT: These findings can guide potential prevention treatments.
Published: 2023

5. Probing the diabetes and colorectal cancer relationship using gene - environment interaction analyses

Author: 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, Bezieau, 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, 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, Bezieau, 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, and Peters, U
Abstract: 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.
Published: 2023

6. Genome-wide interaction analysis of folate for colorectal cancer risk

Author: 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, Mannisto, S, Moreno, V, Murphy, N, Newcomb, PA, Obon-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, FJB, Van Guelpen, B, Visvanathan, K, Wang, J, White, E, Wolk, A, Woods, MO, Ulrich, CM, Hsu, L, Gauderman, WJ, Peters, U, Tsilidis, KK, 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, Mannisto, S, Moreno, V, Murphy, N, Newcomb, PA, Obon-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, FJB, Van Guelpen, B, Visvanathan, K, Wang, J, White, E, Wolk, A, Woods, MO, Ulrich, CM, Hsu, L, Gauderman, WJ, Peters, U, and Tsilidis, KK
Abstract: 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 assoc
Published: 2023

7. Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk

Author: Tian, Y, Kim, AE, Bien, SA, Lin, Y, Qu, C, Harrison, TA, Carreras-Torres, R, Diez-Obrero, V, Dimou, N, Drew, DA, Hidaka, A, Huyghe, JR, Jordahl, KM, Morrison, J, Murphy, N, Obon-Santacana, M, Ulrich, CM, Ose, J, Peoples, AR, Ruiz-Narvaez, EA, Shcherbina, A, Stern, MC, Su, Y-R, van Duijnhoven, FJB, Arndt, V, Baurley, JW, Berndt, S, Bishop, DT, Brenner, H, Buchanan, DD, Chan, AT, Figueiredo, JC, Gallinger, S, Gruber, SB, Harlid, S, Hoffmeister, M, Jenkins, MA, Joshi, AD, Keku, TO, Larsson, SC, Le Marchand, L, Li, L, Giles, GG, Milne, RL, Nan, H, Nassir, R, Ogino, S, Budiarto, A, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Sakoda, LC, Schoen, RE, Slattery, ML, Thibodeau, SN, Van Guelpen, B, Visvanathan, K, White, E, Wolk, A, Woods, MO, Wu, AH, Campbell, PT, Casey, G, Conti, D, Gunter, MJ, Kundaje, A, Lewinger, JP, Moreno, V, Newcomb, PA, Pardamean, B, Thomas, DC, Tsilidis, KK, Peters, U, Gauderman, WJ, Hsu, L, Chang-Claude, J, Tian, Y, Kim, AE, Bien, SA, Lin, Y, Qu, C, Harrison, TA, Carreras-Torres, R, Diez-Obrero, V, Dimou, N, Drew, DA, Hidaka, A, Huyghe, JR, Jordahl, KM, Morrison, J, Murphy, N, Obon-Santacana, M, Ulrich, CM, Ose, J, Peoples, AR, Ruiz-Narvaez, EA, Shcherbina, A, Stern, MC, Su, Y-R, van Duijnhoven, FJB, Arndt, V, Baurley, JW, Berndt, S, Bishop, DT, Brenner, H, Buchanan, DD, Chan, AT, Figueiredo, JC, Gallinger, S, Gruber, SB, Harlid, S, Hoffmeister, M, Jenkins, MA, Joshi, AD, Keku, TO, Larsson, SC, Le Marchand, L, Li, L, Giles, GG, Milne, RL, Nan, H, Nassir, R, Ogino, S, Budiarto, A, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Sakoda, LC, Schoen, RE, Slattery, ML, Thibodeau, SN, Van Guelpen, B, Visvanathan, K, White, E, Wolk, A, Woods, MO, Wu, AH, Campbell, PT, Casey, G, Conti, D, Gunter, MJ, Kundaje, A, Lewinger, JP, Moreno, V, Newcomb, PA, Pardamean, B, Thomas, DC, Tsilidis, KK, Peters, U, Gauderman, WJ, Hsu, L, and Chang-Claude, J
Abstract: BACKGROUND: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. METHODS: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. RESULTS: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4). CONCLUSION: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.
Published: 2022

8. Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses

Author: Seyed Khoei, N., Jenab, M., Murphy, N., Banbury, B.L., Carreras-Torres, R., Viallon, V., Kühn, T., Bueno-de-Mesquita, B., Aleksandrova, K., Cross, A.J., Weiderpass, E., Stepien, M., Bulmer, A., Tjønneland, A., Boutron-Ruault, M.C., Severi, G., Carbonnel, F., Katzke, V., Boeing, H., Bergmann, M.M., Trichopoulou, A., Karakatsani, A., Martimianaki, G., Palli, D., Tagliabue, G., Panico, S., Tumino, R., Sacerdote, C., Skeie, G., Merino, S., Bonet, C., Rodríguez-Barranco, M., Gil, L., Chirlaque, M.D., Ardanaz, E., Myte, R., Hultdin, J., Perez-Cornago, A., Aune, D., Tsilidis, K.K., Albanes, D., Baron, J.A., Berndt, S.I., Bézieau, S., Brenner, H., Campbell, P.T., Casey, G., Chang-Claude, J., Chanock, S.J., Cotterchio, M., Gallinger, S., Gruber, S.B., Haile, R.W., Hampe, J., Hoffmeister, M., Hopper, J.L., Hsu, L., Huyghe, J.R., Jenkins, M.A., Joshi, A.D., Kampman, E., Larsson, S.C., Le Marchand, L., Li, C.I., Li, L., Lindblom, A., Lindor, N.M., Martín, V., Moreno, V., Newcomb, P.A., Offit, K., Ogino, S., Parfrey, P.S., Pharoah, P.D.P., Rennert, G., Sakoda, L.C., Schafmayer, C., Schmit, S.L., Schoen, R.E., Slattery, M.L., Thibodeau, S.N., Ulrich, C.M., van Duijnhoven, F.J.B., Weigl, K., Weinstein, S.J., White, E., Wolk, A., Woods, M.O., Wu, A.H., Zhang, X., Ferrari, P., Anton, G., Peters, A., Peters, U., Gunter, M.J., Wagner, K.H., and Freisling, H.
Subjects: Bilirubin, Cancer, Colorectal Cancer, Anti-oxidants, Mendelian Randomization Analysis
Abstract: Background Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. Methods In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 x 10(-8)) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study. Results The associations between circulating UCB levels and CRC risk differed by sex (P-heterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the mainUGT1A1SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12);P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06);P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (P-heterogeneity >= 0.2). Conclusions Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.
Published: 2020

9. Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses

Author: Seyed Khoei, N. Jenab, M. Murphy, N. Banbury, B.L. Carreras-Torres, R. Viallon, V. Kühn, T. Bueno-De-Mesquita, B. Aleksandrova, K. Cross, A.J. Weiderpass, E. Stepien, M. Bulmer, A. Tjønneland, A. Boutron-Ruault, M.-C. Severi, G. Carbonnel, F. Katzke, V. Boeing, H. Bergmann, M.M. Trichopoulou, A. Karakatsani, A. Martimianaki, G. Palli, D. Tagliabue, G. Panico, S. Tumino, R. Sacerdote, C. Skeie, G. Merino, S. Bonet, C. Rodríguez-Barranco, M. Gil, L. Chirlaque, M.-D. Ardanaz, E. Myte, R. Hultdin, J. Perez-Cornago, A. Aune, D. Tsilidis, K.K. Albanes, D. Baron, J.A. Berndt, S.I. Bézieau, S. Brenner, H. Campbell, P.T. Casey, G. Chan, A.T. Chang-Claude, J. Chanock, S.J. Cotterchio, M. Gallinger, S. Gruber, S.B. Haile, R.W. Hampe, J. Hoffmeister, M. Hopper, J.L. Hsu, L. Huyghe, J.R. Jenkins, M.A. Joshi, A.D. Kampman, E. Larsson, S.C. Le Marchand, L. Li, C.I. Li, L. Lindblom, A. Lindor, N.M. Martín, V. Moreno, V. Newcomb, P.A. Offit, K. Ogino, S. Parfrey, P.S. Pharoah, P.D.P. Rennert, G. Sakoda, L.C. Schafmayer, C. Schmit, S.L. Schoen, R.E. Slattery, M.L. Thibodeau, S.N. Ulrich, C.M. Van Duijnhoven, F.J.B. Weigl, K. Weinstein, S.J. White, E. Wolk, A. Woods, M.O. Wu, A.H. Zhang, X. Ferrari, P. Anton, G. Peters, A. Peters, U. Gunter, M.J. Wagner, K.-H. Freisling, H.
Abstract: Background: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. Methods: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study. Results: The associations between circulating UCB levels and CRC risk differed by sex (P heterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (P heterogeneity ≥ 0.2). Conclusions: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development. © 2020 The Author(s).
Published: 2020

10. Transcriptome-wide association study reveals candidate causal genes for lung cancer.

Author: Bossé, Y., Li, Z, Xia, J., Manem, Venkata, Carreras-Torres, R., Gabriel, A., Gaudreault, N., Kiemeney, L.A.L.M., Amos, C.I., McKay, J.D., Bossé, Y., Li, Z, Xia, J., Manem, Venkata, Carreras-Torres, R., Gabriel, A., Gaudreault, N., Kiemeney, L.A.L.M., Amos, C.I., and McKay, J.D.
Abstract: Contains fulltext : 220580.pdf (Publisher’s version ) (Closed access)
Published: 2020

11. Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses.

Author: English D., Van Guelpen B., Visvanathan K., Vodicka P., Vodickova L., Vymetalkova V., Wang H., White E., Wolk A., Woods M.O., Wu A.H., Zheng W., Peters U., Gunter M.J., Murphy N., Carreras-Torres R., Song M., Chan A.T., Martin R.M., Papadimitriou N., Dimou N., Tsilidis K.K., Banbury B., Bradbury K.E., Besevic J., Rinaldi S., Riboli E., Cross A.J., Travis R.C., Agnoli C., Albanes D., Berndt S.I., Bezieau S., Bishop D.T., Brenner H., Buchanan D.D., Onland-Moret N.C., Burnett-Hartman A., Campbell P.T., Casey G., Castellvi-Bel S., Chang-Claude J., Chirlaque M.-D., de la Chapelle A., Figueiredo J.C., Gallinger S.J., Giles G.G., Gruber S.B., Gsur A., Hampe J., Hampel H., Harrison T.A., Hoffmeister M., Hsu L., Huang W.-Y., Huyghe J.R., Jenkins M.A., Keku T.O., Kuhn T., Kweon S.-S., Le Marchand L., Li C.I., Li L., Lindblom A., Martin V., Milne R.L., Moreno V., Newcomb P.A., Offit K., Ogino S., Ose J., Perduca V., Phipps A.I., Platz E.A., Potter J.D., Qu C., Rennert G., Sakoda L.C., Schafmayer C., Schoen R.E., Slattery M.L., Tangen C.M., Ulrich C.M., van Duijnhoven F.J.B., English D., Van Guelpen B., Visvanathan K., Vodicka P., Vodickova L., Vymetalkova V., Wang H., White E., Wolk A., Woods M.O., Wu A.H., Zheng W., Peters U., Gunter M.J., Murphy N., Carreras-Torres R., Song M., Chan A.T., Martin R.M., Papadimitriou N., Dimou N., Tsilidis K.K., Banbury B., Bradbury K.E., Besevic J., Rinaldi S., Riboli E., Cross A.J., Travis R.C., Agnoli C., Albanes D., Berndt S.I., Bezieau S., Bishop D.T., Brenner H., Buchanan D.D., Onland-Moret N.C., Burnett-Hartman A., Campbell P.T., Casey G., Castellvi-Bel S., Chang-Claude J., Chirlaque M.-D., de la Chapelle A., Figueiredo J.C., Gallinger S.J., Giles G.G., Gruber S.B., Gsur A., Hampe J., Hampel H., Harrison T.A., Hoffmeister M., Hsu L., Huang W.-Y., Huyghe J.R., Jenkins M.A., Keku T.O., Kuhn T., Kweon S.-S., Le Marchand L., Li C.I., Li L., Lindblom A., Martin V., Milne R.L., Moreno V., Newcomb P.A., Offit K., Ogino S., Ose J., Perduca V., Phipps A.I., Platz E.A., Potter J.D., Qu C., Rennert G., Sakoda L.C., Schafmayer C., Schoen R.E., Slattery M.L., Tangen C.M., Ulrich C.M., and van Duijnhoven F.J.B.
Abstract: Background & Aims: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. Method(s): Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) Results: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 x 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 x 10-5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene re
Published: 2020

12. Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses

Author: Seyed Khoei, N, Jenab, M, Murphy, N, Banbury, BL, Carreras-Torres, R, Viallon, V, Kuehn, T, Bueno-de-Mesquita, B, Aleksandrova, K, Cross, AJ, Weiderpass, E, Stepien, M, Bulmer, A, Tjonneland, A, Boutron-Ruault, M-C, Severi, G, Carbonnel, F, Katzke, V, Boeing, H, Bergmann, MM, Trichopoulou, A, Karakatsani, A, Martimianaki, G, Palli, D, Tagliabue, G, Panico, S, Tumino, R, Sacerdote, C, Skeie, G, Merino, S, Bonet, C, Rodriguez-Barranco, M, Gil, L, Chirlaque, M-D, Ardanaz, E, Myte, R, Hultdin, J, Perez-Cornago, A, Aune, D, Tsilidis, K, Albanes, Baron, JA, Berndt, SI, Bezieau, S, Brenner, H, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Chanock, SJ, Cotterchio, M, Gallinger, S, Gruber, SB, Haile, RW, Hampe, J, Hoffmeister, M, Hopper, JL, Hsu, L, Huyghe, JR, Jenkins, MA, Joshi, AD, Kampman, E, Larsson, SC, Le Marchand, L, Li, CI, Li, L, Lindblom, A, Lindor, NM, Martin, V, Moreno, V, Newcomb, PA, Offit, K, Ogino, S, Parfrey, PS, Pharoah, PDP, Rennert, G, Sakoda, LC, Schafmayer, C, Schmit, SL, Schoen, RE, Slattery, ML, Thibodeau, SN, Ulrich, CM, van Duijnhoven, FJB, Weigl, K, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Zhang, X, Ferrari, P, Anton, G, Peters, A, Peters, U, Gunter, MJ, Wagner, K-H, Freisling, H, Seyed Khoei, N, Jenab, M, Murphy, N, Banbury, BL, Carreras-Torres, R, Viallon, V, Kuehn, T, Bueno-de-Mesquita, B, Aleksandrova, K, Cross, AJ, Weiderpass, E, Stepien, M, Bulmer, A, Tjonneland, A, Boutron-Ruault, M-C, Severi, G, Carbonnel, F, Katzke, V, Boeing, H, Bergmann, MM, Trichopoulou, A, Karakatsani, A, Martimianaki, G, Palli, D, Tagliabue, G, Panico, S, Tumino, R, Sacerdote, C, Skeie, G, Merino, S, Bonet, C, Rodriguez-Barranco, M, Gil, L, Chirlaque, M-D, Ardanaz, E, Myte, R, Hultdin, J, Perez-Cornago, A, Aune, D, Tsilidis, K, Albanes, Baron, JA, Berndt, SI, Bezieau, S, Brenner, H, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Chanock, SJ, Cotterchio, M, Gallinger, S, Gruber, SB, Haile, RW, Hampe, J, Hoffmeister, M, Hopper, JL, Hsu, L, Huyghe, JR, Jenkins, MA, Joshi, AD, Kampman, E, Larsson, SC, Le Marchand, L, Li, CI, Li, L, Lindblom, A, Lindor, NM, Martin, V, Moreno, V, Newcomb, PA, Offit, K, Ogino, S, Parfrey, PS, Pharoah, PDP, Rennert, G, Sakoda, LC, Schafmayer, C, Schmit, SL, Schoen, RE, Slattery, ML, Thibodeau, SN, Ulrich, CM, van Duijnhoven, FJB, Weigl, K, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Zhang, X, Ferrari, P, Anton, G, Peters, A, Peters, U, Gunter, MJ, Wagner, K-H, and Freisling, H
Abstract: BACKGROUND: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. METHODS: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study. RESULTS: The associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, we
Published: 2020

13. Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses

Author: Murphy, N, Carreras-Torres, R, Song, M, Chan, AT, Martin, RM, Papadimitriou, N, Dimou, N, Tsilidis, KK, Banbury, B, Bradbury, KE, Besevic, J, Rinaldi, S, Riboli, E, Cross, AJ, Travis, RC, Agnoli, C, Albanes, D, Berndt, SI, Bezieau, S, Bishop, DT, Brenner, H, Buchanan, DD, Onland-Moret, NC, Burnett-Hartman, A, Campbell, PT, Casey, G, Castellvi-Bel, S, Chang-Claude, J, Chirlaque, M-D, de la Chapelle, A, English, D, Figueiredo, JC, Gallinger, SJ, Giles, GG, Gruber, SB, Gsur, A, Hampe, J, Hampel, H, Harrison, TA, Hoffmeister, M, Hsu, L, Huang, W-Y, Huyghe, JR, Jenkins, MA, Keku, TO, Kuhn, T, Kweon, S-S, Le Marchand, L, Li, CI, Li, L, Lindblom, A, Martin, V, Milne, RL, Moreno, V, Newcomb, PA, Offit, K, Ogino, S, Ose, J, Perduca, V, Phipps, AI, Platz, EA, Potter, JD, Qu, C, Rennert, G, Sakoda, LC, Schafmayer, C, Schoen, RE, Slattery, ML, Tangen, CM, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Wang, H, White, E, Wolk, A, Woods, MO, Wu, AH, Zheng, W, Peters, U, Gunter, MJ, Murphy, N, Carreras-Torres, R, Song, M, Chan, AT, Martin, RM, Papadimitriou, N, Dimou, N, Tsilidis, KK, Banbury, B, Bradbury, KE, Besevic, J, Rinaldi, S, Riboli, E, Cross, AJ, Travis, RC, Agnoli, C, Albanes, D, Berndt, SI, Bezieau, S, Bishop, DT, Brenner, H, Buchanan, DD, Onland-Moret, NC, Burnett-Hartman, A, Campbell, PT, Casey, G, Castellvi-Bel, S, Chang-Claude, J, Chirlaque, M-D, de la Chapelle, A, English, D, Figueiredo, JC, Gallinger, SJ, Giles, GG, Gruber, SB, Gsur, A, Hampe, J, Hampel, H, Harrison, TA, Hoffmeister, M, Hsu, L, Huang, W-Y, Huyghe, JR, Jenkins, MA, Keku, TO, Kuhn, T, Kweon, S-S, Le Marchand, L, Li, CI, Li, L, Lindblom, A, Martin, V, Milne, RL, Moreno, V, Newcomb, PA, Offit, K, Ogino, S, Ose, J, Perduca, V, Phipps, AI, Platz, EA, Potter, JD, Qu, C, Rennert, G, Sakoda, LC, Schafmayer, C, Schoen, RE, Slattery, ML, Tangen, CM, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Wang, H, White, E, Wolk, A, Woods, MO, Wu, AH, Zheng, W, Peters, U, and Gunter, MJ
Abstract: BACKGROUND & AIMS: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. METHODS: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 × 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 × 10-5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene regi
Published: 2020

14. Is high vitamin B12 status a cause of lung cancer?

Author: Fanidi, A, Carreras-Torres, R, Larose, TL, Yuan, J-M, Stevens, VL, Weinstein, SJ, Albanes, D, Prentice, R, Pettinger, M, Cai, Q, Blot, WJ, Arslan, AA, Zeleniuch-Jacquotte, A, McCullough, ML, Le Marchand, L, Wilkens, LR, Haiman, CA, Zhang, X, Stampfer, MJ, Smith-Warner, SA, Giovannucci, E, Giles, GG, Hodge, AM, Severi, G, Johansson, M, Grankvist, K, Langhammer, A, Brumpton, BM, Wang, R, Gao, Y-T, Ericson, U, Bojesen, SE, Arnold, SM, Koh, W-P, Shu, X-O, Xiang, Y-B, Li, H, Zheng, W, Lan, Q, Visvanathan, K, Hoffman-Bolton, J, Ueland, PM, Midttun, O, Caporaso, NE, Purdue, M, Freedman, ND, Buring, JE, Lee, I-M, Sesso, HD, Gaziano, JM, Manjer, J, Relton, CL, Hung, RJ, Amos, C, Brennan, P, Fanidi, A, Carreras-Torres, R, Larose, TL, Yuan, J-M, Stevens, VL, Weinstein, SJ, Albanes, D, Prentice, R, Pettinger, M, Cai, Q, Blot, WJ, Arslan, AA, Zeleniuch-Jacquotte, A, McCullough, ML, Le Marchand, L, Wilkens, LR, Haiman, CA, Zhang, X, Stampfer, MJ, Smith-Warner, SA, Giovannucci, E, Giles, GG, Hodge, AM, Severi, G, Johansson, M, Grankvist, K, Langhammer, A, Brumpton, BM, Wang, R, Gao, Y-T, Ericson, U, Bojesen, SE, Arnold, SM, Koh, W-P, Shu, X-O, Xiang, Y-B, Li, H, Zheng, W, Lan, Q, Visvanathan, K, Hoffman-Bolton, J, Ueland, PM, Midttun, O, Caporaso, NE, Purdue, M, Freedman, ND, Buring, JE, Lee, I-M, Sesso, HD, Gaziano, JM, Manjer, J, Relton, CL, Hung, RJ, Amos, C, and Brennan, P
Abstract: Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer etiology via direct measurements of pre-diagnostic circulating vitamin B12 concentrations in a nested case-control study, complemented with a Mendelian randomization (MR) approach in an independent case-control sample. We used pre-diagnostic biomarker data from 5183 case-control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre-diagnostic blood samples from the nested case-control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12 ] = 1.15, 95% confidence interval (95%CI) = 1.06-1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD ] = 1.08, 95%CI = 1.00-1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer.
Published: 2019

15. Appraising the causal relevance of DNA methylation for risk of lung cancer

Author: Battram, T, Richmond, RC, Baglietto, L, Haycock, PC, Perduca, V, Bojesen, SE, Gaunt, TR, Hemani, G, Guida, F, Carreras-Torres, R, Hung, R, Amos, C, Freeman, JR, Sandanger, TM, Nost, TH, Nordestgaard, BG, Teschendorff, AE, Polidoro, S, Vineis, P, Severi, G, Hodge, AM, Giles, GG, Grankvist, K, Johansson, MB, Johansson, M, Smith, GD, Relton, CL, Battram, T, Richmond, RC, Baglietto, L, Haycock, PC, Perduca, V, Bojesen, SE, Gaunt, TR, Hemani, G, Guida, F, Carreras-Torres, R, Hung, R, Amos, C, Freeman, JR, Sandanger, TM, Nost, TH, Nordestgaard, BG, Teschendorff, AE, Polidoro, S, Vineis, P, Severi, G, Hodge, AM, Giles, GG, Grankvist, K, Johansson, MB, Johansson, M, Smith, GD, and Relton, CL
Abstract: BACKGROUND: DNA methylation changes in peripheral blood have recently been identified in relation to lung cancer risk. Some of these changes have been suggested to mediate part of the effect of smoking on lung cancer. However, limitations with conventional mediation analyses mean that the causal nature of these methylation changes has yet to be fully elucidated. METHODS: We first performed a meta-analysis of four epigenome-wide association studies (EWAS) of lung cancer (918 cases, 918 controls). Next, we conducted a two-sample Mendelian randomization analysis, using genetic instruments for methylation at CpG sites identified in the EWAS meta-analysis, and 29 863 cases and 55 586 controls from the TRICL-ILCCO lung cancer consortium, to appraise the possible causal role of methylation at these sites on lung cancer. RESULTS: Sixteen CpG sites were identified from the EWAS meta-analysis [false discovery rate (FDR) < 0.05], for 14 of which we could identify genetic instruments. Mendelian randomization provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites plays a causal role in lung cancer development (FDR > 0.05), including for cg05575921-AHRR where methylation is strongly associated with both smoke exposure and lung cancer risk. CONCLUSIONS: The results contrast with previous observational and mediation analysis, which have made strong claims regarding the causal role of DNA methylation. Thus, previous suggestions of a mediating role of methylation at sites identified in peripheral blood, such as cg05575921-AHRR, could be unfounded. However, this study does not preclude the possibility that differential DNA methylation at other sites is causally involved in lung cancer development, especially within lung tissue.
Published: 2019

16. Association between telomere length and risk of cancer and non-neoplastic diseases: A Mendelian randomization study

Author: Collaboration, Telomeres Mendelian Randomization, Haycock, P, Burgess, S, Nounu, A, Zheng, J, Okoli, G, Bowden, J, Wade, K, Timpson, N, Evans, D, Willeit, P, Aviv, A, Gaunt, T, Hemani, G, Mangino, M, Ellis, H, Kurian, K, Pooley, K, Eeles, R, Lee, J, Fang, S, Chen, W, Law, M, Bowdler, L, Iles, M, Yang, Q, Worrall, B, Markus, H, Hung, R, Amos, C, Spurdle, A, Thompson, D, O'Mara, T, Wolpin, B, Amundadottir, L, Stolzenberg-Solomon, R, Trichopoulou, A, Onland-Moret, N, Lund, E, Duell, E, Canzian, F, Severi, G, Overvad, K, Gunter, M, Tumino, R, Svenson, U, van Rij, A, Baas, A, Bown, M, Samani, N, van t'Hof, F, Tromp, G, Jones, G, Kuivaniemi, H, Elmore, J, Johansson, M, Mckay, J, Scelo, G, Carreras-Torres, R, Gaborieau, V, Brennan, P, Bracci, P, Neale, R, Olson, S, Gallinger, S, Li, D, Petersen, G, Risch, H, Klein, A, Han, J, Abnet, C, Freedman, N, Taylor, P, Maris, J, Aben, K, Kiemeney, L, Vermeulen, S, Wiencke, J, Walsh, K, Wrensch, M, Rice, T, Turnbull, C, Litchfield, K, Paternoster, L, Standl, M, Abecasis, G, SanGiovanni, J, Li, Y, Mijatovic, V, Sapkota, Y, Low, S, Zondervan, K, Montgomery, G, Nyholt, D, van Heel, D, Hunt, K, Arking, D, Ashar, F, Sotoodehnia, N, Woo, D, Rosand, J, Comeau, M, Brown, W, Silverman, E, Hokanson, J, Cho, M, Hui, J, Ferreira, M, Thompson, P, Morrison, A, Felix, J, Smith, N, Christiano, A, Petukhova, L, Betz, R, Fan, X, Zhang, X, Zhu, C, Langefeld, C, Thompson, S, Wang, F, Lin, X, Schwartz, D, Fingerlin, T, Rotter, J, Cotch, M, Jensen, R, Munz, M, Dommisch, H, Schaefer, A, Han, F, Ollila, H, Hillary, R, Albagha, O, Ralston, S, Zeng, C, Zheng, W, Shu, X, Reis, A, Uebe, S, Hüffmeier, U, Kawamura, Y, Otowa, T, Sasaki, T, Hibberd, M, Davila, S, Xie, G, Siminovitch, K, Bei, J, Zeng, Y, Försti, A, Chen, B, Landi, S, Franke, A, Fischer, A, Ellinghaus, D, Flores, C, Noth, I, Ma, S, Foo, J, Liu, J, Kim, J, Cox, D, Delattre, O, Mirabeau, O, Skibola, C, Tang, C, Garcia-Barcelo, M, Chang, K, Su, W, Chang, Y, Martin, N, Gordon, S, Wade, T, Lee, C, Kubo, M, Cha, P, Nakamura, Y, Levy, D, Kimura, M, Hwang, S, Hunt, S, Spector, T, Soranzo, N, Manichaikul, A, Barr, R, Kahali, B, Speliotes, E, Yerges-Armstrong, L, Cheng, C, Jonas, J, Wong, T, Fogh, I, Lin, K, Powell, J, Rice, K, Relton, C, Martin, R, Davey Smith, G, Erasmus MC other, Epidemiology, and Pediatrics
Subjects: 0301 basic medicine, Adult, Male, Cancer Research, Single-nucleotide polymorphism, Genome-wide association study, Disease, Bioinformatics, Polymorphism, Single Nucleotide, Risk Assessment, Article, 03 medical and health sciences, Telomere Homeostasis, SDG 3 - Good Health and Well-being, Neoplasms, Mendelian randomization, Journal Article, medicine, Humans, Genetic Predisposition to Disease, Càncer, Germ-Line Mutation, Aged, Cancer, Aged, 80 and over, business.industry, Nucleotides, Odds ratio, Mendelian Randomization Analysis, Middle Aged, Telomere, medicine.disease, Nucleòtids, 030104 developmental biology, Stem cell division, Oncology, Cardiovascular Diseases, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, ICEP, business, Genome-Wide Association Study, Bristol Population Health Science Institute
Abstract: Importance The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. Objective To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. Data Sources Genomewide association studies (GWAS) published up to January 15, 2015. Study Selection GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. Data Extraction and Synthesis Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. Main Outcomes and Measures Odds ratios (ORs) and 95%confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. Results Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95%CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95%CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95%CI, 0.49-0.81]), celiac disease (OR, 0.42 [95%CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95%CI, 0.05-0.15]). Conclusions and Relevance It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
Published: 2017

17. Association between telomere length and risk of cancer and non-neoplastic diseases a mendelian randomization study

Author: Haycock, PC, Burgess, S, Nounu, A, Zheng, J, Okoli, GN, Bowden, J, Wade, KH, Timpson, NJ, Evans, DM, Willeit, P, Aviv, A, Gaunt, TR, Hemani, G, Mangino, M, Ellis, HP, Kurian, KM, Pooley, KA, Eeles, RA, Lee, JE, Fang, S, Chen, WV, Law, MH, Bowdler, LM, Iles, MM, Yang, Q, Worrall, BB, Markus, HS, Hung, RJ, Amos, CI, Spurdle, AB, Thompson, DJ, O'Mara, TA, Wolpin, B, Amundadottir, L, Stolzenberg-Solomon, R, Trichopoulou, A, Onland-Moret, NC, Lund, E, Duell, EJ, Canzian, F, Severi, G, Overvad, K, Gunter, MJ, Tumino, R, Svenson, U, Van Rij, A, Baas, AF, Bown, MJ, Samani, NJ, Van t'Hof, FNG, Tromp, G, Jones, GT, Kuivaniemi, H, Elmore, JR, Johansson, M, Mckay, J, Scelo, G, Carreras-Torres, R, Gaborieau, V, Brennan, P, Bracci, PM, Neale, RE, Olson, SH, Gallinger, S, Li, D, Petersen, GM, Risch, HA, Klein, AP, Han, J, Abnet, CC, Freedman, ND, Taylor, PR, Maris, JM, Aben, KK, Kiemeney, LA, Vermeulen, SH, Wiencke, JK, and Walsh, KM
Abstract: Copyright 2017 American Medical Association. All rights reserved. IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
Published: 2017

18. MA03.09 Transcriptome-Wide Association Study Reveals Candidate Causal Genes for Lung Cancer

Author: Clemenceau, A., primary, Lamontagne, M., additional, Carreras Torres, R., additional, Obeidat, M., additional, Timens, W., additional, Joubert, P., additional, Amos, C., additional, Mckay, J., additional, and Bossé, Y., additional
Published: 2018
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19. Appraising the causal relevance of DNA methylation for risk of lung cancer

Author: Battram, T, primary, Richmond, RC, additional, Baglietto, L, additional, Haycock, P, additional, Perduca, V, additional, Bojesen, S, additional, Gaunt, TR, additional, Hemani, G, additional, Guida, F, additional, Carreras-Torres, R, additional, Hung, R, additional, Amos, CI, additional, Freeman, JR, additional, Sandanger, TM, additional, Nøst, TH, additional, Nordestgaard, B, additional, Teschendorff, AE, additional, Polidoro, S, additional, Vineis, P, additional, Severi, G, additional, Hodge, A, additional, Giles, G, additional, Grankvist, K, additional, Johansson, MB, additional, Johansson, M, additional, Davey Smith, G, additional, and Relton, CL, additional
Published: 2018
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20. Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study

Author: Haycock, P.C., Burgess, S., Nounu, A., Zheng, J., Okoli, G.N., Bowden, J., Wade, K.H., Timpson, N.J., Evans, D.M., Willeit, P., Aviv, A., Gaunt, T.R., Hemani, G., Mangino, M., Ellis, H.P., Kurian, K.M., Pooley, K.A., Eeles, R.A., Lee, J.E., Fang, S., Chen, W.V., Law, M.H., Bowdler, L.M., Iles, M.M., Yang, Q., Worrall, B.B., Markus, H.S., Hung, R.J., Amos, C.I., Spurdle, A.B., Thompson, D.J., O'Mara, T.A., Wolpin, B., Amundadottir, L., Stolzenberg-Solomon, R., Trichopoulou, A., Onland-Moret, N.C., Lund, E., Duell, E.J., Canzian, F., Severi, G., Overvad, K., Gunter, M.J., Tumino, R., Svenson, U., Rij, A. van, Baas, A.F., Bown, M.J., Samani, N.J., t'Hof, F.N.G. van, Tromp, G., Jones, G.T., Kuivaniemi, H., Elmore, J.R., Johansson, M., McKay, J., Scelo, G., Carreras-Torres, R., Gaborieau, V., Brennan, P., Bracci, P.M., Neale, R.E., Olson, S.H., Gallinger, S., Li, D., Petersen, G.M., Risch, H.A., Klein, A.P., Han, J., Abnet, C.C., Freedman, N.D., Taylor, P.R., Maris, J.M., Aben, K.K.H., Kiemeney, L.A., Vermeulen, S.H., Wiencke, J.K., Walsh, K.M., Wrensch, M., Rice, T., Turnbull, C., Litchfield, K., Paternoster, L., Standl, M., Abecasis, G.R., SanGiovanni, J.P., Li, Y., Mijatovic, V., Sapkota, Y., Low, S.K., Zondervan, K.T., Montgomery, G.W., Nyholt, D.R., Heel, D.A. van, Hunt, K., Arking, D.E., Ashar, F.N., Sotoodehnia, N., Woo, D., et al., Haycock, P.C., Burgess, S., Nounu, A., Zheng, J., Okoli, G.N., Bowden, J., Wade, K.H., Timpson, N.J., Evans, D.M., Willeit, P., Aviv, A., Gaunt, T.R., Hemani, G., Mangino, M., Ellis, H.P., Kurian, K.M., Pooley, K.A., Eeles, R.A., Lee, J.E., Fang, S., Chen, W.V., Law, M.H., Bowdler, L.M., Iles, M.M., Yang, Q., Worrall, B.B., Markus, H.S., Hung, R.J., Amos, C.I., Spurdle, A.B., Thompson, D.J., O'Mara, T.A., Wolpin, B., Amundadottir, L., Stolzenberg-Solomon, R., Trichopoulou, A., Onland-Moret, N.C., Lund, E., Duell, E.J., Canzian, F., Severi, G., Overvad, K., Gunter, M.J., Tumino, R., Svenson, U., Rij, A. van, Baas, A.F., Bown, M.J., Samani, N.J., t'Hof, F.N.G. van, Tromp, G., Jones, G.T., Kuivaniemi, H., Elmore, J.R., Johansson, M., McKay, J., Scelo, G., Carreras-Torres, R., Gaborieau, V., Brennan, P., Bracci, P.M., Neale, R.E., Olson, S.H., Gallinger, S., Li, D., Petersen, G.M., Risch, H.A., Klein, A.P., Han, J., Abnet, C.C., Freedman, N.D., Taylor, P.R., Maris, J.M., Aben, K.K.H., Kiemeney, L.A., Vermeulen, S.H., Wiencke, J.K., Walsh, K.M., Wrensch, M., Rice, T., Turnbull, C., Litchfield, K., Paternoster, L., Standl, M., Abecasis, G.R., SanGiovanni, J.P., Li, Y., Mijatovic, V., Sapkota, Y., Low, S.K., Zondervan, K.T., Montgomery, G.W., Nyholt, D.R., Heel, D.A. van, Hunt, K., Arking, D.E., Ashar, F.N., Sotoodehnia, N., Woo, D., and et al.
Abstract: Contains fulltext : 174181.pdf (publisher's version ) (Closed access), Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015. Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420081 cases (median cases, 2526 per disease) and 1093105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cance
Published: 2017

21. Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study

Author: Carreras-Torres, R., Johansson, M., Haycock, P.C., Wade, K.H., Relton, C.L., Martin, R.M., Smith, G., Albanes, D., Aldrich, M.C., Andrew, A., Arnold, S.M., Bickeboller, H., Bojesen, S.E., Brunnstrom, H., Manjer, J., Bruske, I., Caporaso, N.E., Chen, C., Christiani, D.C., Christian, W.J., Doherty, J.A., Duell, E.J., Field, J.K., Davies, M.P., Marcus, M.W., Goodman, G.E., Grankvist, K., Haugen, A., Hong, Y.C., Kiemeney, L.A.L.M., Heijden, E. van der, Kraft, P., Johansson, M.B., Lam, S., Landi, M.T., Lazarus, P., Marchand, L. Le, Liu, G., Melander, O., Park, S.L., Rennert, G., Risch, A., Haura, E.B., Scelo, G., Zaridze, D., Mukeriya, A., Savic, M., Lissowska, J., Swiatkowska, B., Janout, V., Holcatova, I., Mates, D., Schabath, M.B., Shen, H., Tardon, A., Teare, M.D., Woll, P., Tsao, M.S., Wu, X., Yuan, J.M., Hung, R.J., Amos, C.I., McKay, J., Brennan, P., Carreras-Torres, R., Johansson, M., Haycock, P.C., Wade, K.H., Relton, C.L., Martin, R.M., Smith, G., Albanes, D., Aldrich, M.C., Andrew, A., Arnold, S.M., Bickeboller, H., Bojesen, S.E., Brunnstrom, H., Manjer, J., Bruske, I., Caporaso, N.E., Chen, C., Christiani, D.C., Christian, W.J., Doherty, J.A., Duell, E.J., Field, J.K., Davies, M.P., Marcus, M.W., Goodman, G.E., Grankvist, K., Haugen, A., Hong, Y.C., Kiemeney, L.A.L.M., Heijden, E. van der, Kraft, P., Johansson, M.B., Lam, S., Landi, M.T., Lazarus, P., Marchand, L. Le, Liu, G., Melander, O., Park, S.L., Rennert, G., Risch, A., Haura, E.B., Scelo, G., Zaridze, D., Mukeriya, A., Savic, M., Lissowska, J., Swiatkowska, B., Janout, V., Holcatova, I., Mates, D., Schabath, M.B., Shen, H., Tardon, A., Teare, M.D., Woll, P., Tsao, M.S., Wu, X., Yuan, J.M., Hung, R.J., Amos, C.I., McKay, J., and Brennan, P.
Abstract: Contains fulltext : 174154.pdf (publisher's version ) (Open Access), BACKGROUND: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. METHODS AND FINDINGS: We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79-1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. CONCLUSIONS: Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized
Published: 2017

22. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

Author: McKay, J.D., Hung, R.J., Han, Y., Zong, X., Carreras-Torres, R., Christiani, D.C., Caporaso, N., Johansson, M., Li, Y., Byun, J.Y., Dunning, A., Pooley, K.A., Qian, D.C., Liu, G., Bojesen, S.E., Wu, X., Marchand, L. le, Albanes, D., Bickeböller, H., Aldrich, M.C., Bush, W.S., Tardon, A., Rennert, G., Teare, M.D., Field, J.K., Kiemeney, L.A., Lazarus, P., Haugen, A., Schabath, M.B., Andrew, A.S., Shen, H., Hong, Y.C., Yuan, J.M., Bertazzi, P.A., Pesatori, A.C., Ye, Y., Diao, N., Su, L., Zhang, R., Brhane, Y., Leighl, N., Johansen, J.S., Mellemgaard, A., Saliba, W., Haiman, C.A., Wilkens, L.R., Fernandez-Somoano, A., Fernandez-Tardon, G., Heijden, H.F.M. van der, Kim, J.H., Hu, Z, Davies, M., Brunnström, H., Manjer, J., Melander, O., Muller, D., Overvad, K., Trichopoulou, A., Tumino, R., Doherty, J.A., Barnett, M.P., Chen, C., Goodman, G.E., Cox, A, Taylor, F., Woll, P.J., Brüske, I., Wichmann, H.E., Manz, J., Muley, T.R., Risch, A., Rosenberger, A., Grankvist, K., Shepherd, F.A., Tsao, M.S., Haura, E.B., Bolca, C., Holcatova, I., Janout, V., Kontic, M., Lissowska, J., Mukeria, A., Ognjanovic, S., Orlowski, T.M., Scelo, G., Swiatkowska, B., Zaridze, D., Bakke, P., Skaug, V., Zienolddiny, S., Duell, E.J., Butler, L.M., Koh, W.P., Gao, Y.T., Houlston, R.S., McLaughlin, J., Stevens, V.L., Joubert, P., Lamontagne, M., Nickle, D.C., Obeidat, M., Timens, W., Zhu, B, Kachuri, L., Artigas, M.S., Tobin, M.D., Wain, L.V., Rafnar, T., Thorgeirsson, T.E., Reginsson, G.W., Stefansson, K., Hancock, D.B., Bierut, L.J., Spitz, M.R., Gaddis, N.C., Lutz, S.M., Kamal, A., Pikielny, C., Zhu, D., Lindströem, S., Jiang, X., Tyndale, R.F., Chenevix-Trench, G., Beesley, J., Bossé, Y., Chanock, S., Brennan, P., Landi, M.T., Amos, C.I., McKay, J.D., Hung, R.J., Han, Y., Zong, X., Carreras-Torres, R., Christiani, D.C., Caporaso, N., Johansson, M., Li, Y., Byun, J.Y., Dunning, A., Pooley, K.A., Qian, D.C., Liu, G., Bojesen, S.E., Wu, X., Marchand, L. le, Albanes, D., Bickeböller, H., Aldrich, M.C., Bush, W.S., Tardon, A., Rennert, G., Teare, M.D., Field, J.K., Kiemeney, L.A., Lazarus, P., Haugen, A., Schabath, M.B., Andrew, A.S., Shen, H., Hong, Y.C., Yuan, J.M., Bertazzi, P.A., Pesatori, A.C., Ye, Y., Diao, N., Su, L., Zhang, R., Brhane, Y., Leighl, N., Johansen, J.S., Mellemgaard, A., Saliba, W., Haiman, C.A., Wilkens, L.R., Fernandez-Somoano, A., Fernandez-Tardon, G., Heijden, H.F.M. van der, Kim, J.H., Hu, Z, Davies, M., Brunnström, H., Manjer, J., Melander, O., Muller, D., Overvad, K., Trichopoulou, A., Tumino, R., Doherty, J.A., Barnett, M.P., Chen, C., Goodman, G.E., Cox, A, Taylor, F., Woll, P.J., Brüske, I., Wichmann, H.E., Manz, J., Muley, T.R., Risch, A., Rosenberger, A., Grankvist, K., Shepherd, F.A., Tsao, M.S., Haura, E.B., Bolca, C., Holcatova, I., Janout, V., Kontic, M., Lissowska, J., Mukeria, A., Ognjanovic, S., Orlowski, T.M., Scelo, G., Swiatkowska, B., Zaridze, D., Bakke, P., Skaug, V., Zienolddiny, S., Duell, E.J., Butler, L.M., Koh, W.P., Gao, Y.T., Houlston, R.S., McLaughlin, J., Stevens, V.L., Joubert, P., Lamontagne, M., Nickle, D.C., Obeidat, M., Timens, W., Zhu, B, Kachuri, L., Artigas, M.S., Tobin, M.D., Wain, L.V., Rafnar, T., Thorgeirsson, T.E., Reginsson, G.W., Stefansson, K., Hancock, D.B., Bierut, L.J., Spitz, M.R., Gaddis, N.C., Lutz, S.M., Kamal, A., Pikielny, C., Zhu, D., Lindströem, S., Jiang, X., Tyndale, R.F., Chenevix-Trench, G., Beesley, J., Bossé, Y., Chanock, S., Brennan, P., Landi, M.T., and Amos, C.I.
Abstract: Contains fulltext : 177377.pdf (Publisher’s version ) (Closed access)
Published: 2017

23. Association between telomere length and risk of cancer and non-neoplastic diseases a mendelian randomization study

Author: Haycock, P. (Philip), Burgess, S. (Stephen), Nounu, A. (Aayah), Zheng, J. (Jie), Okoli, G.N. (George N.), Bowden, J., Wade, K.H. (Kaitlin Hazel), Timpson, N.J. (Nicholas J.), Evans, D.M. (David M.), Willeit, P. (Peter), Aviv, A. (Abraham), Gaunt, T.R. (Tom), Hemani, G., Mangino, M. (Massimo), Ellis, H.P. (Hayley Patricia), Kurian, K.M. (Kathreena M.), Pooley, K.A. (Karen A.), Eeles, R. (Rosalind), Lee, J.E. (Jeffrey E.), Fang, S. (Shenying), Chen, W.V. (Wei V.), Law, M.H. (Matthew H.), Bowdler, L.M. (Lisa M.), Iles, M.M. (Mark M.), Yang, Q. (Qiong Fang), Worrall, B.B. (Bradford B.), Markus, H.S. (Hugh), Hung, R.J. (Rayjean J.), Amos, W., Spurdle, A.B. (Amanda), Thompson, D. (Deborah), O'Mara, T.A. (Tracy A.), Wolpin, B. (Brian), Amundadottir, L. (Laufey), Stolzenberg-Solomon, R. (Rachael), Trichopoulou, A. (Antonia), Onland-Moret, N.C. (Charlotte), Lund, E. (Eiliv), Duell, E.J. (Eric), Canzian, F. (Federico), Severi, G. (Gianluca), Overvad, K. (Kim), Gunter, M.J. (Marc J.), Tumino, R. (Rosario), Svenson, U. (Ulrika), Rij, A.M. (Andre) van, Baas, A.F. (Annette), Bown, N., Samani, N.J. (Nilesh), Van t'Hof, F.N.G. (Femke N.G.), Tromp, G. (Gerard), Jones, G.T. (Gregory T.), Kuivaniemi, H. (Helena), Elmore, J.R. (James R.), Johansson, M. (Mattias), Mckay, J. (James), Scelo, G. (Ghislaine), Carreras-Torres, R. (Robert), Gaborieau, V. (Valerie), Brennan, P. (Paul), Bracci, P.M. (Paige M.), Neale, R.E. (Rachel E.), Olson, S.H. (Sara H.), Gallinger, S. (Steve), Li, D. (Donghui), Olson, S.H. (Sara), Risch, H. (Harvey), Klein, A.P. (Alison P.), Han, J., Abnet, C.C. (Christian C.), Freedman, N.D. (Neal D.), Taylor, P.R. (Phil R.), Maris, J.M. (John), Aben, K.K.H. (Katja), Kiemeney, L.A.L.M. (Bart), Vermeulen, S.H.H.M. (Sita), Wiencke, J.K. (John K.), Walsh, K.M. (Kyle M.), Wrensch, M. (Margaret), Rice, T. (Terri), Turnbull, C. (Clare), Litchfield, K. (Kevin), Paternoster, L. (Lavinia), Standl, M. (Marie), Abecasis, G.R. (Gonçalo), SanGiovanni, J.P. (John Paul), Li, Y. (Yong), Mijatovic, V. (Vladan), Sapkota, Y. (Yadav), Low, S.-K. (Siew-Kee), Zondervan, K.T. (Krina), Montgomery, G.W. (Grant W.), Nyholt, D.R. (Dale), Heel, D.A. (David) van, Hunt, K. (Karen), Arking, D.E. (Dan), Ashar, F.N. (Foram N.), Sotoodehnia, N. (Nona), Woo, D. (Daniel), Rosand, J. (Jonathan), Comeau, M.E. (Mary E.), Brown, W.M. (W. Mark), Silverman, E. (Edwin), Hokanson, J.E. (John E.), Cho, M.H. (Michael), Hui, J. (Jennie), Ferreira, M.A. (Manuel A.), Thompson, P.J. (Philip J.), Morrison, A.C. (Alanna), Felix, J.F. (Janine F.), Smith, N.L. (Nicholas L.), Christiano, A.M. (Angela), Petukhova, L. (Lynn), Betz, R.C. (Regina), Fan, X. (Xing), Zhang, X. (Xuejun), Zhu, C. (Caihong), Langefeld, C.D. (Carl), Thompson, S.D. (Susan D.), Wang, F. (Feijie), Lin, X. (Xu), Schwartz, D.A. (David A.), Fingerlin, T.E. (Tasha E.), Rotter, J.I. (Jerome I.), Cotch, M.F. (Mary Frances), Jensen, R.A. (Richard A.), Munz, M. (Matthias), Dommisch, H. (Henrik), Schaefer, A. (Antje), Han, F. (Fang), Ollila, H.M., Hillary, R.P. (Ryan P.), Albagha, O.M.E. (Omar M.), Ralston, S.H. (Stuart), Zeng, C. (Chenjie), Zheng, W. (Wei), Shu, X.-O. (Xiao-Ou), Reis, A. (André), Uebe, S. (Steffen), Hüffmeier, U. (Ulrike), Kawamura, Y. (Yoshiya), Otowa, T. (Takeshi), Sasaki, T. (Tsukasa), Hibberd, M.L. (Martin), Davila, S. (Sonia), Xie, G. (Gang), Siminovitch, K.A. (Katherine), Bei, J.-X. (Jin-Xin), Zeng, Y.X., Försti, A. (Asta), Chen, B. (Bowang), Landi, S. (Stefano), Franke, A. (Andre), Fischer, A. (Annegret), Ellinghaus, D. (David), Flores, C. (Carlos), Noth, I. (Imre), Ma, S.-F. (Shwu-Fan), Foo, J.-N. (Jia-Nee), Liu, J. (Jianjun), Kim, J.-W. (Jong-Won), Cox, D.G. (David), Delattre, O. (Olivier), Mirabeau, O. (Olivier), Skibola, C.F. (Christine F.), Tang, C.S. (Clara S.), Garcia-Barcelo, M., Chang, K.-P. (Kai-Ping), Su, W.-H. (Wen-Hui), Chang, Y.-S. (Yu-Sun), Martin, N.G. (Nicholas G.), Gordon, S.D. (Scott D.), Wade, T.D. (Tracey D.), Lee, C. (Chaeyoung), Kubo, M. (Michiaki), Cha, P.-C. (Pei-Chieng), Nakamura, Y. (Yusuke), Levy, D. (Daniel), Kimura, M. (Masayuki), Hwang, S.-J. (Shih-Jen), Hunt, S.C. (Steven), Spector, T.D. (Timothy), Soranzo, N. (Nicole), Manichaikul, A.W. (Ani W.), Barr, R.G. (Graham), Kahali, B. (Bratati), Speliotes, E.K. (Elizabeth), Yerges-Armstrong, L.M. (Laura), Cheng, C-Y. (Ching-Yu), Jonas, J.B. (Jost B.), Wong, T.Y. (Tien Yin), Fogh, I. (Isabella), Lin, K. (Kuang), Powell, J. (John), Rice, K. (Kenneth), Relton, C.L. (Caroline), Martin, R.M. (Richard M.), Smith, A.V. (Davey), Haycock, P. (Philip), Burgess, S. (Stephen), Nounu, A. (Aayah), Zheng, J. (Jie), Okoli, G.N. (George N.), Bowden, J., Wade, K.H. (Kaitlin Hazel), Timpson, N.J. (Nicholas J.), Evans, D.M. (David M.), Willeit, P. (Peter), Aviv, A. (Abraham), Gaunt, T.R. (Tom), Hemani, G., Mangino, M. (Massimo), Ellis, H.P. (Hayley Patricia), Kurian, K.M. (Kathreena M.), Pooley, K.A. (Karen A.), Eeles, R. (Rosalind), Lee, J.E. (Jeffrey E.), Fang, S. (Shenying), Chen, W.V. (Wei V.), Law, M.H. (Matthew H.), Bowdler, L.M. (Lisa M.), Iles, M.M. (Mark M.), Yang, Q. (Qiong Fang), Worrall, B.B. (Bradford B.), Markus, H.S. (Hugh), Hung, R.J. (Rayjean J.), Amos, W., Spurdle, A.B. (Amanda), Thompson, D. (Deborah), O'Mara, T.A. (Tracy A.), Wolpin, B. (Brian), Amundadottir, L. (Laufey), Stolzenberg-Solomon, R. (Rachael), Trichopoulou, A. (Antonia), Onland-Moret, N.C. (Charlotte), Lund, E. (Eiliv), Duell, E.J. (Eric), Canzian, F. (Federico), Severi, G. (Gianluca), Overvad, K. (Kim), Gunter, M.J. (Marc J.), Tumino, R. (Rosario), Svenson, U. (Ulrika), Rij, A.M. (Andre) van, Baas, A.F. (Annette), Bown, N., Samani, N.J. (Nilesh), Van t'Hof, F.N.G. (Femke N.G.), Tromp, G. (Gerard), Jones, G.T. (Gregory T.), Kuivaniemi, H. (Helena), Elmore, J.R. (James R.), Johansson, M. (Mattias), Mckay, J. (James), Scelo, G. (Ghislaine), Carreras-Torres, R. (Robert), Gaborieau, V. (Valerie), Brennan, P. (Paul), Bracci, P.M. (Paige M.), Neale, R.E. (Rachel E.), Olson, S.H. (Sara H.), Gallinger, S. (Steve), Li, D. (Donghui), Olson, S.H. (Sara), Risch, H. (Harvey), Klein, A.P. (Alison P.), Han, J., Abnet, C.C. (Christian C.), Freedman, N.D. (Neal D.), Taylor, P.R. (Phil R.), Maris, J.M. (John), Aben, K.K.H. (Katja), Kiemeney, L.A.L.M. (Bart), Vermeulen, S.H.H.M. (Sita), Wiencke, J.K. (John K.), Walsh, K.M. (Kyle M.), Wrensch, M. (Margaret), Rice, T. (Terri), Turnbull, C. (Clare), Litchfield, K. (Kevin), Paternoster, L. (Lavinia), Standl, M. (Marie), Abecasis, G.R. (Gonçalo), SanGiovanni, J.P. (John Paul), Li, Y. (Yong), Mijatovic, V. (Vladan), Sapkota, Y. (Yadav), Low, S.-K. (Siew-Kee), Zondervan, K.T. (Krina), Montgomery, G.W. (Grant W.), Nyholt, D.R. (Dale), Heel, D.A. (David) van, Hunt, K. (Karen), Arking, D.E. (Dan), Ashar, F.N. (Foram N.), Sotoodehnia, N. (Nona), Woo, D. (Daniel), Rosand, J. (Jonathan), Comeau, M.E. (Mary E.), Brown, W.M. (W. Mark), Silverman, E. (Edwin), Hokanson, J.E. (John E.), Cho, M.H. (Michael), Hui, J. (Jennie), Ferreira, M.A. (Manuel A.), Thompson, P.J. (Philip J.), Morrison, A.C. (Alanna), Felix, J.F. (Janine F.), Smith, N.L. (Nicholas L.), Christiano, A.M. (Angela), Petukhova, L. (Lynn), Betz, R.C. (Regina), Fan, X. (Xing), Zhang, X. (Xuejun), Zhu, C. (Caihong), Langefeld, C.D. (Carl), Thompson, S.D. (Susan D.), Wang, F. (Feijie), Lin, X. (Xu), Schwartz, D.A. (David A.), Fingerlin, T.E. (Tasha E.), Rotter, J.I. (Jerome I.), Cotch, M.F. (Mary Frances), Jensen, R.A. (Richard A.), Munz, M. (Matthias), Dommisch, H. (Henrik), Schaefer, A. (Antje), Han, F. (Fang), Ollila, H.M., Hillary, R.P. (Ryan P.), Albagha, O.M.E. (Omar M.), Ralston, S.H. (Stuart), Zeng, C. (Chenjie), Zheng, W. (Wei), Shu, X.-O. (Xiao-Ou), Reis, A. (André), Uebe, S. (Steffen), Hüffmeier, U. (Ulrike), Kawamura, Y. (Yoshiya), Otowa, T. (Takeshi), Sasaki, T. (Tsukasa), Hibberd, M.L. (Martin), Davila, S. (Sonia), Xie, G. (Gang), Siminovitch, K.A. (Katherine), Bei, J.-X. (Jin-Xin), Zeng, Y.X., Försti, A. (Asta), Chen, B. (Bowang), Landi, S. (Stefano), Franke, A. (Andre), Fischer, A. (Annegret), Ellinghaus, D. (David), Flores, C. (Carlos), Noth, I. (Imre), Ma, S.-F. (Shwu-Fan), Foo, J.-N. (Jia-Nee), Liu, J. (Jianjun), Kim, J.-W. (Jong-Won), Cox, D.G. (David), Delattre, O. (Olivier), Mirabeau, O. (Olivier), Skibola, C.F. (Christine F.), Tang, C.S. (Clara S.), Garcia-Barcelo, M., Chang, K.-P. (Kai-Ping), Su, W.-H. (Wen-Hui), Chang, Y.-S. (Yu-Sun), Martin, N.G. (Nicholas G.), Gordon, S.D. (Scott D.), Wade, T.D. (Tracey D.), Lee, C. (Chaeyoung), Kubo, M. (Michiaki), Cha, P.-C. (Pei-Chieng), Nakamura, Y. (Yusuke), Levy, D. (Daniel), Kimura, M. (Masayuki), Hwang, S.-J. (Shih-Jen), Hunt, S.C. (Steven), Spector, T.D. (Timothy), Soranzo, N. (Nicole), Manichaikul, A.W. (Ani W.), Barr, R.G. (Graham), Kahali, B. (Bratati), Speliotes, E.K. (Elizabeth), Yerges-Armstrong, L.M. (Laura), Cheng, C-Y. (Ching-Yu), Jonas, J.B. (Jost B.), Wong, T.Y. (Tien Yin), Fogh, I. (Isabella), Lin, K. (Kuang), Powell, J. (John), Rice, K. (Kenneth), Relton, C.L. (Caroline), Martin, R.M. (Richard M.), and Smith, A.V. (Davey)
Abstract: IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer ca
Published: 2017
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24. Population structure from NOS genes correlates with geographical differences in coronary incidence across Europe

Author: Carreras-Torres R, Ferran A, Zanetti D, Esteban E, Varesi L, Pojskic N, Coia V, Chaabani H, Via M, and Moral P
Subjects: CAD epidemiology, complex diseases, human population genetics, nitric oxide synthases, phenotype selection, food and beverages
Abstract: The population analysis of cardiovascular risk and non-risk genetic variation can help to identify adaptive or random demographic processes that shaped coronary incidence variation across geography.
Published: 2016

25. Potential Signals of Natural Selection in the Top Risk Loci for Coronary Artery Disease: 9p21 and 10q11

Author: Zanetti D, Carreras-Torres R, Esteban E, Via M, and Moral P
Published: 2015

26. The causal relevance of body mass index in different histological types of lung cancer: A Mendelian randomization study.

Author: Carreras-Torres, R, Haycock, PC, Relton, CL, Martin, RM, Smith, GD, Kraft, P, Gao, C, Tworoger, S, Le Marchand, L, Wilkens, LR, Park, SL, Haiman, C, Field, JK, Davies, M, Marcus, M, Liu, G, Caporaso, NE, Christiani, DC, Wei, Y, Chen, C, Doherty, JA, Severi, G, Goodman, GE, Hung, RJ, Amos, CI, McKay, J, Johansson, M, Brennan, P, Carreras-Torres, R, Haycock, PC, Relton, CL, Martin, RM, Smith, GD, Kraft, P, Gao, C, Tworoger, S, Le Marchand, L, Wilkens, LR, Park, SL, Haiman, C, Field, JK, Davies, M, Marcus, M, Liu, G, Caporaso, NE, Christiani, DC, Wei, Y, Chen, C, Doherty, JA, Severi, G, Goodman, GE, Hung, RJ, Amos, CI, McKay, J, Johansson, M, and Brennan, P
Abstract: Body mass index (BMI) is inversely associated with lung cancer risk in observational studies, even though it increases the risk of several other cancers, which could indicate confounding by tobacco smoking or reverse causality. We used the two-sample Mendelian randomization (MR) approach to circumvent these limitations of observational epidemiology by constructing a genetic instrument for BMI, based on results from the GIANT consortium, which was evaluated in relation to lung cancer risk using GWAS results on 16,572 lung cancer cases and 21,480 controls. Results were stratified by histological subtype, smoking status and sex. An increase of one standard deviation (SD) in BMI (4.65 Kg/m(2)) raised the risk for lung cancer overall (OR = 1.13; P = 0.10). This was driven by associations with squamous cell (SQ) carcinoma (OR = 1.45; P = 1.2 × 10(-3)) and small cell (SC) carcinoma (OR = 1.81; P = 0.01). An inverse trend was seen for adenocarcinoma (AD) (OR = 0.82; P = 0.06). In stratified analyses, a 1 SD increase in BMI was inversely associated with overall lung cancer in never smokers (OR = 0.50; P = 0.02). These results indicate that higher BMI may increase the risk of certain types of lung cancer, in particular SQ and SC carcinoma.
Published: 2016

27. Genetic risk score of NOS gene variants associated with myocardial infarction correlates with coronary incidence across Europe

Author: Carreras-Torres R, Kundu S, Zanetti D, Esteban E, Via M, and Moral P
Abstract: Coronary artery disease (CAD) mortality and morbidity is present in the European continent in a four-fold gradient across populations, from the South (Spain and France) with the lowest CAD mortality, towards the North (Finland and UK). This observed gradient has not been fully explained by classical or single genetic risk factors, resulting in some cases in the so called Southern European or Mediterranean paradox. Here we approached population genetic risk estimates using genetic risk scores (GRS) constructed with single nucleotide polymorphisms (SNP) from nitric oxide synthases (NOS) genes. These SNPs appeared to be associated with myocardial infarction (MI) in 2165 cases and 2153 controls. The GRSs were computed in 34 general European populations. Although the contribution of these GRS was lower than 1% between cases and controls, the mean GRS per population was positively correlated with coronary incidence explaining 65-85% of the variation among populations (67% in women and 86% in men). This large contribution to CAD incidence variation among populations might be a result of colinearity with several other common genetic and environmental factors. These results are not consistent with the cardiovascular Mediterranean paradox for genetics and support a CAD genetic architecture mainly based on combinations of common genetic polymorphisms. Population genetic risk scores is a promising approach in public health interventions to develop lifestyle programs and prevent intermediate risk factors in certain subpopulations with specific genetic predisposition.
Published: 2014

28. Genetic contributions to the association between adult height and head and neck cancer

Author: Pastorino, R, primary, Puggina, A, additional, Carreras-Torres, R, additional, McKay, JD, additional, and Boccia, S, additional
Published: 2016
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29. Apolipoprotein E/C1/C4/C2 gene cluster diversity in two native Andean populations: Aymaras and Quechuas

Author: Gayà-Vidal M, Athanasiadis G, Carreras-Torres R, Via M, Esteban E, Villena M, Vasquez R, Dugoujon JM, and Moral P
Abstract: The APOE/C1/C4/C2 gene cluster presents high relevance in lipid metabolism and, therefore, has important epidemiological implications. Here, we study for the first time the variation patterns of 25 polymorphisms (10 short tandem repeats, STRs, and 15 single nucleotide polymorphismas, SNPs) in two native Andean samples from Bolivia (45 Aymaras and 45 Quechuas) as well as one European sample (n = 41) as external reference. We estimated diversity parameters, linkage disequilibrium patterns, population structure, and possible selective effects. In general, diversity was low and could be partly attributed to selection (probably due to its physiological importance), since the APOE/C1/C4/C2 region was highly conserved compared to the flanking genes in both Bolivians and Europeans. Moreover, the lower gene diversity in Bolivians compared to Europeans for some markers might indicate different demographic histories. Regarding the APOE isoforms, in addition to ?3 (94%) and ?4 (5%), isoform ?2 (1%) was also detected in Bolivians. In relation to previous hypotheses, our results support that genetic drift or founder effects rather than selection for increased cholesterol absorption are the main factors that have shaped the distribution of APOE isoforms observed in South America.
Published: 2012

30. Genetic risk score of NOS gene variants associated with myocardial infarction correlates with coronary incidence across Europe

Author: Carreras-Torres, R. (Robert), Kundu, S. (Suman), Zanetti, D. (Daniela), Esteban, E. (Tapella), Via, M. (Marc), Moral, P. (Pedro), Carreras-Torres, R. (Robert), Kundu, S. (Suman), Zanetti, D. (Daniela), Esteban, E. (Tapella), Via, M. (Marc), and Moral, P. (Pedro)
Abstract: Coronary artery disease (CAD) mortality and morbidity is present in the European continent in a four-fold gradient across populations, from the South (Spain and France) with the lowest CAD mortality, towards the North (Finland and UK). This observed gradient has not been fully explained by classical or single genetic risk factors, resulting in some cases in the so called Southern European or Mediterranean paradox. Here we approached population genetic risk estimates using genetic risk scores (GRS) constructed with single nucleotide polymorphisms (SNP) from nitric oxide synthases (NOS) genes. These SNPs appeared to be associated with myocardial infarction (MI) in 2165 cases and 2153 controls. The GRSs were computed in 34 general European populations. Although the contribution of these GRS was lower than 1% between cases and controls, the mean GRS per population was positively correlated with coronary incidence explaining 65-85% of the variation among populations (67% in women and 86% in men). This large contribution to CAD incidence variation among populations might be a result of colinearity with several other common genetic and environmental factors. These results are not consistent with the cardiovascular Mediterranean paradox for genetics and support a CAD genetic architecture mainly based on combinations of common genetic polymorphisms. Population genetic risk scores is a promising approach in public health interventions to develop lifestyle programs and prevent intermediate risk factors in certain subpopulations with specific genetic predisposition.
Published: 2014
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31. Assessment of the 9p21.3 locus in severity of coronary artery disease in the presence and absence of type 2 diabetes

Author: Rivera, N.V. (Natalia), Carreras-Torres, R. (Robert), Roncarati, R. (Roberta), Viviani-Anselmi, C. (Chiara), Micco, F. (Francesca) de, Mezzelani, A. (Alessandra), Koch, W. (Werner), Hoppmann, P. (Petra), Kastrati, A. (Adnan), Stewart, A.F.R. (Alexandre), Chen, L. (Leslie), Roberts, R. (Robert), Karssen, L.C. (Lennart), Amin, N. (Najaf), Trimarco, V. (Valentina), Izzo, R. (Raffaele), Iaccarino, G. (Guido), Condorelli, G. (Gerolama), Puca, A.A. (Annibale), Pagnotta, P. (Paolo), Airoldi, F. (Flavio), Trimarco, B. (Bruno), Duijn, C.M. (Cornelia) van, Condorelli, G. (Gianluigi), Briguori, C. (Carlo), Rivera, N.V. (Natalia), Carreras-Torres, R. (Robert), Roncarati, R. (Roberta), Viviani-Anselmi, C. (Chiara), Micco, F. (Francesca) de, Mezzelani, A. (Alessandra), Koch, W. (Werner), Hoppmann, P. (Petra), Kastrati, A. (Adnan), Stewart, A.F.R. (Alexandre), Chen, L. (Leslie), Roberts, R. (Robert), Karssen, L.C. (Lennart), Amin, N. (Najaf), Trimarco, V. (Valentina), Izzo, R. (Raffaele), Iaccarino, G. (Guido), Condorelli, G. (Gerolama), Puca, A.A. (Annibale), Pagnotta, P. (Paolo), Airoldi, F. (Flavio), Trimarco, B. (Bruno), Duijn, C.M. (Cornelia) van, Condorelli, G. (Gianluigi), and Briguori, C. (Carlo)
Abstract: Background: The 9p21.3 locus is strongly associated with the risk of coronary artery disease (CAD) and with type 2 diabetes (T2D). We investigated
Published: 2013
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32. Assessment of the 9p21.3 locus in severity of coronary artery disease in the presence and absence of type 2 diabetes

Author: Rivera, NV, Carreras-Torres, R, Roncarati, R, Viviani-Anselmi, C, De Micco, F, Mezzelani, A, Koch, W, Hoppmann, P, Kastrati, A, Stewart, AFR, Chen, L, Roberts, R, Karssen, Lennart, Amin, Najaf, Trimarco, V, Izzo, R, Iaccarino, G, Condorelli, G, Puca, AA, Pagnotta, P, Airoldi, F, Trimarco, B, Duijn, Cornelia, Briguori, C, Rivera, NV, Carreras-Torres, R, Roncarati, R, Viviani-Anselmi, C, De Micco, F, Mezzelani, A, Koch, W, Hoppmann, P, Kastrati, A, Stewart, AFR, Chen, L, Roberts, R, Karssen, Lennart, Amin, Najaf, Trimarco, V, Izzo, R, Iaccarino, G, Condorelli, G, Puca, AA, Pagnotta, P, Airoldi, F, Trimarco, B, Duijn, Cornelia, and Briguori, C
Abstract: Background: The 9p21.3 locus is strongly associated with the risk of coronary artery disease (CAD) and with type 2 diabetes (T2D). We investigated the association of 9p21.3 variants with severity of CAD (defined by the number of vessel diseased [VD]) in the presence and absence of T2D. Methods: We tested 11 9p21.3-variants for association in a white Italian study (N = 2,908), and carried out replication in 2 independent white populations, a German study (N = 2,028) and a Canadian Study (N=950). SNP association and permutation analyses were conducted. Results: We identified two 9p21.3-variants, rs4977574 (P < 4x10(-4)) and rs2383207 (P < 1.5x10(-3)) that were associated with severity of CAD in subjects without T2D. Association of rs4977574 with severity of CAD was confirmed in the Canadian Study. Results from subgroup analysis among patients with T2D showed an interaction between rs10738610 and T2D with P = 4.82x10(-2). Further investigation showed that rs10738610 (P < 1.99x10(-2)) was found to be significantly associated with severity of CAD Conclusions: The 9p21.3 locus is significantly associated with severity of CAD. The number of associations of 9p21.3 variants with severity of CAD is variable to the presence and absence of T2D. In a CAD-susceptible region of 115 kb, there is only one variant associated with the severity of coronary vessel disease in the presence of type 2 diabetes.
Published: 2013

33. Analysis of Genomic Regions Associated With Coronary Artery Disease Reveals Continent-Specific Single Nucleotide Polymorphisms in North African Populations

Author: Zanetti D, Via M, Carreras-Torres R, Esther Esteban, Chaabani H, Anaibar F, Harich N, Habbal R, Ghalim N, and Moral P

34. Assessment of the 9p21.3 locus in severity of coronary artery disease in the presence and absence of type 2 diabetes

Author: Rivera Natalia V, Carreras-Torres Robert, Roncarati Roberta, Viviani-Anselmi Chiara, De Micco Francesca, Mezzelani Alessandra, Koch Werner, Hoppmann Petra, Kastrati Adnan, Stewart Alexandre FR, Chen Li, Roberts Robert, Karssen Lennart C, Amin Najaf, Trimarco Valentina, Izzo Raffaele, Iaccarino Guido, Condorelli Gerolama, Puca Annibale A, Pagnotta Paolo, Airoldi Flavio, Trimarco Bruno, van Duijn Cornelia M, Condorelli Gianluigi, and Briguori Carlo
Subjects: Severity of CAD, Coronary artery disease, Diabetes mellitus, T2D, 9p21.3, Genetics, Single nucleotide polymorphism, Internal medicine, RC31-1245, QH426-470
Abstract: Abstract Background The 9p21.3 locus is strongly associated with the risk of coronary artery disease (CAD) and with type 2 diabetes (T2D). We investigated the association of 9p21.3 variants with severity of CAD (defined by the number of vessel diseased [VD]) in the presence and absence of T2D. Methods We tested 11 9p21.3-variants for association in a white Italian study (N = 2,908), and carried out replication in 2 independent white populations, a German study (N = 2,028) and a Canadian Study (N=950). SNP association and permutation analyses were conducted. Results We identified two 9p21.3-variants, rs4977574 (P < 4×10-4) and rs2383207 (P < 1.5×10-3) that were associated with severity of CAD in subjects without T2D. Association of rs4977574 with severity of CAD was confirmed in the Canadian Study. Results from subgroup analysis among patients with T2D showed an interaction between rs10738610 and T2D with P = 4.82×10-2. Further investigation showed that rs10738610 (P < 1.99×10-2) was found to be significantly associated with severity of CAD in subjects with T2D. Conclusions The 9p21.3 locus is significantly associated with severity of CAD. The number of associations of 9p21.3 variants with severity of CAD is variable to the presence and absence of T2D. In a CAD-susceptible region of 115 kb, there is only one variant associated with the severity of coronary vessel disease in the presence of type 2 diabetes.
Published: 2013
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35. Multiomic integration analysis identifies atherogenic metabolites mediating between novel immune genes and cardiovascular risk.

Author: Carreras-Torres R, Galván-Femenía I, Farré X, Cortés B, Díez-Obrero V, Carreras A, Moratalla-Navarro F, Iraola-Guzmán S, Blay N, Obón-Santacana M, Moreno V, and de Cid R
Subjects: Humans, Cardiovascular Diseases epidemiology, Cardiovascular Diseases genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Disease Risk Factors, Metabolome, Polymorphism, Single Nucleotide, Atherosclerosis genetics, Atherosclerosis metabolism
Abstract: Background: Understanding genetic-metabolite associations has translational implications for informing cardiovascular risk assessment. Interrogating functional genetic variants enhances our understanding of disease pathogenesis and the development and optimization of targeted interventions., Methods: In this study, a total of 187 plasma metabolite levels were profiled in 4974 individuals of European ancestry of the GCAT| Genomes for Life cohort. Results of genetic analyses were meta-analysed with additional datasets, resulting in up to approximately 40,000 European individuals. Results of meta-analyses were integrated with reference gene expression panels from 58 tissues and cell types to identify predicted gene expression associated with metabolite levels. This approach was also performed for cardiovascular outcomes in three independent large European studies (N = 700,000) to identify predicted gene expression additionally associated with cardiovascular risk. Finally, genetically informed mediation analysis was performed to infer causal mediation in the relationship between gene expression, metabolite levels and cardiovascular risk., Results: A total of 44 genetic loci were associated with 124 metabolites. Lead genetic variants included 11 non-synonymous variants. Predicted expression of 53 fine-mapped genes was associated with 108 metabolite levels; while predicted expression of 6 of these genes was also associated with cardiovascular outcomes, highlighting a new role for regulatory gene HCG27. Additionally, we found that atherogenic metabolite levels mediate the associations between gene expression and cardiovascular risk. Some of these genes showed stronger associations in immune tissues, providing further evidence of the role of immune cells in increasing cardiovascular risk., Conclusions: These findings propose new gene targets that could be potential candidates for drug development aimed at lowering the risk of cardiovascular events through the modulation of blood atherogenic metabolite levels., (© 2024. The Author(s).)
Published: 2024
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36. Exploring the Chemopreventive Effect of Medication on Gene Expression Linked to Colorectal Cancer: An Observational and Mendelian Randomization Analysis in Healthy Colon Mucosa.

Author: Moratalla-Navarro F, Carreras-Torres R, Díez-Obrero V, Devall M, Obón-Santacana M, Díez-Villanueva A, Guinó E, Casey G, Li L, and Moreno V
Subjects: Humans, Male, Chemoprevention methods, Colon metabolism, Colon pathology, Colon drug effects, Gene Expression Regulation, Neoplastic drug effects, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Intestinal Mucosa drug effects, Mendelian Randomization Analysis, Risk Factors, Tumor Microenvironment drug effects, Colorectal Neoplasms genetics, Colorectal Neoplasms prevention & control, Metformin therapeutic use, Metformin pharmacology
Abstract: Gene expression appears altered in apparently normal tissue surrounding tumor tissue. The observed biological alterations in the tumor microenvironment play a crucial role in cancer development and are named the cancer field effect (FE). A robust set of overexpressed FE genes in tissue surrounding colorectal cancer (CRC) tumor were identified in previous studies. Our study aimed to investigate the influence of common medication intake and modifiable risk factors on FE gene expression using a colonic mucosa sample dataset of healthy individuals (BarcUVa-Seq). We applied expression enrichment analysis of the FE genes for each studied medication and factor. Both observational and instrumental (Mendelian randomization) analysis were conducted, and the results were validated using independent datasets. The findings from the observational and instrumental analyses consistently showed that medication intake, especially metformin, considerably downregulated the FE genes. Chemopreventive effects were also noted for antihypertensive drugs targeting the renin-angiotensin system. Conversely, benzodiazepines usage might upregulate FE genes, thus fostering a tumor-promoting microenvironment. In contrast, the findings from the observational and instrumental analyses on modifiable risk factors showed some discrepancies. The instrumental results indicated that obesity and smoking might promote a tumor-favorable microenvironment. These findings offer insights into the biological mechanisms through which risk factors might influence CRC development and highlight the potential chemopreventive roles of metformin and antihypertensive drugs in CRC risk.
Published: 2024
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37. Metagenomic Study Reveals Phage-Bacterial Interactome Dynamics in Gut and Oral Microbiota in Pancreatic Diseases.

Author: Vilà-Quintana L, Fort E, Pardo L, Albiol-Quer MT, Ortiz MR, Capdevila M, Feliu A, Bahí A, Llirós M, García-Velasco A, Morell Ginestà M, Laquente B, Pozas D, Moreno V, Garcia-Gil LJ, Duell EJ, Pimenoff VN, Carreras-Torres R, and Aldeguer X
Subjects: Humans, Pancreatic Neoplasms microbiology, Pancreatic Neoplasms metabolism, Male, Mouth microbiology, Saliva microbiology, Saliva metabolism, Female, Middle Aged, Carcinoma, Pancreatic Ductal microbiology, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal virology, Bacteria genetics, Bacteria classification, Bacteria metabolism, Bacteria isolation & purification, Metagenome, Pancreatitis, Chronic microbiology, Pancreatitis, Chronic metabolism, Pancreatitis, Chronic virology, Pancreatic Diseases microbiology, Pancreatic Diseases metabolism, Pancreatic Diseases virology, Aged, Microbiota genetics, Adult, Gastrointestinal Microbiome, Metagenomics methods, Bacteriophages genetics, Feces microbiology
Abstract: Individuals with pancreatic-related health conditions usually show lower diversity and different composition of bacterial and viral species between the gut and oral microbiomes compared to healthy individuals. We performed a thorough microbiome analysis, using deep shotgun sequencing of stool and saliva samples obtained from patients with chronic pancreatitis (CP), pancreatic ductal adenocarcinoma (PDAC), and healthy controls (HCs).We observed similar microbiota composition at the species level in both the gut and oral samples in PDAC patients compared to HCs, among which the most distinctive finding was that the abundance of oral-originated Fusobacterium nucleatum species did not differ between the oral and the gut samples. Moreover, comparing PDAC patients with HCs, Klebsiella oxytoca was significantly more abundant in the stool samples of PDAC patients, while Streptococcus spp. showed higher abundance in both the oral and stool samples of PDAC patients. Finally, the most important finding was the distinctive gut phage-bacterial interactome pattern among PDAC patients. CrAssphages, particularly Blohavirus , showed mutual exclusion with K. oxytoca species, while Burzaovirus showed co-occurrence with Enterobacteriaceae spp., which have been shown to be capable of inducing DNA damage in human pancreatic cells ex vivo. The interactome findings warrant further mechanistic studies, as our findings may provide new insights into developing microbiota-based diagnostic and therapeutic methods for pancreatic diseases.
Published: 2024
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38. Characterization of additive gene-environment interactions for colorectal cancer risk.

Author: Thomas CE, Lin Y, Kim M, Kawaguchi ES, Qu C, Um CY, Lynch BM, Van Guelpen B, Tsilidis K, Carreras-Torres R, van Duijnhoven FJ, Sakoda LC, Campbell PT, Tian Y, Chang-Claude J, Bézieau S, Budiarto A, Palmer JR, Newcomb PA, Casey G, Le Marchand L, Giannakis M, Li CI, Gsur A, Newton C, Obón-Santacana M, Moreno V, Vodicka P, Brenner H, Hoffmeister M, Pellatt AJ, Schoen RE, Dimou N, Murphy N, Gunter MJ, Castellví-Bel S, Figueiredo JC, Chan AT, Song M, Li L, Bishop DT, Gruber SB, Baurley JW, Bien SA, Conti DV, Huyghe JR, Kundaje A, Su YR, Wang J, Keku TO, Woods MO, Berndt SI, Chanock SJ, Tangen CM, Wolk A, Burnett-Hartman A, Wu AH, White E, Devall MA, Díez-Obrero V, Drew DA, Giovannucci E, Hidaka A, Kim AE, Lewinger JP, Morrison J, Ose J, Papadimitriou N, Pardamean B, Peoples AR, Ruiz-Narvaez EA, Shcherbina A, Stern MC, Chen X, Thomas DC, Platz EA, Gauderman WJ, Peters U, and Hsu L
Abstract: Background: Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure., Methods: Using resources from colorectal cancer consortia including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score including 141 variants associated with CRC risk., Results: There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking [RERI = 0.24, 95% confidence interval, CI, (0.13, 0.36)], ever smoking [0.11 (0.05, 0.16)], high BMI [female 0.09 (0.05, 0.13), male 0.10 (0.05, 0.14)], or high red meat intake [highest versus lowest quartile 0.18 (0.09, 0.27)] was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/NSAID use [-0.16 (-0.20, -0.11)] or higher intake of fruit, fiber, or calcium [highest quartile versus lowest quartile -0.12 (-0.18, -0.050); -0.16 (-0.23, -0.09); -0.11 (-0.18, -0.05), respectively] than those with average genetic susceptibility., Conclusions: Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention., Competing Interests: Conflict of Interest: SB Gruber: Brogent International LLC, co-founder, not related to submitted work. All other authors do not have any conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
Published: 2024
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39. Diet Impacts on Gene Expression in Healthy Colon Tissue: Insights from the BarcUVa-Seq Study.

Author: Obón-Santacana M, Moratalla-Navarro F, Guinó E, Carreras-Torres R, Díez-Obrero V, Bars-Cortina D, Ibáñez-Sanz G, Rodríguez-Alonso L, Mata A, García-Rodríguez A, Devall M, Casey G, Li L, and Moreno V
Subjects: Humans, Male, Female, Cross-Sectional Studies, Middle Aged, Adult, Intestinal Mucosa metabolism, Transcriptome, Gene Expression Regulation, Aged, Protein Interaction Maps, Colon metabolism, Diet
Abstract: (1) Introduction: The global rise of gastrointestinal diseases, including colorectal cancer and inflammatory bowel diseases, highlights the need to understand their causes. Diet is a common risk factor and a crucial regulator of gene expression, with alterations observed in both conditions. This study aims to elucidate the specific biological mechanisms through which diet influences the risk of bowel diseases. (2) Methods: We analyzed data from 436 participants from the BarcUVa-Seq population-based cross-sectional study utilizing gene expression profiles (RNA-Seq) from frozen colonic mucosal biopsies and dietary information from a semi-quantitative food frequency questionnaire. Dietary variables were evaluated based on two dietary patterns and as individual variables. Differential expression gene (DEG) analysis was performed for each dietary factor using edgeR. Protein-protein interaction (PPI) analysis was conducted with STRINGdb v11 for food groups with more than 10 statistically significant DEGs, followed by Reactome-based enrichment analysis for the resulting networks. (3) Results: Our findings reveal that food intake, specifically the consumption of blue fish, alcohol, and potatoes, significantly influences gene expression in the colon of individuals without tumor pathology, particularly in pathways related to DNA repair, immune system function, and protein glycosylation. (4) Discussion: These results demonstrate how these dietary components may influence human metabolic processes and affect the risk of bowel diseases.
Published: 2024
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40. Genome-wide interaction study of dietary intake of fibre, fruits, and vegetables with risk of colorectal cancer.

Author: Papadimitriou N, Kim A, Kawaguchi ES, Morrison J, Diez-Obrero V, Albanes D, Berndt SI, Bézieau S, Bien SA, Bishop DT, Bouras E, Brenner H, Buchanan DD, Campbell PT, Carreras-Torres R, Chan AT, Chang-Claude J, Conti DV, Devall MA, Dimou N, Drew DA, Gruber SB, Harrison TA, Hoffmeister M, Huyghe JR, Joshi AD, Keku TO, Kundaje A, Küry S, Le Marchand L, Lewinger JP, Li L, Lynch BM, Moreno V, Newton CC, Obón-Santacana M, Ose J, Pellatt AJ, Peoples AR, Platz EA, Qu C, Rennert G, Ruiz-Narvaez E, Shcherbina A, Stern MC, Su YR, Thomas DC, Thomas CE, Tian Y, Tsilidis KK, Ulrich CM, Um CY, Visvanathan K, Wang J, White E, Woods MO, Schmit SL, Macrae F, Potter JD, Hopper JL, Peters U, Murphy N, Hsu L, Gunter MJ, and Gauderman WJ
Subjects: Humans, Genotype, Diet, Male, Female, Risk Factors, Fruit, Colorectal Neoplasms genetics, Colorectal Neoplasms etiology, Dietary Fiber administration & dosage, Vegetables, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Gene-Environment Interaction
Abstract: Background: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations., Methods: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously., Findings: The 3-DF joint test revealed two significant loci with p-value <5 × 10 -8 . Rs4730274 close to the SLC26A3 gene showed an association with fibre (p-value: 2.4 × 10 -3 ) and G × fibre interaction with CRC (OR per quartile of fibre increase = 0.87, 0.80, and 0.75 for CC, TC, and TT genotype, respectively; G × E p-value: 1.8 × 10 -7 ). Rs1620977 in the NEGR1 gene showed an association with fruit intake (p-value: 1.0 × 10 -8 ) and G × fruit interaction with CRC (OR per quartile of fruit increase = 0.75, 0.65, and 0.56 for AA, AG, and GG genotype, respectively; G × E -p-value: 0.029)., Interpretation: We identified 2 loci associated with fibre and fruit intake that also modify the association of these dietary factors with CRC risk. Potential mechanisms include chronic inflammatory intestinal disorders, and gut function. However, further studies are needed for mechanistic validation and replication of findings., Funding: National Institutes of Health, National Cancer Institute. Full funding details for the individual consortia are provided in acknowledgments., Competing Interests: Declaration of interests ESK is a co-investigator in a grant from National Institutes of Health (R01CA196569). JW is Stock shareholder of Gilead Sciences Inc. AK has received consulting fees for Illumina Inc., has participated on data safety monitoring boards or advisory boards of TensorBio, PatchBio, Serimmune, and OpenTargets, and has stock or stock options of Illumina, Freenome, Deep Genomics, Immunai, TensorBio, PatchBio, and Serimmune. MCS was a co-investigator in a grant from National Institutes of Health (R01CA201407). VM has received grant support from Instituto de Salud Carlos III and Fundacion Cientifica Asociación Española Contra el Cáncer. SBG is a co-founder of Brogent international LLC. JPL has received additional grant support (5P01CA196569, 6R01CA201407). The remaining authors declare that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)
Published: 2024
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41. Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk.

Author: Tian Y, Lin Y, Qu C, Arndt V, Baurley JW, Berndt SI, Bien SA, Bishop DT, Brenner H, Buchanan DD, Budiarto A, Campbell PT, Carreras-Torres R, Casey G, Chan AT, Chen R, Chen X, Conti DV, Díez-Obrero V, Dimou N, Drew DA, Figueiredo JC, Gallinger S, Giles GG, Gruber SB, Gunter MJ, Harlid S, Harrison TA, Hidaka A, Hoffmeister M, Huyghe JR, Jenkins MA, Jordahl KM, Joshi AD, Keku TO, Kawaguchi E, Kim AE, Kundaje A, Larsson SC, Marchand LL, Lewinger JP, Li L, Moreno V, Morrison J, Murphy N, Nan H, Nassir R, Newcomb PA, Obón-Santacana M, Ogino S, Ose J, Pardamean B, Pellatt AJ, Peoples AR, Platz EA, Potter JD, Prentice RL, Rennert G, Ruiz-Narvaez EA, Sakoda LC, Schoen RE, Shcherbina A, Stern MC, Su YR, Thibodeau SN, Thomas DC, Tsilidis KK, van Duijnhoven FJB, Van Guelpen B, Visvanathan K, White E, Wolk A, Woods MO, Wu AH, Peters U, Gauderman WJ, Hsu L, and Chang-Claude J
Subjects: Humans, Female, Middle Aged, Case-Control Studies, Risk Factors, Aged, Hormone Replacement Therapy adverse effects, Risk Assessment, Menopause, Postmenopause, Estrogen Replacement Therapy adverse effects, Colorectal Neoplasms genetics, Colorectal Neoplasms epidemiology, Genetic Predisposition to Disease
Abstract: Background: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk., Methods: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated., Results: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10 -8 ). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10 -14 ); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10 -3 ), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk., Conclusions: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use., (© 2024. The Author(s).)
Published: 2024
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42. Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.

Author: 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 YR, 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, and Gauderman WJ
Subjects: Humans, Aspirin pharmacology, Receptors, Prostaglandin E, EP4 Subtype genetics, Receptors, Prostaglandin E, EP4 Subtype metabolism, Male, Genetic Predisposition to Disease, Female, Case-Control Studies, Middle Aged, Genetic Loci, Aged, Colorectal Neoplasms genetics, Colorectal Neoplasms drug therapy, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Genome-Wide Association Study, Polymorphism, Single Nucleotide
Abstract: 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.
Published: 2024
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43. Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer.

Author: Peruchet-Noray L, Sedlmeier AM, Dimou N, Baurecht H, Fervers B, Fontvieille E, Konzok J, Tsilidis KK, Christakoudi S, Jansana A, Cordova R, Bohmann P, Stein MJ, Weber A, Bézieau S, Brenner H, Chan AT, Cheng I, Figueiredo JC, Garcia-Etxebarria K, Moreno V, Newton CC, Schmit SL, Song M, Ulrich CM, Ferrari P, Viallon V, Carreras-Torres R, Gunter MJ, and Freisling H
Subjects: Humans, Genome-Wide Association Study, Obesity genetics, Phenotype, Genetic Variation, Risk Factors, Somatotypes, Colorectal Neoplasms genetics
Abstract: It remains unknown whether adiposity subtypes are differentially associated with colorectal cancer (CRC). To move beyond single-trait anthropometric indicators, we derived four multi-trait body shape phenotypes reflecting adiposity subtypes from principal components analysis on body mass index, height, weight, waist-to-hip ratio, and waist and hip circumference. A generally obese (PC1) and a tall, centrally obese (PC3) body shape were both positively associated with CRC risk in observational analyses in 329,828 UK Biobank participants (3728 cases). In genome-wide association studies in 460,198 UK Biobank participants, we identified 3414 genetic variants across four body shapes and Mendelian randomization analyses confirmed positive associations of PC1 and PC3 with CRC risk (52,775 cases/45,940 controls from GECCO/CORECT/CCFR). Brain tissue-specific genetic instruments, mapped to PC1 through enrichment analysis, were responsible for the relationship between PC1 and CRC, while the relationship between PC3 and CRC was predominantly driven by adipose tissue-specific genetic instruments. This study suggests distinct putative causal pathways between adiposity subtypes and CRC.
Published: 2024
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44. Exploring the Associations of Inflammatory and Oxidative Stress Biomarkers with Pancreatic Diseases: An Observational and Mendelian Randomisation Study.

Author: Vilà-Quintana L, Fort E, Pardo L, Albiol-Quer MT, Ortiz MR, Capdevila M, Feliu A, Bahí A, Llirós M, Aguilar E, García-Velasco A, Ginestà MM, Laquente B, Pozas D, Lluansí A, Pimenoff VN, Moreno V, Garcia-Gil LJ, Duell EJ, Carreras-Torres R, and Aldeguer X
Abstract: Identifying biomarkers linked to pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP) is crucial for early detection, treatment, and prevention. Methods: Association analyses of 10 serological biomarkers involved in cell signalling (IFN-γ, IL-6, IL-8, IL-10), oxidative stress (superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzyme activities, total glutathione (GSH), malondialdehyde (MDA) levels), and intestinal permeability proteins (zonulin, I-FABP2) were conducted across PDAC ( n = 12), CP ( n = 21) and control subjects ( n = 23). A Mendelian randomisation (MR) approach was used to assess causality of the identified significant associations in two large genetic cohorts (FinnGen and UK Biobank). Results: Observational results showed a downregulation of SOD and GPx antioxidant enzyme activities in PDAC and CP patients, respectively, and higher MDA levels in CP patients. Logistic regression models revealed significant associations between CP and SOD activity (OR = 0.21, 95% CI [0.05, 0.89], per SD), GPx activity (OR = 0.28, 95% CI [0.10, 0.79], per SD), and MDA levels (OR = 2.05, 95% CI [1.36, 3.08], per SD). MR analyses, however, did not support causality. Conclusions: These findings would not support oxidative stress-related biomarkers as potential targets for pancreatic diseases prevention. Yet, further research is encouraged to assess their viability as non-invasive tools for early diagnosis, particularly in pre-diagnostic CP populations.
Published: 2024
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45. Impact of bread diet on intestinal dysbiosis and irritable bowel syndrome symptoms in quiescent ulcerative colitis: A pilot study.

Author: Lluansí A, Llirós M, Carreras-Torres R, Bahí A, Capdevila M, Feliu A, Vilà-Quintana L, Elias-Masiques N, Cueva E, Peries L, Torrealba L, Miquel-Cusachs JO, Sàbat M, Busquets D, López C, Delgado-Aros S, Garcia-Gil LJ, Elias I, and Aldeguer X
Subjects: Humans, Pilot Projects, Dysbiosis complications, RNA, Ribosomal, 16S, Bread, Diet, Abdominal Pain, Irritable Bowel Syndrome diagnosis, Colitis, Ulcerative complications
Abstract: Gut microbiota may be involved in the presence of irritable bowel syndrome (IBS)-like symptomatology in ulcerative colitis (UC) patients in remission. Bread is an important source of dietary fiber, and a potential prebiotic. To assess the effect of a bread baked using traditional elaboration, in comparison with using modern elaboration procedures, in changing the gut microbiota and relieving IBS-like symptoms in patients with quiescent ulcerative colitis. Thirty-one UC patients in remission with IBS-like symptoms were randomly assigned to a dietary intervention with 200 g/d of either treatment or control bread for 8 weeks. Clinical symptomatology was tested using questionnaires and inflammatory parameters. Changes in fecal microbiota composition were assessed by high-throughput sequencing of the 16S rRNA gene. A decrease in IBS-like symptomatology was observed after both the treatment and control bread interventions as reductions in IBS-Symptom Severity Score values (p-value < 0.001) and presence of abdominal pain (p-value < 0.001). The treatment bread suggestively reduced the Firmicutes/Bacteroidetes ratio (p-value = 0.058). In addition, the Firmicutes/Bacteroidetes ratio seemed to be associated with improving IBS-like symptoms as suggested by a slight decrease in patient without abdominal pain (p-value = 0.059). No statistically significant differential abundances were found at any taxonomic level. The intake of a bread baked using traditional elaboration decreased the Firmicutes/Bacteroidetes ratio, which seemed to be associated with improving IBS-like symptoms in quiescent ulcerative colitis patients. These findings suggest that the traditional bread elaboration has a potential prebiotic effect improving gut health (ClinicalTrials.gov ID number of study: NCT05656391)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lluansí et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Published: 2024
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46. Genome-wide interaction analysis of folate for colorectal cancer risk.

Author: 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 YR, 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, and Tsilidis KK
Subjects: Humans, Risk Factors, Case-Control Studies, Dietary Supplements, Folic Acid metabolism, Colorectal Neoplasms genetics
Abstract: 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., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2023
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47. Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations.

Author: Thomas M, Su YR, 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 DH, 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 SS, Vadaparampil S, Harrison TA, Yamaji T, Keku TO, Vymetalkova V, Arndt V, Jia WH, Shu XO, Lin Y, Ahn YO, 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, and Hsu L
Subjects: Humans, Genome-Wide Association Study, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Risk Factors, Multifactorial Inheritance, Ethnicity genetics, Colorectal Neoplasms diagnosis, Colorectal Neoplasms genetics
Abstract: 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., (© 2023. Springer Nature Limited.)
Published: 2023
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48. Probing the diabetes and colorectal cancer relationship using gene - environment interaction analyses.

Author: 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 YR, 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, and Peters U
Subjects: Humans, Gene-Environment Interaction, Genetic Predisposition to Disease, Risk Factors, Polymorphism, Single Nucleotide, Genome-Wide Association Study methods, Microfilament Proteins genetics, Diabetes Mellitus genetics, Colorectal Neoplasms genetics
Abstract: 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 - OR AA : 1.62, 95% CI: 1.34-1.96; OR AG : 1.41, 95% CI: 1.30-1.54; OR GG : 1.22, 95% CI: 1.13-1.31; p-value 3-d.f. : 5.46 × 10 -11 ) and 13q14.13 (rs9526201, LRCH1 - OR GG : 2.11, 95% CI: 1.56-2.83; OR GA : 1.52, 95% CI: 1.38-1.68; OR AA : 1.13, 95% CI: 1.06-1.21; p-value 2-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., (© 2023. The Author(s).)
Published: 2023
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49. A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk.

Author: 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 YR, 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, and Campbell PT
Subjects: Humans, Body Mass Index, Risk Factors, Genetic Loci, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Genome-Wide Association Study, Intercellular Signaling Peptides and Proteins genetics, Obesity complications, Obesity genetics, Colorectal Neoplasms genetics
Abstract: 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., (©2023 The Authors; Published by the American Association for Cancer Research.)
Published: 2023
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50. Author Correction: Application of Mendelian randomization to explore the causal role of the human gut microbiome in colorectal cancer.

Author: Hatcher C, Richenberg G, Waterson S, Nguyen LH, Joshi AD, Carreras-Torres R, Moreno V, Chan AT, Gunter M, Lin Y, Qu C, Song M, Casey G, Figueiredo JC, Gruber SB, Hampe J, Hampel H, Jenkins MA, Keku TO, Peters U, Tangen CM, Wu AH, Hughes DA, Rühlemann MC, Raes J, Timpson NJ, and Wade KH
Published: 2023
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