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

Elom K. Aglago; Andre Kim; Yi Lin; Conghui Qu; Marina Evangelou; Yu Ren; John Morrison; Demetrius Albanes; Volker Arndt; Elizabeth L. Barry; James W. Baurley; Sonja I. Berndt; Stephanie A. Bien; D.T. Bishop; Emmanouil Bouras; Hermann Brenner; Daniel D. Buchanan; Arif Budiarto; Robert Carreras-Torres; Graham Casey; Tjeng Wawan Cenggoro; Andrew T. Chan; Jenny Chang-Claude; Xuechen Chen; David V. Conti; Matthew Devall; Virginia Diez-Obrero; Niki Dimou; David Drew; Jane C. Figueiredo; Steven Gallinger; Graham G. Giles; Stephen B. Gruber; Andrea Gsur; Marc J. Gunter; Heather Hampel; Sophia Harlid; Akihisa Hidaka; Tabitha A. Harrison; Michael Hoffmeister; Jeroen R. Huyghe; Mark A. Jenkins; Kristina Jordahl; Amit D. Joshi; Eric S. Kawaguchi; Temitope O. Keku; Anshul Kundaje; Susanna C. Larsson; Loic Le Marchand; Juan Pablo Lewinger; Li Li; Brigid M. Lynch; Bharuno Mahesworo; Marko Mandic; Mireia Obón-Santacana; Victor Moreno; Neil Murphy; Hongmei Nan; Rami Nassir; Polly A. Newcomb; Shuji Ogino; Jennifer Ose; Rish K. Pai; Julie R. Palmer; Nikos Papadimitriou; Bens Pardamean; Anita R. Peoples; Elizabeth A. Platz; John D. Potter; Ross L. Prentice; Gad Rennert; Edward Ruiz-Narvaez; Lori C. Sakoda; Peter C. Scacheri; Stephanie L. Schmit; Robert E. Schoen; Anna Shcherbina; Martha L. Slattery; Mariana C. Stern; Yu Ru Su; Catherine M. Tangen; Stephen N. Thibodeau; Duncan C. Thomas; Yu Tian; Cornelia M. Ulrich; Franzel J.B. van Duijnhoven; Bethany Van Guelpen; Kala Visvanathan; Pavel Vodicka; Jun Wang; Emily White; Alicja Wolk; Michael O. Woods; Anna H. Wu; Natalia Zemlianskaia; Li Hsu; W.J. Gauderman; Ulrike Peters; Konstantinos K. Tsilidis; Peter T. Campbell

doi:10.1158/0008-5472.CAN-22-3713

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

Elom K. Aglago, Andre Kim, Yi Lin, Conghui Qu, Marina Evangelou, Yu Ren, John Morrison, Demetrius Albanes, Volker Arndt, Elizabeth L. Barry, James W. Baurley, Sonja I. Berndt, Stephanie A. Bien, D.T. Bishop, Emmanouil Bouras, Hermann Brenner, Daniel D. Buchanan, Arif Budiarto, Robert Carreras-Torres, Graham CaseyTjeng Wawan Cenggoro, Andrew T. Chan, Jenny Chang-Claude, Xuechen Chen, David V. Conti, Matthew Devall, Virginia Diez-Obrero, Niki Dimou, David Drew, Jane C. Figueiredo, Steven Gallinger, Graham G. Giles, Stephen B. Gruber, Andrea Gsur, Marc J. Gunter, Heather Hampel, Sophia Harlid, Akihisa Hidaka, Tabitha A. Harrison, Michael Hoffmeister, Jeroen R. Huyghe, Mark A. Jenkins, Kristina Jordahl, Amit D. Joshi, Eric S. Kawaguchi, Temitope O. Keku, Anshul Kundaje, Susanna C. Larsson, Loic Le Marchand, Juan Pablo Lewinger, Li Li, Brigid M. Lynch, Bharuno Mahesworo, Marko Mandic, Mireia Obón-Santacana, Victor Moreno, Neil Murphy, Hongmei Nan, Rami Nassir, Polly A. Newcomb, Shuji Ogino, Jennifer Ose, Rish K. Pai, Julie R. Palmer, Nikos Papadimitriou, Bens Pardamean, Anita R. Peoples, Elizabeth A. Platz, John D. Potter, Ross L. Prentice, Gad Rennert, Edward Ruiz-Narvaez, Lori C. Sakoda, Peter C. Scacheri, Stephanie L. Schmit, Robert E. Schoen, Anna Shcherbina, Martha L. Slattery, Mariana C. Stern, Yu Ru Su, Catherine M. Tangen, Stephen N. Thibodeau, Duncan C. Thomas, Yu Tian, Cornelia M. Ulrich, Franzel J.B. van Duijnhoven, Bethany Van Guelpen, Kala Visvanathan, Pavel Vodicka, Jun Wang, Emily White, Alicja Wolk, Michael O. Woods, Anna H. Wu, Natalia Zemlianskaia, Li Hsu, W.J. Gauderman^*, Ulrike Peters^*, Konstantinos K. Tsilidis^*, Peter T. Campbell^*

^*Corresponding author for this work

Nutrition and Disease

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	2572-2583
Number of pages	12
Journal	Cancer Research
Volume	83
Issue number	15
DOIs	https://doi.org/10.1158/0008-5472.CAN-22-3713
Publication status	Published - 1 Aug 2023

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Aglago, E. K., Kim, A., Lin, Y., Qu, C., Evangelou, M., Ren, Y., Morrison, J., Albanes, D., Arndt, V., Barry, E. L., Baurley, J. W., Berndt, S. I., Bien, S. A., Bishop, D. T., Bouras, E., Brenner, H., Buchanan, D. D., Budiarto, A., Carreras-Torres, R., ... Campbell, P. T. (2023). A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk. Cancer Research, 83(15), 2572-2583. https://doi.org/10.1158/0008-5472.CAN-22-3713

@article{79e29475487644778f6e1c3d204b7655,

title = "A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk",

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.",

author = "Aglago, {Elom K.} and Andre Kim and Yi Lin and Conghui Qu and Marina Evangelou and Yu Ren and John Morrison and Demetrius Albanes and Volker Arndt and Barry, {Elizabeth L.} and Baurley, {James W.} and Berndt, {Sonja I.} and Bien, {Stephanie A.} and D.T. Bishop and Emmanouil Bouras and Hermann Brenner and Buchanan, {Daniel D.} and Arif Budiarto and Robert Carreras-Torres and Graham Casey and Cenggoro, {Tjeng Wawan} and Chan, {Andrew T.} and Jenny Chang-Claude and Xuechen Chen and Conti, {David V.} and Matthew Devall and Virginia Diez-Obrero and Niki Dimou and David Drew and Figueiredo, {Jane C.} and Steven Gallinger and Giles, {Graham G.} and Gruber, {Stephen B.} and Andrea Gsur and Gunter, {Marc J.} and Heather Hampel and Sophia Harlid and Akihisa Hidaka and Harrison, {Tabitha A.} and Michael Hoffmeister and Huyghe, {Jeroen R.} and Jenkins, {Mark A.} and Kristina Jordahl and Joshi, {Amit D.} and Kawaguchi, {Eric S.} and Keku, {Temitope O.} and Anshul Kundaje and Larsson, {Susanna C.} and Marchand, {Loic Le} and Lewinger, {Juan Pablo} and Li Li and Lynch, {Brigid M.} and Bharuno Mahesworo and Marko Mandic and Mireia Ob{\'o}n-Santacana and Victor Moreno and Neil Murphy and Hongmei Nan and Rami Nassir and Newcomb, {Polly A.} and Shuji Ogino and Jennifer Ose and Pai, {Rish K.} and Palmer, {Julie R.} and Nikos Papadimitriou and Bens Pardamean and Peoples, {Anita R.} and Platz, {Elizabeth A.} and Potter, {John D.} and Prentice, {Ross L.} and Gad Rennert and Edward Ruiz-Narvaez and Sakoda, {Lori C.} and Scacheri, {Peter C.} and Schmit, {Stephanie L.} and Schoen, {Robert E.} and Anna Shcherbina and Slattery, {Martha L.} and Stern, {Mariana C.} and Su, {Yu Ru} and Tangen, {Catherine M.} and Thibodeau, {Stephen N.} and Thomas, {Duncan C.} and Yu Tian and Ulrich, {Cornelia M.} and {van Duijnhoven}, {Franzel J.B.} and {Van Guelpen}, Bethany and Kala Visvanathan and Pavel Vodicka and Jun Wang and Emily White and Alicja Wolk and Woods, {Michael O.} and Wu, {Anna H.} and Natalia Zemlianskaia and Li Hsu and W.J. Gauderman and Ulrike Peters and Tsilidis, {Konstantinos K.} and Campbell, {Peter T.}",

year = "2023",

month = aug,

day = "1",

doi = "10.1158/0008-5472.CAN-22-3713",

language = "English",

volume = "83",

pages = "2572--2583",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research",

number = "15",

}

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, 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 2023, 'A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk', Cancer Research, vol. 83, no. 15, pp. 2572-2583. https://doi.org/10.1158/0008-5472.CAN-22-3713

TY - JOUR

T1 - A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

AU - Aglago, Elom K.

AU - Kim, Andre

AU - Lin, Yi

AU - Qu, Conghui

AU - Evangelou, Marina

AU - Ren, Yu

AU - Morrison, John

AU - Albanes, Demetrius

AU - Arndt, Volker

AU - Barry, Elizabeth L.

AU - Baurley, James W.

AU - Berndt, Sonja I.

AU - Bien, Stephanie A.

AU - Bishop, D.T.

AU - Bouras, Emmanouil

AU - Brenner, Hermann

AU - Buchanan, Daniel D.

AU - Budiarto, Arif

AU - Carreras-Torres, Robert

AU - Casey, Graham

AU - Cenggoro, Tjeng Wawan

AU - Chan, Andrew T.

AU - Chang-Claude, Jenny

AU - Chen, Xuechen

AU - Conti, David V.

AU - Devall, Matthew

AU - Diez-Obrero, Virginia

AU - Dimou, Niki

AU - Drew, David

AU - Figueiredo, Jane C.

AU - Gallinger, Steven

AU - Giles, Graham G.

AU - Gruber, Stephen B.

AU - Gsur, Andrea

AU - Gunter, Marc J.

AU - Hampel, Heather

AU - Harlid, Sophia

AU - Hidaka, Akihisa

AU - Harrison, Tabitha A.

AU - Hoffmeister, Michael

AU - Huyghe, Jeroen R.

AU - Jenkins, Mark A.

AU - Jordahl, Kristina

AU - Joshi, Amit D.

AU - Kawaguchi, Eric S.

AU - Keku, Temitope O.

AU - Kundaje, Anshul

AU - Larsson, Susanna C.

AU - Marchand, Loic Le

AU - Lewinger, Juan Pablo

AU - Li, Li

AU - Lynch, Brigid M.

AU - Mahesworo, Bharuno

AU - Mandic, Marko

AU - Obón-Santacana, Mireia

AU - Moreno, Victor

AU - Murphy, Neil

AU - Nan, Hongmei

AU - Nassir, Rami

AU - Newcomb, Polly A.

AU - Ogino, Shuji

AU - Ose, Jennifer

AU - Pai, Rish K.

AU - Palmer, Julie R.

AU - Papadimitriou, Nikos

AU - Pardamean, Bens

AU - Peoples, Anita R.

AU - Platz, Elizabeth A.

AU - Potter, John D.

AU - Prentice, Ross L.

AU - Rennert, Gad

AU - Ruiz-Narvaez, Edward

AU - Sakoda, Lori C.

AU - Scacheri, Peter C.

AU - Schmit, Stephanie L.

AU - Schoen, Robert E.

AU - Shcherbina, Anna

AU - Slattery, Martha L.

AU - Stern, Mariana C.

AU - Su, Yu Ru

AU - Tangen, Catherine M.

AU - Thibodeau, Stephen N.

AU - Thomas, Duncan C.

AU - Tian, Yu

AU - Ulrich, Cornelia M.

AU - van Duijnhoven, Franzel J.B.

AU - Van Guelpen, Bethany

AU - Visvanathan, Kala

AU - Vodicka, Pavel

AU - Wang, Jun

AU - White, Emily

AU - Wolk, Alicja

AU - Woods, Michael O.

AU - Wu, Anna H.

AU - Zemlianskaia, Natalia

AU - Hsu, Li

AU - Gauderman, W.J.

AU - Peters, Ulrike

AU - Tsilidis, Konstantinos K.

AU - Campbell, Peter T.

PY - 2023/8/1

Y1 - 2023/8/1

N2 - 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.

AB - 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.

U2 - 10.1158/0008-5472.CAN-22-3713

DO - 10.1158/0008-5472.CAN-22-3713

M3 - Article

C2 - 37249599

AN - SCOPUS:85166391630

SN - 0008-5472

VL - 83

SP - 2572

EP - 2583

JO - Cancer Research

JF - Cancer Research

IS - 15

ER -

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

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