Probing the diabetes and colorectal cancer relationship using gene – environment interaction analyses

Niki Dimou; Andre E. Kim; Orlagh Flanagan; Neil Murphy; Virginia Diez-Obrero; Anna Shcherbina; Elom K. Aglago; Emmanouil Bouras; Peter T. Campbell; Graham Casey; Steven Gallinger; Stephen B. Gruber; Mark A. Jenkins; Yi Lin; Victor Moreno; Edward Ruiz-Narvaez; Mariana C. Stern; Yu Tian; Kostas K. Tsilidis; Volker Arndt; Elizabeth L. Barry; James W. Baurley; Sonja I. Berndt; Stéphane Bézieau; Stephanie A. Bien; D. Timothy Bishop; Hermann Brenner; Arif Budiarto; Robert Carreras-Torres; Tjeng Wawan Cenggoro; Andrew T. Chan; Jenny Chang-Claude; Stephen J. Chanock; Xuechen Chen; David V. Conti; Christopher H. Dampier; Matthew Devall; David A. Drew; Jane C. Figueiredo; Graham G. Giles; Andrea Gsur; Tabitha A. Harrison; Akihisa Hidaka; Michael Hoffmeister; Jeroen R. Huyghe; Kristina Jordahl; Eric Kawaguchi; Temitope O. Keku; Susanna C. Larsson; Loic Le Marchand; Juan Pablo Lewinger; Li Li; Bharuno Mahesworo; John Morrison; Polly A. Newcomb; Christina C. Newton; Mireia Obon-Santacana; Jennifer Ose; Rish K. Pai; Julie R. Palmer; Nikos Papadimitriou; Bens Pardamean; Anita R. Peoples; Paul D.P. Pharoah; Elizabeth A. Platz; John D. Potter; Gad Rennert; Peter C. Scacheri; Robert E. Schoen; Yu Ru Su; Catherine M. Tangen; Stephen N. Thibodeau; Duncan C. Thomas; Cornelia M. Ulrich; Caroline Y. Um; Franzel J.B. van Duijnhoven; Kala Visvanathan; Pavel Vodicka; Ludmila Vodickova; Emily White; Alicja Wolk; Michael O. Woods; Conghui Qu; Anshul Kundaje; Li Hsu; W. James Gauderman; Marc J. Gunter; Ulrike Peters

doi:10.1038/s41416-023-02312-z

Probing the diabetes and colorectal cancer relationship using gene – environment interaction analyses

Niki Dimou, Andre E. Kim, Orlagh Flanagan, Neil Murphy, Virginia Diez-Obrero, Anna Shcherbina, Elom K. Aglago, Emmanouil Bouras, Peter T. Campbell, Graham Casey, Steven Gallinger, Stephen B. Gruber, Mark A. Jenkins, Yi Lin, Victor Moreno, Edward Ruiz-Narvaez, Mariana C. Stern, Yu Tian, Kostas K. Tsilidis, Volker ArndtElizabeth L. Barry, James W. Baurley, Sonja I. Berndt, Stéphane Bézieau, Stephanie A. Bien, D. Timothy Bishop, Hermann Brenner, Arif Budiarto, Robert Carreras-Torres, Tjeng Wawan Cenggoro, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Xuechen Chen, David V. Conti, Christopher H. Dampier, Matthew Devall, David A. Drew, Jane C. Figueiredo, Graham G. Giles, Andrea Gsur, Tabitha A. Harrison, Akihisa Hidaka, Michael Hoffmeister, Jeroen R. Huyghe, Kristina Jordahl, Eric Kawaguchi, Temitope O. Keku, Susanna C. Larsson, Loic Le Marchand, Juan Pablo Lewinger, Li Li, Bharuno Mahesworo, John Morrison, Polly A. Newcomb, Christina C. Newton, Mireia Obon-Santacana, Jennifer Ose, Rish K. Pai, Julie R. Palmer, Nikos Papadimitriou, Bens Pardamean, Anita R. Peoples, Paul D.P. Pharoah, Elizabeth A. Platz, John D. Potter, Gad Rennert, Peter C. Scacheri, Robert E. Schoen, Yu Ru Su, Catherine M. Tangen, Stephen N. Thibodeau, Duncan C. Thomas, Cornelia M. Ulrich, Caroline Y. Um, Franzel J.B. van Duijnhoven, Kala Visvanathan, Pavel Vodicka, Ludmila Vodickova, Emily White, Alicja Wolk, Michael O. Woods, Conghui Qu, Anshul Kundaje, Li Hsu, W. James Gauderman, Marc J. Gunter, Ulrike Peters

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

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.

Original language	English (US)
Pages (from-to)	511-520
Number of pages	10
Journal	British journal of cancer
Volume	129
Issue number	3
DOIs	https://doi.org/10.1038/s41416-023-02312-z
State	Published - Aug 24 2023

ASJC Scopus subject areas

Oncology
Cancer Research

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Dimou, N., Kim, A. E., Flanagan, O., Murphy, N., Diez-Obrero, V., Shcherbina, A., Aglago, E. K., Bouras, E., Campbell, P. T., Casey, G., Gallinger, S., Gruber, S. B., Jenkins, M. A., Lin, Y., Moreno, V., Ruiz-Narvaez, E., Stern, M. C., Tian, Y., Tsilidis, K. K., ... Peters, U. (2023). Probing the diabetes and colorectal cancer relationship using gene – environment interaction analyses. British journal of cancer, 129(3), 511-520. https://doi.org/10.1038/s41416-023-02312-z

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 & Peters, U 2023, 'Probing the diabetes and colorectal cancer relationship using gene – environment interaction analyses', British journal of cancer, vol. 129, no. 3, pp. 511-520. https://doi.org/10.1038/s41416-023-02312-z

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title = "Probing the diabetes and colorectal cancer relationship using gene – environment interaction analyses",

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.",

author = "Niki Dimou and Kim, {Andre E.} and Orlagh Flanagan and Neil Murphy and Virginia Diez-Obrero and Anna Shcherbina and Aglago, {Elom K.} and Emmanouil Bouras and Campbell, {Peter T.} and Graham Casey and Steven Gallinger and Gruber, {Stephen B.} and Jenkins, {Mark A.} and Yi Lin and Victor Moreno and Edward Ruiz-Narvaez and Stern, {Mariana C.} and Yu Tian and Tsilidis, {Kostas K.} and Volker Arndt and Barry, {Elizabeth L.} and Baurley, {James W.} and Berndt, {Sonja I.} and St{\'e}phane B{\'e}zieau and Bien, {Stephanie A.} and Bishop, {D. Timothy} and Hermann Brenner and Arif Budiarto and Robert Carreras-Torres and Cenggoro, {Tjeng Wawan} and Chan, {Andrew T.} and Jenny Chang-Claude and Chanock, {Stephen J.} and Xuechen Chen and Conti, {David V.} and Dampier, {Christopher H.} and Matthew Devall and Drew, {David A.} and Figueiredo, {Jane C.} and Giles, {Graham G.} and Andrea Gsur and Harrison, {Tabitha A.} and Akihisa Hidaka and Michael Hoffmeister and Huyghe, {Jeroen R.} and Kristina Jordahl and Eric Kawaguchi and Keku, {Temitope O.} and Larsson, {Susanna C.} and {Le Marchand}, Loic and Lewinger, {Juan Pablo} and Li Li and Bharuno Mahesworo and John Morrison and Newcomb, {Polly A.} and Newton, {Christina C.} and Mireia Obon-Santacana and Jennifer Ose and Pai, {Rish K.} and Palmer, {Julie R.} and Nikos Papadimitriou and Bens Pardamean and Peoples, {Anita R.} and Pharoah, {Paul D.P.} and Platz, {Elizabeth A.} and Potter, {John D.} and Gad Rennert and Scacheri, {Peter C.} and Schoen, {Robert E.} and Su, {Yu Ru} and Tangen, {Catherine M.} and Thibodeau, {Stephen N.} and Thomas, {Duncan C.} and Ulrich, {Cornelia M.} and Um, {Caroline Y.} and {van Duijnhoven}, {Franzel J.B.} and Kala Visvanathan and Pavel Vodicka and Ludmila Vodickova and Emily White and Alicja Wolk and Woods, {Michael O.} and Conghui Qu and Anshul Kundaje and Li Hsu and Gauderman, {W. James} and Gunter, {Marc J.} and Ulrike Peters",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = aug,

day = "24",

doi = "10.1038/s41416-023-02312-z",

language = "English (US)",

volume = "129",

pages = "511--520",

journal = "British journal of cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

number = "3",

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TY - JOUR

T1 - Probing the diabetes and colorectal cancer relationship using gene – environment interaction analyses

AU - Dimou, Niki

AU - Kim, Andre E.

AU - Flanagan, Orlagh

AU - Murphy, Neil

AU - Diez-Obrero, Virginia

AU - Shcherbina, Anna

AU - Aglago, Elom K.

AU - Bouras, Emmanouil

AU - Campbell, Peter T.

AU - Casey, Graham

AU - Gallinger, Steven

AU - Gruber, Stephen B.

AU - Jenkins, Mark A.

AU - Lin, Yi

AU - Moreno, Victor

AU - Ruiz-Narvaez, Edward

AU - Stern, Mariana C.

AU - Tian, Yu

AU - Tsilidis, Kostas K.

AU - Arndt, Volker

AU - Barry, Elizabeth L.

AU - Baurley, James W.

AU - Berndt, Sonja I.

AU - Bézieau, Stéphane

AU - Bien, Stephanie A.

AU - Bishop, D. Timothy

AU - Brenner, Hermann

AU - Budiarto, Arif

AU - Carreras-Torres, Robert

AU - Cenggoro, Tjeng Wawan

AU - Chan, Andrew T.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J.

AU - Chen, Xuechen

AU - Conti, David V.

AU - Dampier, Christopher H.

AU - Devall, Matthew

AU - Drew, David A.

AU - Figueiredo, Jane C.

AU - Giles, Graham G.

AU - Gsur, Andrea

AU - Harrison, Tabitha A.

AU - Hidaka, Akihisa

AU - Hoffmeister, Michael

AU - Huyghe, Jeroen R.

AU - Jordahl, Kristina

AU - Kawaguchi, Eric

AU - Keku, Temitope O.

AU - Larsson, Susanna C.

AU - Le Marchand, Loic

AU - Lewinger, Juan Pablo

AU - Li, Li

AU - Mahesworo, Bharuno

AU - Morrison, John

AU - Newcomb, Polly A.

AU - Newton, Christina C.

AU - Obon-Santacana, Mireia

AU - Ose, Jennifer

AU - Pai, Rish K.

AU - Palmer, Julie R.

AU - Papadimitriou, Nikos

AU - Pardamean, Bens

AU - Peoples, Anita R.

AU - Pharoah, Paul D.P.

AU - Platz, Elizabeth A.

AU - Potter, John D.

AU - Rennert, Gad

AU - Scacheri, Peter C.

AU - Schoen, Robert E.

AU - Su, Yu Ru

AU - Tangen, Catherine M.

AU - Thibodeau, Stephen N.

AU - Thomas, Duncan C.

AU - Ulrich, Cornelia M.

AU - Um, Caroline Y.

AU - van Duijnhoven, Franzel J.B.

AU - Visvanathan, Kala

AU - Vodicka, Pavel

AU - Vodickova, Ludmila

AU - White, Emily

AU - Wolk, Alicja

AU - Woods, Michael O.

AU - Qu, Conghui

AU - Kundaje, Anshul

AU - Hsu, Li

AU - Gauderman, W. James

AU - Gunter, Marc J.

AU - Peters, Ulrike

PY - 2023/8/24

Y1 - 2023/8/24

N2 - 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.

AB - Background: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis. Methods: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test). Results: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 – ORAA: 1.62, 95% CI: 1.34–1.96; ORAG: 1.41, 95% CI: 1.30–1.54; ORGG: 1.22, 95% CI: 1.13–1.31; p-value3-d.f.: 5.46 × 10−11) and 13q14.13 (rs9526201, LRCH1 – ORGG: 2.11, 95% CI: 1.56–2.83; ORGA: 1.52, 95% CI: 1.38–1.68; ORAA: 1.13, 95% CI: 1.06–1.21; p-value2-d.f.: 7.84 × 10−09). Discussion: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.

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UR - http://www.scopus.com/inward/citedby.url?scp=85162876788&partnerID=8YFLogxK

U2 - 10.1038/s41416-023-02312-z

DO - 10.1038/s41416-023-02312-z

M3 - Article

C2 - 37365285

AN - SCOPUS:85162876788

SN - 0007-0920

VL - 129

SP - 511

EP - 520

JO - British journal of cancer

JF - British journal of cancer

IS - 3

ER -

Probing the diabetes and colorectal cancer relationship using gene – environment interaction analyses

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