Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors

Stefan Nickels; Thérèse Truong; Rebecca Hein; Kristen Stevens; Katharina Buck; Sabine Behrens; Ursula Eilber; Martina Schmidt; Lothar Häberle; Alina Vrieling; Mia Gaudet; Jonine Figueroa; Nils Schoof; Amanda B. Spurdle; Anja Rudolph; Peter A. Fasching; John L. Hopper; Enes Makalic; Daniel F. Schmidt; Melissa C. Southey; Matthias W. Beckmann; Arif B. Ekici; Olivia Fletcher; Lorna Gibson; Isabel dos Santos Silva; Julian Peto; Manjeet K. Humphreys; Jean Wang; Emilie Cordina-Duverger; Florence Menegaux; Børge G. Nordestgaard; Stig E. Bojesen; Charlotte Lanng; Hoda Anton-Culver; Argyrios Ziogas; Leslie Bernstein; Christina A. Clarke; Hermann Brenner; Heiko Müller; Volker Arndt; Christa Stegmaier; Hiltrud Brauch; Thomas Brüning; Volker Harth; Arto Mannermaa; Vesa Kataja; Veli Matti Kosma; Jaana M. Hartikainen; Diether Lambrechts; Dominiek Smeets; Patrick Neven; Robert Paridaens; Dieter Flesch-Janys; Nadia Obi; Shan Wang-Gohrke; Fergus J. Couch; Janet E. Olson; Celine M. Vachon; Graham G. Giles; Gianluca Severi; Laura Baglietto; Kenneth Offit; Esther M. John; Alexander Miron; Irene L. Andrulis; Julia A. Knight; Gord Glendon; Anna Marie Mulligan; Stephen J. Chanock; Jolanta Lissowska; Jianjun Liu; Angela Cox; Helen Cramp; Dan Connley; Sabapathy Balasubramanian; Alison M. Dunning; Mitul Shah; Amy Trentham-Dietz; Polly Newcomb; Linda Titus; Kathleen Egan; Elizabeth K. Cahoon; Preetha Rajaraman; Alice J. Sigurdson; Michele M. Doody; Pascal Guénel; Paul D.P. Pharoah; Marjanka K. Schmidt; Per Hall; Doug F. Easton; Montserrat Garcia-Closas; Roger L. Milne; Jenny Chang-Claude; H. B. Christina Justenhoven; Yon Dschun Ko; Christian Baisch; Hans Peter Fischer; Ute Hamann; Beate Pesch; Sylvia Rabstein; Anne Lotz; Eija Myöhänen; Helena Kemiläinen; Heather Thorne; Eveline Niedermayr; D. Bowtell; G. Chenevix-Trench; A. deFazio; D. Gertig; A. Green; P. Webb

doi:10.1371/journal.pgen.1003284

Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors

Stefan Nickels, Thérèse Truong, Rebecca Hein, Kristen Stevens, Katharina Buck, Sabine Behrens, Ursula Eilber, Martina Schmidt, Lothar Häberle, Alina Vrieling, Mia Gaudet, Jonine Figueroa, Nils Schoof, Amanda B. Spurdle, Anja Rudolph, Peter A. Fasching, John L. Hopper, Enes Makalic, Daniel F. Schmidt, Melissa C. SoutheyMatthias W. Beckmann, Arif B. Ekici, Olivia Fletcher, Lorna Gibson, Isabel dos Santos Silva, Julian Peto, Manjeet K. Humphreys, Jean Wang, Emilie Cordina-Duverger, Florence Menegaux, Børge G. Nordestgaard, Stig E. Bojesen, Charlotte Lanng, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina A. Clarke, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Hiltrud Brauch, Thomas Brüning, Volker Harth, Arto Mannermaa, Vesa Kataja, Veli Matti Kosma, Jaana M. Hartikainen, Diether Lambrechts, Dominiek Smeets, Patrick Neven, Robert Paridaens, Dieter Flesch-Janys, Nadia Obi, Shan Wang-Gohrke, Fergus J. Couch, Janet E. Olson, Celine M. Vachon, Graham G. Giles, Gianluca Severi, Laura Baglietto, Kenneth Offit, Esther M. John, Alexander Miron, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Anna Marie Mulligan, Stephen J. Chanock, Jolanta Lissowska, Jianjun Liu, Angela Cox, Helen Cramp, Dan Connley, Sabapathy Balasubramanian, Alison M. Dunning, Mitul Shah, Amy Trentham-Dietz, Polly Newcomb, Linda Titus, Kathleen Egan, Elizabeth K. Cahoon, Preetha Rajaraman, Alice J. Sigurdson, Michele M. Doody, Pascal Guénel, Paul D.P. Pharoah, Marjanka K. Schmidt, Per Hall, Doug F. Easton, Montserrat Garcia-Closas, Roger L. Milne, Jenny Chang-Claude, H. B. Christina Justenhoven, Yon Dschun Ko, Christian Baisch, Hans Peter Fischer, Ute Hamann, Beate Pesch, Sylvia Rabstein, Anne Lotz, Eija Myöhänen, Helena Kemiläinen, Heather Thorne, Eveline Niedermayr, D. Bowtell, G. Chenevix-Trench, A. deFazio, D. Gertig, A. Green, P. Webb

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Abstract

Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (P_interaction = 2.4×10^-6) and between CASP8-rs17468277 and alcohol consumption (P_interaction = 3.1×10^-4). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (P_interaction = 5.3×10^-5), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.

Original language	English (US)
Article number	e1003284
Journal	PLoS genetics
Volume	9
Issue number	3
DOIs	https://doi.org/10.1371/journal.pgen.1003284
State	Published - 2013

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

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Nickels, S., Truong, T., Hein, R., Stevens, K., Buck, K., Behrens, S., Eilber, U., Schmidt, M., Häberle, L., Vrieling, A., Gaudet, M., Figueroa, J., Schoof, N., Spurdle, A. B., Rudolph, A., Fasching, P. A., Hopper, J. L., Makalic, E., Schmidt, D. F., ... Webb, P. (2013). Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors. PLoS genetics, 9(3), Article e1003284. https://doi.org/10.1371/journal.pgen.1003284

Nickels, S, Truong, T, Hein, R, Stevens, K, Buck, K, Behrens, S, Eilber, U, Schmidt, M, Häberle, L, Vrieling, A, Gaudet, M, Figueroa, J, Schoof, N, Spurdle, AB, Rudolph, A, Fasching, PA, Hopper, JL, Makalic, E, Schmidt, DF, Southey, MC, Beckmann, MW, Ekici, AB, Fletcher, O, Gibson, L, dos Santos Silva, I, Peto, J, Humphreys, MK, Wang, J, Cordina-Duverger, E, Menegaux, F, Nordestgaard, BG, Bojesen, SE, Lanng, C, Anton-Culver, H, Ziogas, A, Bernstein, L, Clarke, CA, Brenner, H, Müller, H, Arndt, V, Stegmaier, C, Brauch, H, Brüning, T, Harth, V, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Lambrechts, D, Smeets, D, Neven, P, Paridaens, R, Flesch-Janys, D, Obi, N, Wang-Gohrke, S, Couch, FJ , Olson, JE , Vachon, CM, Giles, GG, Severi, G, Baglietto, L, Offit, K, John, EM, Miron, A, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Chanock, SJ, Lissowska, J, Liu, J, Cox, A, Cramp, H, Connley, D, Balasubramanian, S, Dunning, AM, Shah, M, Trentham-Dietz, A, Newcomb, P, Titus, L, Egan, K, Cahoon, EK, Rajaraman, P, Sigurdson, AJ, Doody, MM, Guénel, P, Pharoah, PDP, Schmidt, MK, Hall, P, Easton, DF, Garcia-Closas, M, Milne, RL, Chang-Claude, J, Christina Justenhoven, HB, Ko, YD, Baisch, C, Fischer, HP, Hamann, U, Pesch, B, Rabstein, S, Lotz, A, Myöhänen, E, Kemiläinen, H, Thorne, H, Niedermayr, E, Bowtell, D, Chenevix-Trench, G, deFazio, A, Gertig, D, Green, A & Webb, P 2013, 'Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors', PLoS genetics, vol. 9, no. 3, e1003284. https://doi.org/10.1371/journal.pgen.1003284

@article{c9e22a8ec1dc4cc0a5d8b77c1c33b074,

title = "Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors",

abstract = "Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4×10-6) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1×10-4). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3×10-5), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.",

author = "Stefan Nickels and Th{\'e}r{\`e}se Truong and Rebecca Hein and Kristen Stevens and Katharina Buck and Sabine Behrens and Ursula Eilber and Martina Schmidt and Lothar H{\"a}berle and Alina Vrieling and Mia Gaudet and Jonine Figueroa and Nils Schoof and Spurdle, {Amanda B.} and Anja Rudolph and Fasching, {Peter A.} and Hopper, {John L.} and Enes Makalic and Schmidt, {Daniel F.} and Southey, {Melissa C.} and Beckmann, {Matthias W.} and Ekici, {Arif B.} and Olivia Fletcher and Lorna Gibson and {dos Santos Silva}, Isabel and Julian Peto and Humphreys, {Manjeet K.} and Jean Wang and Emilie Cordina-Duverger and Florence Menegaux and Nordestgaard, {B{\o}rge G.} and Bojesen, {Stig E.} and Charlotte Lanng and Hoda Anton-Culver and Argyrios Ziogas and Leslie Bernstein and Clarke, {Christina A.} and Hermann Brenner and Heiko M{\"u}ller and Volker Arndt and Christa Stegmaier and Hiltrud Brauch and Thomas Br{\"u}ning and Volker Harth and Arto Mannermaa and Vesa Kataja and Kosma, {Veli Matti} and Hartikainen, {Jaana M.} and Diether Lambrechts and Dominiek Smeets and Patrick Neven and Robert Paridaens and Dieter Flesch-Janys and Nadia Obi and Shan Wang-Gohrke and Couch, {Fergus J.} and Olson, {Janet E.} and Vachon, {Celine M.} and Giles, {Graham G.} and Gianluca Severi and Laura Baglietto and Kenneth Offit and John, {Esther M.} and Alexander Miron and Andrulis, {Irene L.} and Knight, {Julia A.} and Gord Glendon and Mulligan, {Anna Marie} and Chanock, {Stephen J.} and Jolanta Lissowska and Jianjun Liu and Angela Cox and Helen Cramp and Dan Connley and Sabapathy Balasubramanian and Dunning, {Alison M.} and Mitul Shah and Amy Trentham-Dietz and Polly Newcomb and Linda Titus and Kathleen Egan and Cahoon, {Elizabeth K.} and Preetha Rajaraman and Sigurdson, {Alice J.} and Doody, {Michele M.} and Pascal Gu{\'e}nel and Pharoah, {Paul D.P.} and Schmidt, {Marjanka K.} and Per Hall and Easton, {Doug F.} and Montserrat Garcia-Closas and Milne, {Roger L.} and Jenny Chang-Claude and {Christina Justenhoven}, {H. B.} and Ko, {Yon Dschun} and Christian Baisch and Fischer, {Hans Peter} and Ute Hamann and Beate Pesch and Sylvia Rabstein and Anne Lotz and Eija My{\"o}h{\"a}nen and Helena Kemil{\"a}inen and Heather Thorne and Eveline Niedermayr and D. Bowtell and G. Chenevix-Trench and A. deFazio and D. Gertig and A. Green and P. Webb",

year = "2013",

doi = "10.1371/journal.pgen.1003284",

language = "English (US)",

volume = "9",

journal = "PLoS genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "3",

}

TY - JOUR

T1 - Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors

AU - Nickels, Stefan

AU - Truong, Thérèse

AU - Hein, Rebecca

AU - Stevens, Kristen

AU - Buck, Katharina

AU - Behrens, Sabine

AU - Eilber, Ursula

AU - Schmidt, Martina

AU - Häberle, Lothar

AU - Vrieling, Alina

AU - Gaudet, Mia

AU - Figueroa, Jonine

AU - Schoof, Nils

AU - Spurdle, Amanda B.

AU - Rudolph, Anja

AU - Fasching, Peter A.

AU - Hopper, John L.

AU - Makalic, Enes

AU - Schmidt, Daniel F.

AU - Southey, Melissa C.

AU - Beckmann, Matthias W.

AU - Ekici, Arif B.

AU - Fletcher, Olivia

AU - Gibson, Lorna

AU - dos Santos Silva, Isabel

AU - Peto, Julian

AU - Humphreys, Manjeet K.

AU - Wang, Jean

AU - Cordina-Duverger, Emilie

AU - Menegaux, Florence

AU - Nordestgaard, Børge G.

AU - Bojesen, Stig E.

AU - Lanng, Charlotte

AU - Anton-Culver, Hoda

AU - Ziogas, Argyrios

AU - Bernstein, Leslie

AU - Clarke, Christina A.

AU - Brenner, Hermann

AU - Müller, Heiko

AU - Arndt, Volker

AU - Stegmaier, Christa

AU - Brauch, Hiltrud

AU - Brüning, Thomas

AU - Harth, Volker

AU - Mannermaa, Arto

AU - Kataja, Vesa

AU - Kosma, Veli Matti

AU - Hartikainen, Jaana M.

AU - Lambrechts, Diether

AU - Smeets, Dominiek

AU - Neven, Patrick

AU - Paridaens, Robert

AU - Flesch-Janys, Dieter

AU - Obi, Nadia

AU - Wang-Gohrke, Shan

AU - Couch, Fergus J.

AU - Olson, Janet E.

AU - Vachon, Celine M.

AU - Giles, Graham G.

AU - Severi, Gianluca

AU - Baglietto, Laura

AU - Offit, Kenneth

AU - John, Esther M.

AU - Miron, Alexander

AU - Andrulis, Irene L.

AU - Knight, Julia A.

AU - Glendon, Gord

AU - Mulligan, Anna Marie

AU - Chanock, Stephen J.

AU - Lissowska, Jolanta

AU - Liu, Jianjun

AU - Cox, Angela

AU - Cramp, Helen

AU - Connley, Dan

AU - Balasubramanian, Sabapathy

AU - Dunning, Alison M.

AU - Shah, Mitul

AU - Trentham-Dietz, Amy

AU - Newcomb, Polly

AU - Titus, Linda

AU - Egan, Kathleen

AU - Cahoon, Elizabeth K.

AU - Rajaraman, Preetha

AU - Sigurdson, Alice J.

AU - Doody, Michele M.

AU - Guénel, Pascal

AU - Pharoah, Paul D.P.

AU - Schmidt, Marjanka K.

AU - Hall, Per

AU - Easton, Doug F.

AU - Garcia-Closas, Montserrat

AU - Milne, Roger L.

AU - Chang-Claude, Jenny

AU - Christina Justenhoven, H. B.

AU - Ko, Yon Dschun

AU - Baisch, Christian

AU - Fischer, Hans Peter

AU - Hamann, Ute

AU - Pesch, Beate

AU - Rabstein, Sylvia

AU - Lotz, Anne

AU - Myöhänen, Eija

AU - Kemiläinen, Helena

AU - Thorne, Heather

AU - Niedermayr, Eveline

AU - Bowtell, D.

AU - Chenevix-Trench, G.

AU - deFazio, A.

AU - Gertig, D.

AU - Green, A.

AU - Webb, P.

PY - 2013

Y1 - 2013

N2 - Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4×10-6) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1×10-4). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3×10-5), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.

AB - Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4×10-6) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1×10-4). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3×10-5), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.

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Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors

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