Body mass index and breast cancer survival: a Mendelian randomization analysis

Qi Guo; Stephen Burgess; Constance Turman; Manjeet K Bolla; Qin Wang; Michael Lush; Jean Abraham; Kristiina Aittomäki; Irene L Andrulis; Carmel Apicella; Volker Arndt; Myrto Barrdahl; Javier Benitez; Christine D Berg; Carl Blomqvist; Stig E Bojesen; Bernardo Bonanni; Judith S Brand; Hermann Brenner; Annegien Broeks; Barbara Burwinkel; Carlos Caldas; Daniele Campa; Federico Canzian; Jenny Chang-Claude; Stephen J Chanock; Suet-Feung Chin; Fergus J Couch; Angela Cox; Simon S Cross; Cezary Cybulski; Kamila Czene; Hatef Darabi; Peter Devilee; W Ryan Diver; Alison M Dunning; Helena M Earl; Diana M Eccles; Arif B Ekici; Mikael Eriksson; D Gareth Evans; Peter A Fasching; Jonine Figueroa; Dieter Flesch-Janys; Henrik Flyger; Susan M Gapstur; Mia M Gaudet; Graham G Giles; Gord Glendon; Mervi Grip; Jacek Gronwald; Lothar Haeberle; Per Hall; Ute Hamann; Susan Hankinson; Jaana M Hartikainen; Alexander Hein; Louise Hiller; Frans B Hogervorst; Bernd Holleczek; Maartje J Hooning; Robert N Hoover; Keith Humphreys; David J Hunter; Anika Hüsing; Anna Jakubowska; Arja Jukkola-Vuorinen; Rudolf Kaaks; Maria Kabisch; Vesa Kataja; kConFab/AOCS Investigators; Julia A Knight; Linetta B Koppert; Veli-Matti Kosma; Vessela N Kristensen; Diether Lambrechts; Loic Le Marchand; Jingmei Li; Annika Lindblom; Sara Lindström; Jolanta Lissowska; Jan Lubinski; Mitchell J Machiela; Arto Mannermaa; Siranoush Manoukian; Sara Margolin; Federik Marme; John WM Martens; Catriona McLean; Primitiva Menéndez; Roger L Milne; Anna Marie Mulligan; Taru A Muranen; Heli Nevanlinna; Patrick Neven; Sune F Nielsen; Børge G Nordestgaard; Janet E Olson; Jose IA Perez; Paolo Peterlongo; Kelly-Anne Phillips; Christopher J Poole; Katri Pylkäs; Paolo Radice; Nazneen Rahman; Thomas Rüdiger; Anja Rudolph; Elinor J Sawyer; Fredrick Schumacher; Petra Seibold; Caroline Seynaeve; Mitul Shah; Ann Smeets; Melissa C Southey; Rob A E M Tollenaar; Ian Tomlinson; Helen Tsimiklis; Hans Ulrich Ulmer; Celine Vachon; Ans MW van den Ouweland; Laura J Van't Veer; Hans Wildiers; Walter Willett; Robert Winqvist; M Pilar Zamora; Georgia Chenevix-Trench; Thilo Dörk; Douglas F. Easton; Montserrat García-Closas; Peter Kraft; John L Hopper; Wei Zheng; Marjanka K Schmidt; Paul DP Pharoah

doi:10.1093/ije/dyx131

Body mass index and breast cancer survival: a Mendelian randomization analysis

Qi Guo, Stephen Burgess, Constance Turman, Manjeet K Bolla, Qin Wang, Michael Lush, Jean Abraham, Kristiina Aittomäki, Irene L Andrulis, Carmel Apicella, Volker Arndt, Myrto Barrdahl, Javier Benitez, Christine D Berg, Carl Blomqvist, Stig E Bojesen, Bernardo Bonanni, Judith S Brand, Hermann Brenner, Annegien BroeksBarbara Burwinkel, Carlos Caldas, Daniele Campa, Federico Canzian, Jenny Chang-Claude, Stephen J Chanock, Suet-Feung Chin, Fergus J Couch, Angela Cox, Simon S Cross, Cezary Cybulski, Kamila Czene, Hatef Darabi, Peter Devilee, W Ryan Diver, Alison M Dunning, Helena M Earl, Diana M Eccles, Arif B Ekici, Mikael Eriksson, D Gareth Evans, Peter A Fasching, Jonine Figueroa, Dieter Flesch-Janys, Henrik Flyger, Susan M Gapstur, Mia M Gaudet, Graham G Giles, Gord Glendon, Mervi Grip, Jacek Gronwald, Lothar Haeberle, Per Hall, Ute Hamann, Susan Hankinson, Jaana M Hartikainen, Alexander Hein, Louise Hiller, Frans B Hogervorst, Bernd Holleczek, Maartje J Hooning, Robert N Hoover, Keith Humphreys, David J Hunter, Anika Hüsing, Anna Jakubowska, Arja Jukkola-Vuorinen, Rudolf Kaaks, Maria Kabisch, Vesa Kataja, kConFab/AOCS Investigators, Julia A Knight, Linetta B Koppert, Veli-Matti Kosma, Vessela N Kristensen, Diether Lambrechts, Loic Le Marchand, Jingmei Li, Annika Lindblom, Sara Lindström, Jolanta Lissowska, Jan Lubinski, Mitchell J Machiela, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, Federik Marme, John WM Martens, Catriona McLean, Primitiva Menéndez, Roger L Milne, Anna Marie Mulligan, Taru A Muranen, Heli Nevanlinna, Patrick Neven, Sune F Nielsen, Børge G Nordestgaard, Janet E Olson, Jose IA Perez, Paolo Peterlongo, Kelly-Anne Phillips, Christopher J Poole, Katri Pylkäs, Paolo Radice, Nazneen Rahman, Thomas Rüdiger, Anja Rudolph, Elinor J Sawyer, Fredrick Schumacher, Petra Seibold, Caroline Seynaeve, Mitul Shah, Ann Smeets, Melissa C Southey, Rob A E M Tollenaar, Ian Tomlinson, Helen Tsimiklis, Hans Ulrich Ulmer, Celine Vachon, Ans MW van den Ouweland, Laura J Van't Veer, Hans Wildiers, Walter Willett, Robert Winqvist, M Pilar Zamora, Georgia Chenevix-Trench, Thilo Dörk, Douglas F. Easton, Montserrat García-Closas, Peter Kraft, John L Hopper, Wei Zheng, Marjanka K Schmidt, Paul DP Pharoah

Department of Clinical Medicine

16 Citations (Scopus)

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Abstract

Background: There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer.

Methods: We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis.

Results: BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13, P = 0.95).

Conclusions: Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.

Original language	English
Journal	International Journal of Epidemiology
Volume	46
Issue number	6
Pages (from-to)	1814-1822
ISSN	0300-5771
DOIs	https://doi.org/10.1093/ije/dyx131
Publication status	Published - 1 Dec 2017

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Body mass index and breast cancer survival: a Mendelian randomization analysisFinal published version, 313 KBLicence: CC BY

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Guo, Q., Burgess, S., Turman, C., Bolla, M. K., Wang, Q., Lush, M., Abraham, J., Aittomäki, K., Andrulis, I. L., Apicella, C., Arndt, V., Barrdahl, M., Benitez, J., Berg, C. D., Blomqvist, C., Bojesen, S. E., Bonanni, B., Brand, J. S., Brenner, H., ... Pharoah, P. DP. (2017). Body mass index and breast cancer survival: a Mendelian randomization analysis. International Journal of Epidemiology, 46(6), 1814-1822. https://doi.org/10.1093/ije/dyx131

Guo, Q, Burgess, S, Turman, C, Bolla, MK, Wang, Q, Lush, M, Abraham, J, Aittomäki, K, Andrulis, IL, Apicella, C, Arndt, V, Barrdahl, M, Benitez, J, Berg, CD, Blomqvist, C, Bojesen, SE, Bonanni, B, Brand, JS, Brenner, H, Broeks, A, Burwinkel, B, Caldas, C, Campa, D, Canzian, F, Chang-Claude, J, Chanock, SJ, Chin, S-F, Couch, FJ, Cox, A, Cross, SS, Cybulski, C, Czene, K, Darabi, H, Devilee, P, Diver, WR, Dunning, AM, Earl, HM, Eccles, DM, Ekici, AB, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flesch-Janys, D, Flyger, H, Gapstur, SM, Gaudet, MM, Giles, GG, Glendon, G, Grip, M, Gronwald, J, Haeberle, L, Hall, P, Hamann, U, Hankinson, S, Hartikainen, JM, Hein, A, Hiller, L, Hogervorst, FB, Holleczek, B, Hooning, MJ, Hoover, RN, Humphreys, K, Hunter, DJ, Hüsing, A, Jakubowska, A, Jukkola-Vuorinen, A, Kaaks, R, Kabisch, M, Kataja, V, kConFab/AOCS Investigators, Knight, JA, Koppert, LB, Kosma, V-M, Kristensen, VN, Lambrechts, D, Marchand, LL, Li, J, Lindblom, A, Lindström, S, Lissowska, J, Lubinski, J, Machiela, MJ, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Martens, JWM, McLean, C, Menéndez, P, Milne, RL, Mulligan, AM, Muranen, TA, Nevanlinna, H, Neven, P, Nielsen, SF, Nordestgaard, BG, Olson, JE, Perez, JIA, Peterlongo, P, Phillips, K-A, Poole, CJ, Pylkäs, K, Radice, P, Rahman, N, Rüdiger, T, Rudolph, A, Sawyer, EJ, Schumacher, F, Seibold, P, Seynaeve, C, Shah, M, Smeets, A, Southey, MC, Tollenaar, RAEM, Tomlinson, I, Tsimiklis, H, Ulmer, HU, Vachon, C, van den Ouweland, AMW, Van't Veer, LJ, Wildiers, H, Willett, W, Winqvist, R, Pilar Zamora, M, Chenevix-Trench, G, Dörk, T, Easton, DF, García-Closas, M, Kraft, P, Hopper, JL, Zheng, W, Schmidt, MK & Pharoah, PDP 2017, 'Body mass index and breast cancer survival: a Mendelian randomization analysis', International Journal of Epidemiology, vol. 46, no. 6, pp. 1814-1822. https://doi.org/10.1093/ije/dyx131

@article{5e460eae12bb4769a4fa9e7756e4dd0b,

title = "Body mass index and breast cancer survival: a Mendelian randomization analysis",

abstract = "Background: There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer.Methods: We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis.Results: BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13, P = 0.95).Conclusions: Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.",

author = "Qi Guo and Stephen Burgess and Constance Turman and Bolla, {Manjeet K} and Qin Wang and Michael Lush and Jean Abraham and Kristiina Aittom{\"a}ki and Andrulis, {Irene L} and Carmel Apicella and Volker Arndt and Myrto Barrdahl and Javier Benitez and Berg, {Christine D} and Carl Blomqvist and Bojesen, {Stig E} and Bernardo Bonanni and Brand, {Judith S} and Hermann Brenner and Annegien Broeks and Barbara Burwinkel and Carlos Caldas and Daniele Campa and Federico Canzian and Jenny Chang-Claude and Chanock, {Stephen J} and Suet-Feung Chin and Couch, {Fergus J} and Angela Cox and Cross, {Simon S} and Cezary Cybulski and Kamila Czene and Hatef Darabi and Peter Devilee and Diver, {W Ryan} and Dunning, {Alison M} and Earl, {Helena M} and Eccles, {Diana M} and Ekici, {Arif B} and Mikael Eriksson and Evans, {D Gareth} and Fasching, {Peter A} and Jonine Figueroa and Dieter Flesch-Janys and Henrik Flyger and Gapstur, {Susan M} and Gaudet, {Mia M} and Giles, {Graham G} and Gord Glendon and Mervi Grip and Jacek Gronwald and Lothar Haeberle and Per Hall and Ute Hamann and Susan Hankinson and Hartikainen, {Jaana M} and Alexander Hein and Louise Hiller and Hogervorst, {Frans B} and Bernd Holleczek and Hooning, {Maartje J} and Hoover, {Robert N} and Keith Humphreys and Hunter, {David J} and Anika H{\"u}sing and Anna Jakubowska and Arja Jukkola-Vuorinen and Rudolf Kaaks and Maria Kabisch and Vesa Kataja and {kConFab/AOCS Investigators} and Knight, {Julia A} and Koppert, {Linetta B} and Veli-Matti Kosma and Kristensen, {Vessela N} and Diether Lambrechts and Marchand, {Loic Le} and Jingmei Li and Annika Lindblom and Sara Lindstr{\"o}m and Jolanta Lissowska and Jan Lubinski and Machiela, {Mitchell J} and Arto Mannermaa and Siranoush Manoukian and Sara Margolin and Federik Marme and Martens, {John WM} and Catriona McLean and Primitiva Men{\'e}ndez and Milne, {Roger L} and Mulligan, {Anna Marie} and Muranen, {Taru A} and Heli Nevanlinna and Patrick Neven and Nielsen, {Sune F} and Nordestgaard, {B{\o}rge G} and Olson, {Janet E} and Perez, {Jose IA} and Paolo Peterlongo and Kelly-Anne Phillips and Poole, {Christopher J} and Katri Pylk{\"a}s and Paolo Radice and Nazneen Rahman and Thomas R{\"u}diger and Anja Rudolph and Sawyer, {Elinor J} and Fredrick Schumacher and Petra Seibold and Caroline Seynaeve and Mitul Shah and Ann Smeets and Southey, {Melissa C} and Tollenaar, {Rob A E M} and Ian Tomlinson and Helen Tsimiklis and Ulmer, {Hans Ulrich} and Celine Vachon and {van den Ouweland}, {Ans MW} and {Van't Veer}, {Laura J} and Hans Wildiers and Walter Willett and Robert Winqvist and {Pilar Zamora}, M and Georgia Chenevix-Trench and Thilo D{\"o}rk and Easton, {Douglas F.} and Montserrat Garc{\'i}a-Closas and Peter Kraft and Hopper, {John L} and Wei Zheng and Schmidt, {Marjanka K} and Pharoah, {Paul DP}",

note = "{\textcopyright} The Author 2017. Published by Oxford University Press on behalf of the International Epidemiological Association",

year = "2017",

month = dec,

day = "1",

doi = "10.1093/ije/dyx131",

language = "English",

volume = "46",

pages = "1814--1822",

journal = "International Journal of Epidemiology",

issn = "0300-5771",

publisher = "Oxford University Press",

number = "6",

}

TY - JOUR

T1 - Body mass index and breast cancer survival

T2 - a Mendelian randomization analysis

AU - Guo, Qi

AU - Burgess, Stephen

AU - Turman, Constance

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - Lush, Michael

AU - Abraham, Jean

AU - Aittomäki, Kristiina

AU - Andrulis, Irene L

AU - Apicella, Carmel

AU - Arndt, Volker

AU - Barrdahl, Myrto

AU - Benitez, Javier

AU - Berg, Christine D

AU - Blomqvist, Carl

AU - Bojesen, Stig E

AU - Bonanni, Bernardo

AU - Brand, Judith S

AU - Brenner, Hermann

AU - Broeks, Annegien

AU - Burwinkel, Barbara

AU - Caldas, Carlos

AU - Campa, Daniele

AU - Canzian, Federico

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J

AU - Chin, Suet-Feung

AU - Couch, Fergus J

AU - Cox, Angela

AU - Cross, Simon S

AU - Cybulski, Cezary

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Devilee, Peter

AU - Diver, W Ryan

AU - Dunning, Alison M

AU - Earl, Helena M

AU - Eccles, Diana M

AU - Ekici, Arif B

AU - Eriksson, Mikael

AU - Evans, D Gareth

AU - Fasching, Peter A

AU - Figueroa, Jonine

AU - Flesch-Janys, Dieter

AU - Flyger, Henrik

AU - Gapstur, Susan M

AU - Gaudet, Mia M

AU - Giles, Graham G

AU - Glendon, Gord

AU - Grip, Mervi

AU - Gronwald, Jacek

AU - Haeberle, Lothar

AU - Hall, Per

AU - Hamann, Ute

AU - Hankinson, Susan

AU - Hartikainen, Jaana M

AU - Hein, Alexander

AU - Hiller, Louise

AU - Hogervorst, Frans B

AU - Holleczek, Bernd

AU - Hooning, Maartje J

AU - Hoover, Robert N

AU - Humphreys, Keith

AU - Hunter, David J

AU - Hüsing, Anika

AU - Jakubowska, Anna

AU - Jukkola-Vuorinen, Arja

AU - Kaaks, Rudolf

AU - Kabisch, Maria

AU - Kataja, Vesa

AU - kConFab/AOCS Investigators

AU - Knight, Julia A

AU - Koppert, Linetta B

AU - Kosma, Veli-Matti

AU - Kristensen, Vessela N

AU - Lambrechts, Diether

AU - Marchand, Loic Le

AU - Li, Jingmei

AU - Lindblom, Annika

AU - Lindström, Sara

AU - Lissowska, Jolanta

AU - Lubinski, Jan

AU - Machiela, Mitchell J

AU - Mannermaa, Arto

AU - Manoukian, Siranoush

AU - Margolin, Sara

AU - Marme, Federik

AU - Martens, John WM

AU - McLean, Catriona

AU - Menéndez, Primitiva

AU - Milne, Roger L

AU - Mulligan, Anna Marie

AU - Muranen, Taru A

AU - Nevanlinna, Heli

AU - Neven, Patrick

AU - Nielsen, Sune F

AU - Nordestgaard, Børge G

AU - Olson, Janet E

AU - Perez, Jose IA

AU - Peterlongo, Paolo

AU - Phillips, Kelly-Anne

AU - Poole, Christopher J

AU - Pylkäs, Katri

AU - Radice, Paolo

AU - Rahman, Nazneen

AU - Rüdiger, Thomas

AU - Rudolph, Anja

AU - Sawyer, Elinor J

AU - Schumacher, Fredrick

AU - Seibold, Petra

AU - Seynaeve, Caroline

AU - Shah, Mitul

AU - Smeets, Ann

AU - Southey, Melissa C

AU - Tollenaar, Rob A E M

AU - Tomlinson, Ian

AU - Tsimiklis, Helen

AU - Ulmer, Hans Ulrich

AU - Vachon, Celine

AU - van den Ouweland, Ans MW

AU - Van't Veer, Laura J

AU - Wildiers, Hans

AU - Willett, Walter

AU - Winqvist, Robert

AU - Pilar Zamora, M

AU - Chenevix-Trench, Georgia

AU - Dörk, Thilo

AU - Easton, Douglas F.

AU - García-Closas, Montserrat

AU - Kraft, Peter

AU - Hopper, John L

AU - Zheng, Wei

AU - Schmidt, Marjanka K

AU - Pharoah, Paul DP

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Background: There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer.Methods: We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis.Results: BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13, P = 0.95).Conclusions: Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.

AB - Background: There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer.Methods: We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis.Results: BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13, P = 0.95).Conclusions: Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.

U2 - 10.1093/ije/dyx131

DO - 10.1093/ije/dyx131

M3 - Journal article

C2 - 29232439

SN - 0300-5771

VL - 46

SP - 1814

EP - 1822

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

IS - 6

ER -

Body mass index and breast cancer survival: a Mendelian randomization analysis

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