The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study

Mattias Johansson; Robert Carreras-Torres; Ghislaine Scelo; Mark P. Purdue; Daniela Mariosa; David C. Muller; Nicolas J. Timpson; Philip C. Haycock; Kevin M. Brown; Zhaoming Wang; Yuanqing Ye; Jonathan N. Hofmann; Matthieu Foll; Valerie Gaborieau; Mitchell J. Machiela; Leandro M. Colli; Peng Li; Jean Guillaume Garnier; Helene Blanche; Anne Boland; Laurie Burdette; Egor Prokhortchouk; Konstantin G. Skryabin; Meredith Yeager; Sanja Radojevic-Skodric; Simona Ognjanovic; Lenka Foretova; Ivana Holcatova; Vladimir Janout; Dana Mates; Anush Mukeriya; Stefan Rascu; David Zaridze; Vladimir Bencko; Cezary Cybulski; Eleonora Fabianova; Viorel Jinga; Jolanta Lissowska; Jan Lubinski; Marie Navratilova; Peter Rudnai; Simone Benhamou; Geraldine Cancel-Tassin; Olivier Cussenot; Elisabete Weiderpass; Börje Ljungberg; Raviprakash Tumkur Sitaram; Christel Häggström; Fiona Bruinsma; Susan J. Jordan; Gianluca Severi; Ingrid Winship; Kristian Hveem; Lars J. Vatten; Tony Fletcher; Susanna C. Larsson; Alicja Wolk; Rosamonde E. Banks; Peter J. Selby; Douglas F. Easton; Gabriella Andreotti; Laura E. Beane Freeman; Stella Koutros; Satu Männistö; Stephanie Weinstein; Peter E. Clark; Todd L. Edwards; Loren Lipworth; Susan M. Gapstur; Victoria L. Stevens; Hallie Carol; Matthew L. Freedman; Mark M. Pomerantz; Eunyoung Cho; Kathryn M. Wilson; J. Michael Gaziano; Howard D. Sesso; Neal D. Freedman; Alexander S. Parker; Jeanette E. Eckel-Passow; Wen Yi Huang; Richard J. Kahnoski; Brian R. Lane; Sabrina L. Noyes; David Petillo; Bin Tean Teh; Ulrike Peters; Emily White; Garnet L. Anderson; Lisa Johnson; Juhua Luo; Julie Buring; I. Min Lee; Wong Ho Chow; Lee E. Moore; Timothy Eisen; Marc Henrion; James Larkin; Poulami Barman; Bradley C. Leibovich; Toni K. Choueiri; G. Mark Lathrop; Jean Francois Deleuze; Marc Gunter; James D. McKay; Xifeng Wu; Richard S. Houlston; Stephen J. Chanock; Caroline Relton; J. Brent Richards; Richard M. Martin; George Davey Smith; Paul Brennan

doi:10.1371/journal.pmed.1002724

The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study

Mattias Johansson, Robert Carreras-Torres, Ghislaine Scelo, Mark P. Purdue, Daniela Mariosa, David C. Muller, Nicolas J. Timpson, Philip C. Haycock, Kevin M. Brown, Zhaoming Wang, Yuanqing Ye, Jonathan N. Hofmann, Matthieu Foll, Valerie Gaborieau, Mitchell J. Machiela, Leandro M. Colli, Peng Li, Jean Guillaume Garnier, Helene Blanche, Anne BolandLaurie Burdette, Egor Prokhortchouk, Konstantin G. Skryabin, Meredith Yeager, Sanja Radojevic-Skodric, Simona Ognjanovic, Lenka Foretova, Ivana Holcatova, Vladimir Janout, Dana Mates, Anush Mukeriya, Stefan Rascu, David Zaridze, Vladimir Bencko, Cezary Cybulski, Eleonora Fabianova, Viorel Jinga, Jolanta Lissowska, Jan Lubinski, Marie Navratilova, Peter Rudnai, Simone Benhamou, Geraldine Cancel-Tassin, Olivier Cussenot, Elisabete Weiderpass, Börje Ljungberg, Raviprakash Tumkur Sitaram, Christel Häggström, Fiona Bruinsma, Susan J. Jordan, Gianluca Severi, Ingrid Winship, Kristian Hveem, Lars J. Vatten, Tony Fletcher, Susanna C. Larsson, Alicja Wolk, Rosamonde E. Banks, Peter J. Selby, Douglas F. Easton, Gabriella Andreotti, Laura E. Beane Freeman, Stella Koutros, Satu Männistö, Stephanie Weinstein, Peter E. Clark, Todd L. Edwards, Loren Lipworth, Susan M. Gapstur, Victoria L. Stevens, Hallie Carol, Matthew L. Freedman, Mark M. Pomerantz, Eunyoung Cho, Kathryn M. Wilson, J. Michael Gaziano, Howard D. Sesso, Neal D. Freedman, Alexander S. Parker, Jeanette E. Eckel-Passow, Wen Yi Huang, Richard J. Kahnoski, Brian R. Lane, Sabrina L. Noyes, David Petillo, Bin Tean Teh, Ulrike Peters, Emily White, Garnet L. Anderson, Lisa Johnson, Juhua Luo, Julie Buring, I. Min Lee, Wong Ho Chow, Lee E. Moore, Timothy Eisen, Marc Henrion, James Larkin, Poulami Barman, Bradley C. Leibovich, Toni K. Choueiri, G. Mark Lathrop, Jean Francois Deleuze, Marc Gunter, James D. McKay, Xifeng Wu, Richard S. Houlston, Stephen J. Chanock, Caroline Relton, J. Brent Richards, Richard M. Martin, George Davey Smith, Paul Brennan

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

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Abstract

Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (OR _SD ) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (OR _SD : 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (OR _SD : 1.63, 95% CI 1.40-1.90) and body fat percentage (OR _SD : 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (OR _SD : 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; OR _SD : 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (OR _SD : 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

Original language	English (US)
Article number	e1002724
Journal	PLoS Medicine
Volume	16
Issue number	1
DOIs	https://doi.org/10.1371/journal.pmed.1002724
State	Published - 2019

ASJC Scopus subject areas

General Medicine

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Johansson, M., Carreras-Torres, R., Scelo, G., Purdue, M. P., Mariosa, D., Muller, D. C., Timpson, N. J., Haycock, P. C., Brown, K. M., Wang, Z., Ye, Y., Hofmann, J. N., Foll, M., Gaborieau, V., Machiela, M. J., Colli, L. M., Li, P., Garnier, J. G., Blanche, H., ... Brennan, P. (2019). The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study. PLoS Medicine, 16(1), Article e1002724. https://doi.org/10.1371/journal.pmed.1002724

Johansson, M, Carreras-Torres, R, Scelo, G, Purdue, MP, Mariosa, D, Muller, DC, Timpson, NJ, Haycock, PC, Brown, KM, Wang, Z, Ye, Y, Hofmann, JN, Foll, M, Gaborieau, V, Machiela, MJ, Colli, LM, Li, P, Garnier, JG, Blanche, H, Boland, A, Burdette, L, Prokhortchouk, E, Skryabin, KG, Yeager, M, Radojevic-Skodric, S, Ognjanovic, S, Foretova, L, Holcatova, I, Janout, V, Mates, D, Mukeriya, A, Rascu, S, Zaridze, D, Bencko, V, Cybulski, C, Fabianova, E, Jinga, V, Lissowska, J, Lubinski, J, Navratilova, M, Rudnai, P, Benhamou, S, Cancel-Tassin, G, Cussenot, O, Weiderpass, E, Ljungberg, B, Tumkur Sitaram, R, Häggström, C, Bruinsma, F, Jordan, SJ, Severi, G, Winship, I, Hveem, K, Vatten, LJ, Fletcher, T, Larsson, SC, Wolk, A, Banks, RE, Selby, PJ, Easton, DF, Andreotti, G, Beane Freeman, LE, Koutros, S, Männistö, S, Weinstein, S, Clark, PE, Edwards, TL, Lipworth, L, Gapstur, SM, Stevens, VL, Carol, H, Freedman, ML, Pomerantz, MM, Cho, E, Wilson, KM, Gaziano, JM, Sesso, HD, Freedman, ND, Parker, AS , Eckel-Passow, JE, Huang, WY, Kahnoski, RJ, Lane, BR, Noyes, SL, Petillo, D, Teh, BT, Peters, U, White, E, Anderson, GL, Johnson, L, Luo, J, Buring, J, Lee, IM, Chow, WH, Moore, LE, Eisen, T, Henrion, M, Larkin, J, Barman, P, Leibovich, BC, Choueiri, TK, Lathrop, GM, Deleuze, JF, Gunter, M, McKay, JD, Wu, X, Houlston, RS, Chanock, SJ, Relton, C, Richards, JB, Martin, RM, Davey Smith, G & Brennan, P 2019, 'The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study', PLoS Medicine, vol. 16, no. 1, e1002724. https://doi.org/10.1371/journal.pmed.1002724

@article{284f60be103e4c90ae05b99bfcef2f0c,

title = "The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study",

abstract = " Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (OR SD ) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (OR SD : 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (OR SD : 1.63, 95% CI 1.40-1.90) and body fat percentage (OR SD : 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (OR SD : 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; OR SD : 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (OR SD : 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.",

author = "Mattias Johansson and Robert Carreras-Torres and Ghislaine Scelo and Purdue, {Mark P.} and Daniela Mariosa and Muller, {David C.} and Timpson, {Nicolas J.} and Haycock, {Philip C.} and Brown, {Kevin M.} and Zhaoming Wang and Yuanqing Ye and Hofmann, {Jonathan N.} and Matthieu Foll and Valerie Gaborieau and Machiela, {Mitchell J.} and Colli, {Leandro M.} and Peng Li and Garnier, {Jean Guillaume} and Helene Blanche and Anne Boland and Laurie Burdette and Egor Prokhortchouk and Skryabin, {Konstantin G.} and Meredith Yeager and Sanja Radojevic-Skodric and Simona Ognjanovic and Lenka Foretova and Ivana Holcatova and Vladimir Janout and Dana Mates and Anush Mukeriya and Stefan Rascu and David Zaridze and Vladimir Bencko and Cezary Cybulski and Eleonora Fabianova and Viorel Jinga and Jolanta Lissowska and Jan Lubinski and Marie Navratilova and Peter Rudnai and Simone Benhamou and Geraldine Cancel-Tassin and Olivier Cussenot and Elisabete Weiderpass and B{\"o}rje Ljungberg and {Tumkur Sitaram}, Raviprakash and Christel H{\"a}ggstr{\"o}m and Fiona Bruinsma and Jordan, {Susan J.} and Gianluca Severi and Ingrid Winship and Kristian Hveem and Vatten, {Lars J.} and Tony Fletcher and Larsson, {Susanna C.} and Alicja Wolk and Banks, {Rosamonde E.} and Selby, {Peter J.} and Easton, {Douglas F.} and Gabriella Andreotti and {Beane Freeman}, {Laura E.} and Stella Koutros and Satu M{\"a}nnist{\"o} and Stephanie Weinstein and Clark, {Peter E.} and Edwards, {Todd L.} and Loren Lipworth and Gapstur, {Susan M.} and Stevens, {Victoria L.} and Hallie Carol and Freedman, {Matthew L.} and Pomerantz, {Mark M.} and Eunyoung Cho and Wilson, {Kathryn M.} and Gaziano, {J. Michael} and Sesso, {Howard D.} and Freedman, {Neal D.} and Parker, {Alexander S.} and Eckel-Passow, {Jeanette E.} and Huang, {Wen Yi} and Kahnoski, {Richard J.} and Lane, {Brian R.} and Noyes, {Sabrina L.} and David Petillo and Teh, {Bin Tean} and Ulrike Peters and Emily White and Anderson, {Garnet L.} and Lisa Johnson and Juhua Luo and Julie Buring and Lee, {I. Min} and Chow, {Wong Ho} and Moore, {Lee E.} and Timothy Eisen and Marc Henrion and James Larkin and Poulami Barman and Leibovich, {Bradley C.} and Choueiri, {Toni K.} and Lathrop, {G. Mark} and Deleuze, {Jean Francois} and Marc Gunter and McKay, {James D.} and Xifeng Wu and Houlston, {Richard S.} and Chanock, {Stephen J.} and Caroline Relton and Richards, {J. Brent} and Martin, {Richard M.} and {Davey Smith}, George and Paul Brennan",

year = "2019",

doi = "10.1371/journal.pmed.1002724",

language = "English (US)",

volume = "16",

journal = "PLoS Medicine",

issn = "1549-1277",

number = "1",

}

TY - JOUR

T1 - The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study

AU - Johansson, Mattias

AU - Carreras-Torres, Robert

AU - Scelo, Ghislaine

AU - Purdue, Mark P.

AU - Mariosa, Daniela

AU - Muller, David C.

AU - Timpson, Nicolas J.

AU - Haycock, Philip C.

AU - Brown, Kevin M.

AU - Wang, Zhaoming

AU - Ye, Yuanqing

AU - Hofmann, Jonathan N.

AU - Foll, Matthieu

AU - Gaborieau, Valerie

AU - Machiela, Mitchell J.

AU - Colli, Leandro M.

AU - Li, Peng

AU - Garnier, Jean Guillaume

AU - Blanche, Helene

AU - Boland, Anne

AU - Burdette, Laurie

AU - Prokhortchouk, Egor

AU - Skryabin, Konstantin G.

AU - Yeager, Meredith

AU - Radojevic-Skodric, Sanja

AU - Ognjanovic, Simona

AU - Foretova, Lenka

AU - Holcatova, Ivana

AU - Janout, Vladimir

AU - Mates, Dana

AU - Mukeriya, Anush

AU - Rascu, Stefan

AU - Zaridze, David

AU - Bencko, Vladimir

AU - Cybulski, Cezary

AU - Fabianova, Eleonora

AU - Jinga, Viorel

AU - Lissowska, Jolanta

AU - Lubinski, Jan

AU - Navratilova, Marie

AU - Rudnai, Peter

AU - Benhamou, Simone

AU - Cancel-Tassin, Geraldine

AU - Cussenot, Olivier

AU - Weiderpass, Elisabete

AU - Ljungberg, Börje

AU - Tumkur Sitaram, Raviprakash

AU - Häggström, Christel

AU - Bruinsma, Fiona

AU - Jordan, Susan J.

AU - Severi, Gianluca

AU - Winship, Ingrid

AU - Hveem, Kristian

AU - Vatten, Lars J.

AU - Fletcher, Tony

AU - Larsson, Susanna C.

AU - Wolk, Alicja

AU - Banks, Rosamonde E.

AU - Selby, Peter J.

AU - Easton, Douglas F.

AU - Andreotti, Gabriella

AU - Beane Freeman, Laura E.

AU - Koutros, Stella

AU - Männistö, Satu

AU - Weinstein, Stephanie

AU - Clark, Peter E.

AU - Edwards, Todd L.

AU - Lipworth, Loren

AU - Gapstur, Susan M.

AU - Stevens, Victoria L.

AU - Carol, Hallie

AU - Freedman, Matthew L.

AU - Pomerantz, Mark M.

AU - Cho, Eunyoung

AU - Wilson, Kathryn M.

AU - Gaziano, J. Michael

AU - Sesso, Howard D.

AU - Freedman, Neal D.

AU - Parker, Alexander S.

AU - Eckel-Passow, Jeanette E.

AU - Huang, Wen Yi

AU - Kahnoski, Richard J.

AU - Lane, Brian R.

AU - Noyes, Sabrina L.

AU - Petillo, David

AU - Teh, Bin Tean

AU - Peters, Ulrike

AU - White, Emily

AU - Anderson, Garnet L.

AU - Johnson, Lisa

AU - Luo, Juhua

AU - Buring, Julie

AU - Lee, I. Min

AU - Chow, Wong Ho

AU - Moore, Lee E.

AU - Eisen, Timothy

AU - Henrion, Marc

AU - Larkin, James

AU - Barman, Poulami

AU - Leibovich, Bradley C.

AU - Choueiri, Toni K.

AU - Lathrop, G. Mark

AU - Deleuze, Jean Francois

AU - Gunter, Marc

AU - McKay, James D.

AU - Wu, Xifeng

AU - Houlston, Richard S.

AU - Chanock, Stephen J.

AU - Relton, Caroline

AU - Richards, J. Brent

AU - Martin, Richard M.

AU - Davey Smith, George

AU - Brennan, Paul

PY - 2019

Y1 - 2019

N2 - Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (OR SD ) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (OR SD : 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (OR SD : 1.63, 95% CI 1.40-1.90) and body fat percentage (OR SD : 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (OR SD : 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; OR SD : 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (OR SD : 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

AB - Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (OR SD ) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (OR SD : 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (OR SD : 1.63, 95% CI 1.40-1.90) and body fat percentage (OR SD : 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (OR SD : 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; OR SD : 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (OR SD : 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

UR - http://www.scopus.com/inward/record.url?scp=85059499698&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059499698&partnerID=8YFLogxK

U2 - 10.1371/journal.pmed.1002724

DO - 10.1371/journal.pmed.1002724

M3 - Article

C2 - 30605491

AN - SCOPUS:85059499698

SN - 1549-1277

VL - 16

JO - PLoS Medicine

JF - PLoS Medicine

IS - 1

M1 - e1002724

ER -

The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study

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