Genome-wide gene⇓diabetes and gene⇓obesity interaction scan in 8,255 cases and 11,900 controls from panscan and PanC4 consortia

Hongwei Tang; Lai Jiang; Rachael Z. Stolzenberg-Solomon; Alan A. Arslan; Laura E. Beane Freeman; Paige M. Bracci; Paul Brennan; Federico Canzian; Mengmeng Du; Steven Gallinger; Graham G. Giles; Phyllis J. Goodman; Charles Kooperberg; Loc Le Marchand; Rachel E. Neale; Xiao Ou Shu; Kala Visvanathan; Emily White; Wei Zheng; Demetrius Albanes; Gabriella Andreotti; Ana Babic; William R. Bamlet; Sonja I. Berndt; Amanda Blackford; Bas Bueno-De-Mesquita; Julie E. Buring; Daniele Campa; Stephen J. Chanock; Erica Childs; Eric J. Duell; Charles Fuchs; J. Michael Gaziano; Michael Goggins; Patricia Hartge; Manal H. Hassam; Elizabeth A. Holly; Robert N. Hoover; Rayjean J. Hung; Robert C. Kurtz; I. Min Lee; Nuria Malats; Roger L. Milne; Kimmie Ng; Ann L. Oberg; Irene Orlow; Ulrike Peters; Miquel Porta; Kari G. Rabe; Nathaniel Rothman; Ghislaine Scelo; Howard D. Sesso; Debra T. Silverman; Ian M. Thompson; Anne Tjønneland; Antonia Trichopoulou; Jean Wactawski-Wende; Nicolas Wentzensen; Lynne R. Wilkens; Herbert Yu; Anne Zeleniuch-Jacquotte; Laufey T. Amundadottir; Eric J. Jacobs; Gloria M. Petersen; Brian M. Wolpin; Harvey A. Risch; Nilanjan Chatterjee; Alison P. Klein; Donghui Li; Peter Kraft; Peng Wei

doi:10.1158/1055-9965.EPI-20-0275

Genome-wide gene⇓diabetes and gene⇓obesity interaction scan in 8,255 cases and 11,900 controls from panscan and PanC4 consortia

Hongwei Tang, Lai Jiang, Rachael Z. Stolzenberg-Solomon, Alan A. Arslan, Laura E. Beane Freeman, Paige M. Bracci, Paul Brennan, Federico Canzian, Mengmeng Du, Steven Gallinger, Graham G. Giles, Phyllis J. Goodman, Charles Kooperberg, Loc Le Marchand, Rachel E. Neale, Xiao Ou Shu, Kala Visvanathan, Emily White, Wei Zheng, Demetrius AlbanesGabriella Andreotti, Ana Babic, William R. Bamlet, Sonja I. Berndt, Amanda Blackford, Bas Bueno-De-Mesquita, Julie E. Buring, Daniele Campa, Stephen J. Chanock, Erica Childs, Eric J. Duell, Charles Fuchs, J. Michael Gaziano, Michael Goggins, Patricia Hartge, Manal H. Hassam, Elizabeth A. Holly, Robert N. Hoover, Rayjean J. Hung, Robert C. Kurtz, I. Min Lee, Nuria Malats, Roger L. Milne, Kimmie Ng, Ann L. Oberg, Irene Orlow, Ulrike Peters, Miquel Porta, Kari G. Rabe, Nathaniel Rothman, Ghislaine Scelo, Howard D. Sesso, Debra T. Silverman, Ian M. Thompson, Anne Tjønneland, Antonia Trichopoulou, Jean Wactawski-Wende, Nicolas Wentzensen, Lynne R. Wilkens, Herbert Yu, Anne Zeleniuch-Jacquotte, Laufey T. Amundadottir, Eric J. Jacobs, Gloria M. Petersen, Brian M. Wolpin, Harvey A. Risch, Nilanjan Chatterjee, Alison P. Klein, Donghui Li, Peter Kraft, Peng Wei

Quantitative Health Sciences

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

2 Scopus citations

Abstract

Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. Methods: We conducted a gene–environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m²) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case–control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 10⁶) was observed in the meta-analysis (P_GxE ¼ 1.2 10⁶, P_Joint ¼ 4.2 10⁷). Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. Impact: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

Original language	English (US)
Pages (from-to)	1784-1791
Number of pages	8
Journal	Cancer Epidemiology Biomarkers and Prevention
Volume	29
Issue number	9
DOIs	https://doi.org/10.1158/1055-9965.EPI-20-0275
State	Published - Sep 2020

ASJC Scopus subject areas

Medicine(all)

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10.1158/1055-9965.EPI-20-0275

Cite this

Tang, H., Jiang, L., Stolzenberg-Solomon, R. Z., Arslan, A. A., Beane Freeman, L. E., Bracci, P. M., Brennan, P., Canzian, F., Du, M., Gallinger, S., Giles, G. G., Goodman, P. J., Kooperberg, C., Le Marchand, L., Neale, R. E., Shu, X. O., Visvanathan, K., White, E., Zheng, W., ... Wei, P. (2020). Genome-wide gene⇓diabetes and gene⇓obesity interaction scan in 8,255 cases and 11,900 controls from panscan and PanC4 consortia. Cancer Epidemiology Biomarkers and Prevention, 29(9), 1784-1791. https://doi.org/10.1158/1055-9965.EPI-20-0275

Tang, H, Jiang, L, Stolzenberg-Solomon, RZ, Arslan, AA, Beane Freeman, LE, Bracci, PM, Brennan, P, Canzian, F, Du, M, Gallinger, S, Giles, GG, Goodman, PJ, Kooperberg, C, Le Marchand, L, Neale, RE, Shu, XO, Visvanathan, K, White, E, Zheng, W, Albanes, D, Andreotti, G, Babic, A, Bamlet, WR, Berndt, SI, Blackford, A, Bueno-De-Mesquita, B, Buring, JE, Campa, D, Chanock, SJ, Childs, E, Duell, EJ, Fuchs, C, Michael Gaziano, J, Goggins, M, Hartge, P, Hassam, MH, Holly, EA, Hoover, RN, Hung, RJ, Kurtz, RC, Lee, IM, Malats, N, Milne, RL, Ng, K, Oberg, AL, Orlow, I, Peters, U, Porta, M, Rabe, KG, Rothman, N, Scelo, G, Sesso, HD, Silverman, DT, Thompson, IM, Tjønneland, A, Trichopoulou, A, Wactawski-Wende, J, Wentzensen, N, Wilkens, LR, Yu, H, Zeleniuch-Jacquotte, A, Amundadottir, LT, Jacobs, EJ, Petersen, GM, Wolpin, BM, Risch, HA, Chatterjee, N, Klein, AP, Li, D, Kraft, P & Wei, P 2020, 'Genome-wide gene⇓diabetes and gene⇓obesity interaction scan in 8,255 cases and 11,900 controls from panscan and PanC4 consortia', Cancer Epidemiology Biomarkers and Prevention, vol. 29, no. 9, pp. 1784-1791. https://doi.org/10.1158/1055-9965.EPI-20-0275

@article{728353a89f8e41769f2b5f24b31e03f5,

title = "Genome-wide gene⇓diabetes and gene⇓obesity interaction scan in 8,255 cases and 11,900 controls from panscan and PanC4 consortia",

abstract = "Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. Methods: We conducted a gene–environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case–control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 106) was observed in the meta-analysis (PGxE ¼ 1.2 106, PJoint ¼ 4.2 107). Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. Impact: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.",

author = "Hongwei Tang and Lai Jiang and Stolzenberg-Solomon, {Rachael Z.} and Arslan, {Alan A.} and {Beane Freeman}, {Laura E.} and Bracci, {Paige M.} and Paul Brennan and Federico Canzian and Mengmeng Du and Steven Gallinger and Giles, {Graham G.} and Goodman, {Phyllis J.} and Charles Kooperberg and {Le Marchand}, Loc and Neale, {Rachel E.} and Shu, {Xiao Ou} and Kala Visvanathan and Emily White and Wei Zheng and Demetrius Albanes and Gabriella Andreotti and Ana Babic and Bamlet, {William R.} and Berndt, {Sonja I.} and Amanda Blackford and Bas Bueno-De-Mesquita and Buring, {Julie E.} and Daniele Campa and Chanock, {Stephen J.} and Erica Childs and Duell, {Eric J.} and Charles Fuchs and {Michael Gaziano}, J. and Michael Goggins and Patricia Hartge and Hassam, {Manal H.} and Holly, {Elizabeth A.} and Hoover, {Robert N.} and Hung, {Rayjean J.} and Kurtz, {Robert C.} and Lee, {I. Min} and Nuria Malats and Milne, {Roger L.} and Kimmie Ng and Oberg, {Ann L.} and Irene Orlow and Ulrike Peters and Miquel Porta and Rabe, {Kari G.} and Nathaniel Rothman and Ghislaine Scelo and Sesso, {Howard D.} and Silverman, {Debra T.} and Thompson, {Ian M.} and Anne Tj{\o}nneland and Antonia Trichopoulou and Jean Wactawski-Wende and Nicolas Wentzensen and Wilkens, {Lynne R.} and Herbert Yu and Anne Zeleniuch-Jacquotte and Amundadottir, {Laufey T.} and Jacobs, {Eric J.} and Petersen, {Gloria M.} and Wolpin, {Brian M.} and Risch, {Harvey A.} and Nilanjan Chatterjee and Klein, {Alison P.} and Donghui Li and Peter Kraft and Peng Wei",

note = "Funding Information: C. Fuchs reports other commercial research support from Agios, Bain Capital, Unum Therapeutics, CytomX Therapeutics, Daiichi Sankyo, Eli Lilly, Entrinsic Health, Evolveimmune Therapeutics, Genentech, Merck, and Taiho; has ownership interest (including patents) in CytomX Therapeutics, Entrinsic Health, and Evolveimmune Therapeutics; and reports other remuneration from Amylin Pharma. K. Ng reports receiving commercial research grants from Celgene and Revolution Medicines. No potential conflicts of interest were disclosed by other authors. Funding Information: the National Program of Cancer Registries of the Centers for Disease Control and Prevention for the funds that support the collection and availability of the cancer registry data. We thank all the CLUE participants. The Melbourne Collaborative Cohort Study (MCCS) recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057 and 396414 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. The NYU study (to A Zeleniuch-Jacquotte and A.A. Arslan) was funded by NIH R01 CA098661, UM1 CA182934, and center grants P30 CA016087 and P30 ES000260. The PANKRAS II Study in Spain was supported by research grants from Instituto de Salud Carlos III-FEDER, Spain; Fondo de Investigaciones Sanitarias (FIS; #PI13/00082 and #PI15/01573) and Red Tem{\'a}tica de Investigaci{\'o}n Cooperativa en C{\'a}ncer, Spain (#RD12/0036/0050); European Cooperation in Science and Technology (COST Action #BM1204: EU_Pancreas), Ministerio de Ciencia y Tecnolog{\'i}a (CICYT SAF 2000-0097), Fondo de Investigaci{\'o}n Sanitaria (95/0017), Madrid, Spain; Generalitat de Catalunya (CIRIT - SGR); and “Red tem{\'a}tica de investigaci{\'o}n cooperativa de centros en C{\'a}ncer” (C03/10), “Red tem{\'a}tica de investigaci{\'o}n cooperativa de centros en Epidemiolog{\'i}a y salud p{\'u}blica” (C03/09), and CIBER de Epidemiolog{\'i}a (CIBERESP), Madrid, Spain. The Physicians' Health Study was supported by research grants CA-097193, CA-34944, CA-40360, HL-26490, and HL-34595 from the NIH (Bethesda, MD). The Women's Health Study was supported by research grants CA-047988, HL-043851, HL-080467, and Funding Information: This work was supported by the NIH grants R01CA169122 (to P. Wei) and UH2CA191284 (to P. Kraft). The IARC/Central Europe study was supported by NIH grant R03 CA123546-02 and grants from the Ministry of Health of the Czech Republic (NR 9029-4/2006, NR9422-3, NR9998-3, and MH CZ-DRO-MMCI 00209805). The work at Johns Hopkins University was supported by the NCI grants P50CA062924 and R01CA97075. Additional support was provided by the Lustgarten Foundation, and Susan Wojcicki and Dennis Troper and the Sol Goldman Pancreas Cancer Research Center. This work was supported by an NCI grant R01 CA154823. The Mayo Clinic Biospecimen Resource for Pancreas Research study is supported by the Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701). The MD Anderson Cancer Center study was supported by the NIH grant R01CA98030 and a grant from the Khalifa Bin Zayed Al Nahyan Foundation. The Memorial Sloan Kettering Cancer Center Pancreatic Tumor Registry was supported by P30CA008748, the Geoffrey Beene Foundation, the Arnold and Arlene Goldstein Family Foundation, and the Society of MSKCC. The PACIFIC Study was supported by the NCI grant R01CA102765, and Kaiser Permanente and Group Health Cooperative. The Queensland Pancreatic Cancer Study was supported by a grant from the National Health and Medical Research Council of Australia (NHMRC; grant number 442302). R.E. Neale was supported by an NHMRC Senior Research Fellowship (#1060183). The UCSF pancreas study was supported by NIH-NCI grants (R01CA1009767, R01CA109767-S1, and R0CA059706) and the Joan Rombauer Pancreatic Cancer Fund. The Yale (CT) pancreas cancer study was supported by the NCI grant 5R01CA098870. The cooperation of 30 Connecticut hospitals, including Stamford Hospital, in allowing patient access, is gratefully acknowledged. The Connecticut Pancreas Cancer Study was approved by the State of Connecticut Department of Public Health Human Investigation Committee. Certain data used in that study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. Studies included in PANDoRA were partly funded by: the Czech Science Foundation (No. P301/12/1734), the Internal Grant Agency of the Czech Ministry of Health (IGA NT 13 263); the Baden-Wu€rttemberg State Ministry of Research, Science and Arts (to Prof. H. Brenner), the Heidelberger EPZ-Pancobank (to Prof. M.W. Bu€chler and team: Prof. T. Hackert, Dr. N. A. Giese, Dr. Ch. Tjaden, E. Soyka, and M. Meinhardt; Heidelberger Stiftung Chirurgie and BMBF grant 01GS08114), the BMBH (to Prof. P. Schirmacher; BMBF grant 01EY1101), the “5 ⨯ 1000” voluntary contribution of the Italian Government, the Italian Ministry of Health (RC1203GA57, RC1303GA53, RC1303GA54, and RC1303GA50), the Italian Association for Research on Cancer (to Prof. A. Scarpa; AIRC n. 12182), the Italian Ministry of Research (to Prof. A. Scarpa; FIRB - RBAP10AHJB), the Italian FIMP-Ministry of Health (to Prof. A. Scarpa; 12 CUP_J33G13000210001), and by the National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, United Kingdom. We would like to acknowledge the contribution of Dr Frederike Dijk and Prof. Oliver Busch (Academic Medical Center, Amsterdam, the Netherlands). The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study II cohort. Cancer incidence data for CLUE were provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Department of Health and Mental Hygiene (Baltimore, MD; http://phpa.dhmh.maryland.gov/cancer, 410-767-4055). We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",

year = "2020",

month = sep,

doi = "10.1158/1055-9965.EPI-20-0275",

language = "English (US)",

volume = "29",

pages = "1784--1791",

journal = "Cancer Epidemiology Biomarkers and Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research Inc.",

number = "9",

}

TY - JOUR

T1 - Genome-wide gene⇓diabetes and gene⇓obesity interaction scan in 8,255 cases and 11,900 controls from panscan and PanC4 consortia

AU - Tang, Hongwei

AU - Jiang, Lai

AU - Stolzenberg-Solomon, Rachael Z.

AU - Arslan, Alan A.

AU - Beane Freeman, Laura E.

AU - Bracci, Paige M.

AU - Brennan, Paul

AU - Canzian, Federico

AU - Du, Mengmeng

AU - Gallinger, Steven

AU - Giles, Graham G.

AU - Goodman, Phyllis J.

AU - Kooperberg, Charles

AU - Le Marchand, Loc

AU - Neale, Rachel E.

AU - Shu, Xiao Ou

AU - Visvanathan, Kala

AU - White, Emily

AU - Zheng, Wei

AU - Albanes, Demetrius

AU - Andreotti, Gabriella

AU - Babic, Ana

AU - Bamlet, William R.

AU - Berndt, Sonja I.

AU - Blackford, Amanda

AU - Bueno-De-Mesquita, Bas

AU - Buring, Julie E.

AU - Campa, Daniele

AU - Chanock, Stephen J.

AU - Childs, Erica

AU - Duell, Eric J.

AU - Fuchs, Charles

AU - Michael Gaziano, J.

AU - Goggins, Michael

AU - Hartge, Patricia

AU - Hassam, Manal H.

AU - Holly, Elizabeth A.

AU - Hoover, Robert N.

AU - Hung, Rayjean J.

AU - Kurtz, Robert C.

AU - Lee, I. Min

AU - Malats, Nuria

AU - Milne, Roger L.

AU - Ng, Kimmie

AU - Oberg, Ann L.

AU - Orlow, Irene

AU - Peters, Ulrike

AU - Porta, Miquel

AU - Rabe, Kari G.

AU - Rothman, Nathaniel

AU - Scelo, Ghislaine

AU - Sesso, Howard D.

AU - Silverman, Debra T.

AU - Thompson, Ian M.

AU - Tjønneland, Anne

AU - Trichopoulou, Antonia

AU - Wactawski-Wende, Jean

AU - Wentzensen, Nicolas

AU - Wilkens, Lynne R.

AU - Yu, Herbert

AU - Zeleniuch-Jacquotte, Anne

AU - Amundadottir, Laufey T.

AU - Jacobs, Eric J.

AU - Petersen, Gloria M.

AU - Wolpin, Brian M.

AU - Risch, Harvey A.

AU - Chatterjee, Nilanjan

AU - Klein, Alison P.

AU - Li, Donghui

AU - Kraft, Peter

AU - Wei, Peng

N1 - Funding Information: C. Fuchs reports other commercial research support from Agios, Bain Capital, Unum Therapeutics, CytomX Therapeutics, Daiichi Sankyo, Eli Lilly, Entrinsic Health, Evolveimmune Therapeutics, Genentech, Merck, and Taiho; has ownership interest (including patents) in CytomX Therapeutics, Entrinsic Health, and Evolveimmune Therapeutics; and reports other remuneration from Amylin Pharma. K. Ng reports receiving commercial research grants from Celgene and Revolution Medicines. No potential conflicts of interest were disclosed by other authors. Funding Information: the National Program of Cancer Registries of the Centers for Disease Control and Prevention for the funds that support the collection and availability of the cancer registry data. We thank all the CLUE participants. The Melbourne Collaborative Cohort Study (MCCS) recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057 and 396414 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. The NYU study (to A Zeleniuch-Jacquotte and A.A. Arslan) was funded by NIH R01 CA098661, UM1 CA182934, and center grants P30 CA016087 and P30 ES000260. The PANKRAS II Study in Spain was supported by research grants from Instituto de Salud Carlos III-FEDER, Spain; Fondo de Investigaciones Sanitarias (FIS; #PI13/00082 and #PI15/01573) and Red Temática de Investigación Cooperativa en Cáncer, Spain (#RD12/0036/0050); European Cooperation in Science and Technology (COST Action #BM1204: EU_Pancreas), Ministerio de Ciencia y Tecnología (CICYT SAF 2000-0097), Fondo de Investigación Sanitaria (95/0017), Madrid, Spain; Generalitat de Catalunya (CIRIT - SGR); and “Red temática de investigación cooperativa de centros en Cáncer” (C03/10), “Red temática de investigación cooperativa de centros en Epidemiología y salud pública” (C03/09), and CIBER de Epidemiología (CIBERESP), Madrid, Spain. The Physicians' Health Study was supported by research grants CA-097193, CA-34944, CA-40360, HL-26490, and HL-34595 from the NIH (Bethesda, MD). The Women's Health Study was supported by research grants CA-047988, HL-043851, HL-080467, and Funding Information: This work was supported by the NIH grants R01CA169122 (to P. Wei) and UH2CA191284 (to P. Kraft). The IARC/Central Europe study was supported by NIH grant R03 CA123546-02 and grants from the Ministry of Health of the Czech Republic (NR 9029-4/2006, NR9422-3, NR9998-3, and MH CZ-DRO-MMCI 00209805). The work at Johns Hopkins University was supported by the NCI grants P50CA062924 and R01CA97075. Additional support was provided by the Lustgarten Foundation, and Susan Wojcicki and Dennis Troper and the Sol Goldman Pancreas Cancer Research Center. This work was supported by an NCI grant R01 CA154823. The Mayo Clinic Biospecimen Resource for Pancreas Research study is supported by the Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701). The MD Anderson Cancer Center study was supported by the NIH grant R01CA98030 and a grant from the Khalifa Bin Zayed Al Nahyan Foundation. The Memorial Sloan Kettering Cancer Center Pancreatic Tumor Registry was supported by P30CA008748, the Geoffrey Beene Foundation, the Arnold and Arlene Goldstein Family Foundation, and the Society of MSKCC. The PACIFIC Study was supported by the NCI grant R01CA102765, and Kaiser Permanente and Group Health Cooperative. The Queensland Pancreatic Cancer Study was supported by a grant from the National Health and Medical Research Council of Australia (NHMRC; grant number 442302). R.E. Neale was supported by an NHMRC Senior Research Fellowship (#1060183). The UCSF pancreas study was supported by NIH-NCI grants (R01CA1009767, R01CA109767-S1, and R0CA059706) and the Joan Rombauer Pancreatic Cancer Fund. The Yale (CT) pancreas cancer study was supported by the NCI grant 5R01CA098870. The cooperation of 30 Connecticut hospitals, including Stamford Hospital, in allowing patient access, is gratefully acknowledged. The Connecticut Pancreas Cancer Study was approved by the State of Connecticut Department of Public Health Human Investigation Committee. Certain data used in that study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. Studies included in PANDoRA were partly funded by: the Czech Science Foundation (No. P301/12/1734), the Internal Grant Agency of the Czech Ministry of Health (IGA NT 13 263); the Baden-Wu€rttemberg State Ministry of Research, Science and Arts (to Prof. H. Brenner), the Heidelberger EPZ-Pancobank (to Prof. M.W. Bu€chler and team: Prof. T. Hackert, Dr. N. A. Giese, Dr. Ch. Tjaden, E. Soyka, and M. Meinhardt; Heidelberger Stiftung Chirurgie and BMBF grant 01GS08114), the BMBH (to Prof. P. Schirmacher; BMBF grant 01EY1101), the “5 ⨯ 1000” voluntary contribution of the Italian Government, the Italian Ministry of Health (RC1203GA57, RC1303GA53, RC1303GA54, and RC1303GA50), the Italian Association for Research on Cancer (to Prof. A. Scarpa; AIRC n. 12182), the Italian Ministry of Research (to Prof. A. Scarpa; FIRB - RBAP10AHJB), the Italian FIMP-Ministry of Health (to Prof. A. Scarpa; 12 CUP_J33G13000210001), and by the National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, United Kingdom. We would like to acknowledge the contribution of Dr Frederike Dijk and Prof. Oliver Busch (Academic Medical Center, Amsterdam, the Netherlands). The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study II cohort. Cancer incidence data for CLUE were provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Department of Health and Mental Hygiene (Baltimore, MD; http://phpa.dhmh.maryland.gov/cancer, 410-767-4055). We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and Publisher Copyright: © 2020 American Association for Cancer Research.

PY - 2020/9

Y1 - 2020/9

N2 - Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. Methods: We conducted a gene–environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case–control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 106) was observed in the meta-analysis (PGxE ¼ 1.2 106, PJoint ¼ 4.2 107). Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. Impact: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

AB - Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. Methods: We conducted a gene–environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case–control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 106) was observed in the meta-analysis (PGxE ¼ 1.2 106, PJoint ¼ 4.2 107). Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. Impact: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

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U2 - 10.1158/1055-9965.EPI-20-0275

DO - 10.1158/1055-9965.EPI-20-0275

M3 - Article

C2 - 32546605

AN - SCOPUS:85100222584

SN - 1055-9965

VL - 29

SP - 1784

EP - 1791

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

IS - 9

ER -

Genome-wide gene⇓diabetes and gene⇓obesity interaction scan in 8,255 cases and 11,900 controls from panscan and PanC4 consortia

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