Genome-Wide Interaction Analysis of Genetic Variants with Menopausal Hormone Therapy for Colorectal Cancer Risk

Yu Tian; Andre E Kim; Stephanie A Bien; Yi Lin; Conghui Qu; Tabitha A Harrison; Robert Carreras-Torres; Virginia Díez-Obrero; Niki Dimou; David A Drew; Akihisa Hidaka; Jeroen R Huyghe; Kristina M Jordahl; John Morrison; Neil Murphy; Mireia Obón-Santacana; Cornelia M Ulrich; Jennifer Ose; Anita R Peoples; Edward A Ruiz-Narvaez; Anna Shcherbina; Mariana C Stern; Yu-Ru Su; Franzel J. B Van Duijnhoven; Volker Arndt; James W Baurley; Sonja I Berndt; D. Timothy Bishop; Hermann Brenner; Daniel D Buchanan; Andrew T Chan; Jane C Figueiredo; Steven Gallinger; Stephen B Gruber; Sophia Harlid; Michael Hoffmeister; Mark A Jenkins; Amit D Joshi; Temitope O Keku; Susanna C Larsson; Loic Le Marchand; Li Li; Graham G Giles; Roger L Milne; Hongmei Nan; Rami Nassir; Shuji Ogino; Arif Budiarto; Elizabeth A Platz; John D Potter; Ross L Prentice; Gad Rennert; Lori C Sakoda; Robert E Schoen; Martha L Slattery; Stephen N Thibodeau; Bethany Van Guelpen; Kala Visvanathan; Emily White; Alicja Wolk; Michael O Woods; Anna H Wu; Peter T Campbell; Graham Casey; David V Conti; Marc J Gunter; Anshul Kundaje; Juan Pablo Lewinger; Victor Moreno; Polly A Newcomb; Bens Pardamean; Duncan C Thomas; Konstantinos K Tsilidis; Ulrike Peters; W. James Gauderman; Li Hsu; Jenny Chang-Claude

doi:10.1093/jnci/djac094

Genome-Wide Interaction Analysis of Genetic Variants with Menopausal Hormone Therapy for Colorectal Cancer Risk

Yu Tian, Andre E Kim, Stephanie A Bien, Yi Lin, Conghui Qu, Tabitha A Harrison, Robert Carreras-Torres, Virginia Díez-Obrero, Niki Dimou, David A Drew, Akihisa Hidaka, Jeroen R Huyghe, Kristina M Jordahl, John Morrison, Neil Murphy, Mireia Obón-Santacana, Cornelia M Ulrich, Jennifer Ose, Anita R Peoples, Edward A Ruiz-NarvaezAnna Shcherbina, Mariana C Stern, Yu-Ru Su, Franzel J. B Van Duijnhoven, Volker Arndt, James W Baurley, Sonja I Berndt, D. Timothy Bishop, Hermann Brenner, Daniel D Buchanan, Andrew T Chan, Jane C Figueiredo, Steven Gallinger, Stephen B Gruber, Sophia Harlid, Michael Hoffmeister, Mark A Jenkins, Amit D Joshi, Temitope O Keku, Susanna C Larsson, Loic Le Marchand, Li Li, Graham G Giles, Roger L Milne, Hongmei Nan, Rami Nassir, Shuji Ogino, Arif Budiarto, Elizabeth A Platz, John D Potter, Ross L Prentice, Gad Rennert, Lori C Sakoda, Robert E Schoen, Martha L Slattery, Stephen N Thibodeau, Bethany Van Guelpen, Kala Visvanathan, Emily White, Alicja Wolk, Michael O Woods, Anna H Wu, Peter T Campbell, Graham Casey, David V Conti, Marc J Gunter, Anshul Kundaje, Juan Pablo Lewinger, Victor Moreno, Polly A Newcomb, Bens Pardamean, Duncan C Thomas, Konstantinos K Tsilidis, Ulrike Peters, W. James Gauderman, Li Hsu, Jenny Chang-Claude

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Background: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk.

Methods: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2-or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants.

Results: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-Associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-Associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4).

Conclusion: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.

Original language	English
Pages (from-to)	1135-1148
Number of pages	14
Journal	Journal of the National Cancer Institute
Volume	114
Issue number	8
Early online date	5 May 2022
DOIs	https://doi.org/10.1093/jnci/djac094
Publication status	Published - Aug 2022
Externally published	Yes

Funding

Funders	Funder number
National Cancer Institute	U01CA167551, P30CA015704, ZIACP010152, R01CA207371, U01CA137088, R01CA189184, U01CA206110
NIH Office of the Director	S10OD028685
Not added	MR/M012190/1
UK Research and Innovation	75977
National Health and Medical Research Council	209057, 509348

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Tian, Y., Kim, A. E., Bien, S. A., Lin, Y., Qu, C., Harrison, T. A., Carreras-Torres, R., Díez-Obrero, V., Dimou, N., Drew, D. A., Hidaka, A., Huyghe, J. R., Jordahl, K. M., Morrison, J., Murphy, N., Obón-Santacana, M., Ulrich, C. M., Ose, J., Peoples, A. R., ... Chang-Claude, J. (2022). Genome-Wide Interaction Analysis of Genetic Variants with Menopausal Hormone Therapy for Colorectal Cancer Risk. Journal of the National Cancer Institute, 114(8), 1135-1148. https://doi.org/10.1093/jnci/djac094

@article{e0ab48b169ff4cef89f70ed96c21f8ff,

title = "Genome-Wide Interaction Analysis of Genetic Variants with Menopausal Hormone Therapy for Colorectal Cancer Risk",

abstract = "Background: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. Methods: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2-or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. Results: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95\% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95\% CI = 0.53 to 0.79; and OR = 0.73, 95\% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-Associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95\% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-Associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95\% CI = 0.70 to 0.87) for TT, 0.68 (95\% CI = 0.63 to 0.73) for TC, and 0.66 (95\% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4). Conclusion: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.",

author = "Yu Tian and Kim, \{Andre E\} and Bien, \{Stephanie A\} and Yi Lin and Conghui Qu and Harrison, \{Tabitha A\} and Robert Carreras-Torres and Virginia D{\'i}ez-Obrero and Niki Dimou and Drew, \{David A\} and Akihisa Hidaka and Huyghe, \{Jeroen R\} and Jordahl, \{Kristina M\} and John Morrison and Neil Murphy and Mireia Ob{\'o}n-Santacana and Ulrich, \{Cornelia M\} and Jennifer Ose and Peoples, \{Anita R\} and Ruiz-Narvaez, \{Edward A\} and Anna Shcherbina and Stern, \{Mariana C\} and Yu-Ru Su and \{Van Duijnhoven\}, \{Franzel J. B\} and Volker Arndt and Baurley, \{James W\} and Berndt, \{Sonja I\} and Bishop, \{D. Timothy\} and Hermann Brenner and Buchanan, \{Daniel D\} and Chan, \{Andrew T\} and Figueiredo, \{Jane C\} and Steven Gallinger and Gruber, \{Stephen B\} and Sophia Harlid and Michael Hoffmeister and Jenkins, \{Mark A\} and Joshi, \{Amit D\} and Keku, \{Temitope O\} and Larsson, \{Susanna C\} and \{Le Marchand\}, Loic and Li Li and Giles, \{Graham G\} and Milne, \{Roger L\} and Hongmei Nan and Rami Nassir and Shuji Ogino and Arif Budiarto and Platz, \{Elizabeth A\} and Potter, \{John D\} and Prentice, \{Ross L\} and Gad Rennert and Sakoda, \{Lori C\} and Schoen, \{Robert E\} and Slattery, \{Martha L\} and Thibodeau, \{Stephen N\} and \{Van Guelpen\}, Bethany and Kala Visvanathan and Emily White and Alicja Wolk and Woods, \{Michael O\} and Wu, \{Anna H\} and Campbell, \{Peter T\} and Graham Casey and Conti, \{David V\} and Gunter, \{Marc J\} and Anshul Kundaje and Lewinger, \{Juan Pablo\} and Victor Moreno and Newcomb, \{Polly A\} and Bens Pardamean and Thomas, \{Duncan C\} and Tsilidis, \{Konstantinos K\} and Ulrike Peters and Gauderman, \{W. James\} and Li Hsu and Jenny Chang-Claude",

year = "2022",

month = aug,

doi = "10.1093/jnci/djac094",

language = "English",

volume = "114",

pages = "1135--1148",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "8",

}

Tian, Y, Kim, AE, Bien, SA, Lin, Y, Qu, C, Harrison, TA, Carreras-Torres, R, Díez-Obrero, V, Dimou, N, Drew, DA, Hidaka, A, Huyghe, JR, Jordahl, KM, Morrison, J, Murphy, N, Obón-Santacana, M, Ulrich, CM, Ose, J, Peoples, AR, Ruiz-Narvaez, EA, Shcherbina, A, Stern, MC, Su, Y-R, Van Duijnhoven, FJB, Arndt, V, Baurley, JW, Berndt, SI, Bishop, DT, Brenner, H, Buchanan, DD, Chan, AT, Figueiredo, JC, Gallinger, S, Gruber, SB, Harlid, S, Hoffmeister, M, Jenkins, MA, Joshi, AD, Keku, TO, Larsson, SC, Le Marchand, L, Li, L, Giles, GG, Milne, RL, Nan, H, Nassir, R, Ogino, S, Budiarto, A, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Sakoda, LC, Schoen, RE, Slattery, ML, Thibodeau, SN, Van Guelpen, B, Visvanathan, K, White, E, Wolk, A, Woods, MO, Wu, AH, Campbell, PT, Casey, G, Conti, DV, Gunter, MJ, Kundaje, A, Lewinger, JP, Moreno, V, Newcomb, PA, Pardamean, B, Thomas, DC, Tsilidis, KK, Peters, U, Gauderman, WJ, Hsu, L & Chang-Claude, J 2022, 'Genome-Wide Interaction Analysis of Genetic Variants with Menopausal Hormone Therapy for Colorectal Cancer Risk', Journal of the National Cancer Institute, vol. 114, no. 8, pp. 1135-1148. https://doi.org/10.1093/jnci/djac094

TY - JOUR

T1 - Genome-Wide Interaction Analysis of Genetic Variants with Menopausal Hormone Therapy for Colorectal Cancer Risk

AU - Tian, Yu

AU - Kim, Andre E

AU - Bien, Stephanie A

AU - Lin, Yi

AU - Qu, Conghui

AU - Harrison, Tabitha A

AU - Carreras-Torres, Robert

AU - Díez-Obrero, Virginia

AU - Dimou, Niki

AU - Drew, David A

AU - Hidaka, Akihisa

AU - Huyghe, Jeroen R

AU - Jordahl, Kristina M

AU - Morrison, John

AU - Murphy, Neil

AU - Obón-Santacana, Mireia

AU - Ulrich, Cornelia M

AU - Ose, Jennifer

AU - Peoples, Anita R

AU - Ruiz-Narvaez, Edward A

AU - Shcherbina, Anna

AU - Stern, Mariana C

AU - Su, Yu-Ru

AU - Van Duijnhoven, Franzel J. B

AU - Arndt, Volker

AU - Baurley, James W

AU - Berndt, Sonja I

AU - Bishop, D. Timothy

AU - Brenner, Hermann

AU - Buchanan, Daniel D

AU - Chan, Andrew T

AU - Figueiredo, Jane C

AU - Gallinger, Steven

AU - Gruber, Stephen B

AU - Harlid, Sophia

AU - Hoffmeister, Michael

AU - Jenkins, Mark A

AU - Joshi, Amit D

AU - Keku, Temitope O

AU - Larsson, Susanna C

AU - Le Marchand, Loic

AU - Li, Li

AU - Giles, Graham G

AU - Milne, Roger L

AU - Nan, Hongmei

AU - Nassir, Rami

AU - Ogino, Shuji

AU - Budiarto, Arif

AU - Platz, Elizabeth A

AU - Potter, John D

AU - Prentice, Ross L

AU - Rennert, Gad

AU - Sakoda, Lori C

AU - Schoen, Robert E

AU - Slattery, Martha L

AU - Thibodeau, Stephen N

AU - Van Guelpen, Bethany

AU - Visvanathan, Kala

AU - White, Emily

AU - Wolk, Alicja

AU - Woods, Michael O

AU - Wu, Anna H

AU - Campbell, Peter T

AU - Casey, Graham

AU - Conti, David V

AU - Gunter, Marc J

AU - Kundaje, Anshul

AU - Lewinger, Juan Pablo

AU - Moreno, Victor

AU - Newcomb, Polly A

AU - Pardamean, Bens

AU - Thomas, Duncan C

AU - Tsilidis, Konstantinos K

AU - Peters, Ulrike

AU - Gauderman, W. James

AU - Hsu, Li

AU - Chang-Claude, Jenny

PY - 2022/8

Y1 - 2022/8

N2 - Background: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. Methods: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2-or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. Results: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-Associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-Associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4). Conclusion: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.

AB - Background: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. Methods: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2-or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. Results: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-Associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-Associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4). Conclusion: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.

UR - http://www.scopus.com/inward/record.url?scp=85135598788&partnerID=8YFLogxK

U2 - 10.1093/jnci/djac094

DO - 10.1093/jnci/djac094

M3 - Article

SN - 0027-8874

VL - 114

SP - 1135

EP - 1148

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 8

ER -

Genome-Wide Interaction Analysis of Genetic Variants with Menopausal Hormone Therapy for Colorectal Cancer Risk

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