Abstract
As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case–control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10 −4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46–0.60) compared to 0.71 (95%CI = 0.66–0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1–5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene–environment analysis in ovarian cancer.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2192-2205 |
| Number of pages | 14 |
| Journal | International Journal of Cancer |
| Volume | 144 |
| Issue number | 9 |
| DOIs | |
| State | Published - May 1 2019 |
Keywords
- G × E
- additive interaction
- genetics
- ovarian cancer
ASJC Scopus subject areas
- Oncology
- Cancer Research
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A comprehensive gene–environment interaction analysis in Ovarian Cancer using genome-wide significant common variants. / Kim, Sehee; Wang, Miao; Tyrer, Jonathan P.; Jensen, Allan; Wiensch, Ashley; Liu, Gang; Lee, Alice W.; Ness, Roberta B.; Salvatore, Maxwell; Tworoger, Shelley S.; Whittemore, Alice S.; Anton-Culver, Hoda; Sieh, Weiva; Olson, Sara H.; Berchuck, Andrew; Goode, Ellen L.; Goodman, Marc T.; Doherty, Jennifer Anne; Chenevix-Trench, Georgia; Rossing, Mary Anne; Webb, Penelope M.; Giles, Graham G.; Terry, Kathryn L.; Ziogas, Argyrios; Fortner, Renée T.; Menon, Usha; Gayther, Simon A.; Wu, Anna H.; Song, Honglin; Brooks-Wilson, Angela; Bandera, Elisa V.; Cook, Linda S.; Cramer, Daniel W.; Milne, Roger L.; Winham, Stacey J.; Kjaer, Susanne K.; Modugno, Francesmary; Thompson, Pamela J.; Chang-Claude, Jenny; Harris, Holly R.; Schildkraut, Joellen M.; Le, Nhu D.; Wentzensen, Nico; Trabert, Britton; Høgdall, Estrid; Huntsman, David; Pike, Malcolm C.; Pharoah, Paul D.P.; Pearce, Celeste Leigh; Mukherjee, Bhramar.
In: International Journal of Cancer, Vol. 144, No. 9, 01.05.2019, p. 2192-2205.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - A comprehensive gene–environment interaction analysis in Ovarian Cancer using genome-wide significant common variants
AU - Kim, Sehee
AU - Wang, Miao
AU - Tyrer, Jonathan P.
AU - Jensen, Allan
AU - Wiensch, Ashley
AU - Liu, Gang
AU - Lee, Alice W.
AU - Ness, Roberta B.
AU - Salvatore, Maxwell
AU - Tworoger, Shelley S.
AU - Whittemore, Alice S.
AU - Anton-Culver, Hoda
AU - Sieh, Weiva
AU - Olson, Sara H.
AU - Berchuck, Andrew
AU - Goode, Ellen L.
AU - Goodman, Marc T.
AU - Doherty, Jennifer Anne
AU - Chenevix-Trench, Georgia
AU - Rossing, Mary Anne
AU - Webb, Penelope M.
AU - Giles, Graham G.
AU - Terry, Kathryn L.
AU - Ziogas, Argyrios
AU - Fortner, Renée T.
AU - Menon, Usha
AU - Gayther, Simon A.
AU - Wu, Anna H.
AU - Song, Honglin
AU - Brooks-Wilson, Angela
AU - Bandera, Elisa V.
AU - Cook, Linda S.
AU - Cramer, Daniel W.
AU - Milne, Roger L.
AU - Winham, Stacey J.
AU - Kjaer, Susanne K.
AU - Modugno, Francesmary
AU - Thompson, Pamela J.
AU - Chang-Claude, Jenny
AU - Harris, Holly R.
AU - Schildkraut, Joellen M.
AU - Le, Nhu D.
AU - Wentzensen, Nico
AU - Trabert, Britton
AU - Høgdall, Estrid
AU - Huntsman, David
AU - Pike, Malcolm C.
AU - Pharoah, Paul D.P.
AU - Pearce, Celeste Leigh
AU - Mukherjee, Bhramar
N1 - Funding Information: Key words: ovarian cancer, genetics, additive interaction, G × E Abbreviations: AR: absolute risk; BMI: body mass index; BSO: bilateral salpingo-oophorectomy; CI: confidence interval; df: degrees of freedom; G × E: gene–environment interaction; GWAS: genome-wide association study; LRT: likelihood ratio test; OCAC: Ovarian Cancer Association Consortium; OCP: oral contraceptive pill; OR: odds ratio; RD: risk difference; SNP: single nucleotide polymorphism Additional Supporting Information may be found in the online version of this article. S.K. and M. W. contributed equally to this work Grant sponsor: California Cancer Center Research Program; Grant numbers: 00-01389V-20170, 2II0200; Grant sponsor: Canadian Institutes of Health Research; Grant number: MOP-86727; Grant sponsor: Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania and The Cancer Foundation of Western Australia; Grant numbers: Multi-State Applications 182, 191, 211; Grant sponsor: Cancer Institute of New Jersey; Grant sponsor: Ovarian Cancer Research Fund; Grant number: PPD/RPCI.074; Grant sponsor: Deutsches Krebsforschungszentrum; Grant sponsor: Fred C. and Katherine B. Andersen Foundation; Grant sponsor: German Federal Ministry of Education and Research; Grant number: 01 GB 9401; Grant sponsor: Intramural Research Program of the National Cancer Institute; Grant sponsor: Kræftens Bekæmpelse; Grant number: 94 222 52; Grant sponsor: Lon V Smith Foundation; Grant number: LVS-39420; Grant sponsor: Mayo Foundation; Grant sponsor: Medical Research and Materiel Command; Grant number: DAMD17-01-1-0729; Grant sponsor: Mermaid I project; Grant sponsor: Minnesota Ovarian Cancer Alliance; Grant sponsor: National Cancer Institute; Grant numbers: 1 R01CA160669-01A1, K07-CA080668, NIH-K07 CA095666, NIH-K22-CA138563, P30 CA04, P30 CA046592, P30-CA008748, P30-CA072720, P50-CA159981, R01 CA076016, R01-CA61107, R01-CA83918, R01-CA95023, R21-CA222867; Grant sponsor: National Cancer Institute’s Genetic Associations and Mechanisms in Oncology; Grant number: U19-CA148112; Grant sponsor: National Center for Research Resources; Grant number: M01-RR000056; Grant sponsor: National Health and Medical Research Council; Grant numbers: 1043134, 199600, ID400281, ID400413, 209057, 396414, 1074383; Grant sponsor: National Health Research and Development Program, Health Canada; Grant number: 6613-1415-53; Grant sponsor: National Institute for Health Research University College London Hospitals Biomedical Research Centre; Grant sponsor: National Institute of Environmental Health Sciences; Grant number: NIH ES 20811 BM; Grant sponsor: National Institutes of Health; Grant numbers: K22 CA193860, N01-CN-55424, N01-PC-67001, N01CN025403, N01PC67010, P01 CA87969, P01CA17054, P30-CA15083, P30CA14089, P50-CA105009, P50-CA136393, R01 CA49449, R01-CA0568860, R01-CA063678, R01 -CA074850, R01-CA080742, R01-CA112523, R01-CA122443, R01-CA54419, R01-CA58598, R01-CA67262, R01-CA76016, R01-CA87538, R01 CA61132, R03CA113148, R03CA115195, T32 ES013678, U01 CA69417, U01 CA71966, UM1 CA176726, UM1 CA186107; Grant sponsor: National Science Foundation; Grant number: NSF DMS 1406712 BM; Grant sponsor: Ovarian Cancer Australia; Grant sponsor: Peter MacCallum Foundation; Grant sponsor: Seventh Framework Programme; Grant number: 223175 HEALTH F2 2009-223175; Grant sponsor: The Eve Appeal (The Oak Foundation); Grant sponsor: U.S. Department of Defense; Grant numbers: DAMD17-02-1-0666DAMD17-02-1 -0669W81XWH-10-1-02802; Grant sponsor: Connecticut Department of Public Health; Grant sponsor: State of Connecticut Department of Public Health DOI: 10.1002/ijc.32029 History: Received 15 Aug 2018; Accepted 24 Oct 2018; Online 29 Nov 2018 Correspondence to: Bhramar Mukherjee, SPH Tower, 1415 Washington Heights, Ann Arbor MI 48109, USA, Tel.: 734-764-6544; Fax: 734-764-3192, E-mail: bhramar@umich.edu Funding Information: The AOCS also acknowledges the cooperation of the participating institutions in Australia and acknowledges the contribution of the study nurses, research assistants and all clinical and scientific collaborators to the study. The complete AOCS Study Group can be found at www.aocstudy.org. We would like to thank all of the women who participated in these research programs. The cooperation of the 32 Connecticut hospitals, including Stamford Hospital, in allowing patient access, is gratefully acknowledged. Our study was approved by the State of Connecticut Department of Public Health Human Investigation Committee. Certain data used in our study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data. The German Ovarian Cancer Study (GER) thank Ursula Eilber for competent technical assistance. The NHS/NHSII studies thank the after state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. We particularly thank I. Jacobs, M.Widschwendter, E. Wozniak, A. Ryan, J. Ford and N. Balogun for their contribution to the study. We also thank Harvey Risch for contributing data for this analysis. Usha Menon has shares in Abcodia Ltd., which has an interest in early cancer detection. Publisher Copyright: © 2018 UICC
PY - 2019/5/1
Y1 - 2019/5/1
N2 - As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case–control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10 −4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46–0.60) compared to 0.71 (95%CI = 0.66–0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1–5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene–environment analysis in ovarian cancer.
AB - As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case–control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10 −4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46–0.60) compared to 0.71 (95%CI = 0.66–0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1–5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene–environment analysis in ovarian cancer.
KW - G × E
KW - additive interaction
KW - genetics
KW - ovarian cancer
UR - http://www.scopus.com/inward/record.url?scp=85060352233&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85060352233&partnerID=8YFLogxK
U2 - 10.1002/ijc.32029
DO - 10.1002/ijc.32029
M3 - Article
C2 - 30499236
AN - SCOPUS:85060352233
VL - 144
SP - 2192
EP - 2205
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 9
ER -