Reproductive aging-associated common genetic variants and the risk of breast cancer

Chunyan He, Daniel I. Chasman, Jill Dreyfus, Shih Jen Hwang, Rikje Ruiter, Serena Sanna, Julie E. Buring, Lindsay Fernández-Rhodes, Nora Franceschini, Susan E. Hankinson, Albert Hofman, Kathryn L. Lunetta, Giuseppe Palmieri, Eleonora Porcu, Fernando Rivadeneira, Lynda M. Rose, Greta L. Splansky, Lisette Stolk, André G. Uitterlinden, Stephen J. ChanockLaura Crisponi, Ellen W. Demerath, Joanne M. Murabito, Paul M. Ridker, Bruno H. Stricker, David J. Hunter

    Research output: Contribution to journalArticle

    14 Citations (Scopus)

    Abstract

    Introduction: A younger age at menarche and an older age at menopause are well established risk factors for breast cancer. Recent genome-wide association studies have identified several novel genetic loci associated with these two traits. However, the association between these loci and breast cancer risk is unknown.Methods: In this study, we investigated 19 and 17 newly identified single nucleotide polymorphisms (SNPs) from the ReproGen Consortium that have been associated with age at menarche and age at natural menopause, respectively, and assessed their associations with breast cancer risk in 6 population-based studies among up to 3,683 breast cancer cases and 34,174 controls in white women of European ancestry. In addition, we used these SNPs to calculate genetic risk scores (GRSs) based on their associations with each trait.Results: After adjusting for age and potential population stratification, two age at menarche associated SNPs (rs1079866 and rs7821178) and one age at natural menopause associated SNP (rs2517388) were associated with breast cancer risk (p values, 0.003, 0.009 and 0.023, respectively). The odds ratios for breast cancer corresponding to per-risk-allele were 1.14 (95% CI, 1.05 to 1.24), 1.08 (95% CI, 1.02 to 1.15) and 1.10 (95% CI, 1.01 to 1.20), respectively, and were in the direction predicted by their associations with age at menarche or age at natural menopause. These associations did not appear to be attenuated by further controlling for self-reported age at menarche, age at natural menopause, or known breast cancer susceptibility loci. Although we did not observe a statistically significant association between any GRS for reproductive aging and breast cancer risk, the 4 th and 5 th highest quintiles of the younger age at menarche GRS had odds ratios of 1.14 (95% CI, 1.01 to 1.28) and 1.13 (95% CI, 1.00 to 1.27), respectively, compared to the lowest quintile.Conclusions: Our study suggests that three genetic variants, independent of their associations with age at menarche or age at natural menopause, were associated with breast cancer risk and may contribute modestly to breast cancer risk prediction; however, the combination of the 19 age at menarche or the 17 age at natural menopause associated SNPs did not appear to be useful for identifying a high risk subgroup for breast cancer.

    Original languageEnglish
    Article numberR54
    JournalBreast Cancer Research
    Volume14
    Issue number2
    DOIs
    StatePublished - Mar 20 2012

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    Menarche
    Breast Neoplasms
    Menopause
    Single Nucleotide Polymorphism
    Odds Ratio
    Genetic Loci
    Genome-Wide Association Study
    Population
    Alleles

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology
    • Medicine(all)

    Cite this

    He, C., Chasman, D. I., Dreyfus, J., Hwang, S. J., Ruiter, R., Sanna, S., ... Hunter, D. J. (2012). Reproductive aging-associated common genetic variants and the risk of breast cancer. Breast Cancer Research, 14(2), [R54]. https://doi.org/10.1186/bcr3155

    Reproductive aging-associated common genetic variants and the risk of breast cancer. / He, Chunyan; Chasman, Daniel I.; Dreyfus, Jill; Hwang, Shih Jen; Ruiter, Rikje; Sanna, Serena; Buring, Julie E.; Fernández-Rhodes, Lindsay; Franceschini, Nora; Hankinson, Susan E.; Hofman, Albert; Lunetta, Kathryn L.; Palmieri, Giuseppe; Porcu, Eleonora; Rivadeneira, Fernando; Rose, Lynda M.; Splansky, Greta L.; Stolk, Lisette; Uitterlinden, André G.; Chanock, Stephen J.; Crisponi, Laura; Demerath, Ellen W.; Murabito, Joanne M.; Ridker, Paul M.; Stricker, Bruno H.; Hunter, David J.

    In: Breast Cancer Research, Vol. 14, No. 2, R54, 20.03.2012.

    Research output: Contribution to journalArticle

    He, C, Chasman, DI, Dreyfus, J, Hwang, SJ, Ruiter, R, Sanna, S, Buring, JE, Fernández-Rhodes, L, Franceschini, N, Hankinson, SE, Hofman, A, Lunetta, KL, Palmieri, G, Porcu, E, Rivadeneira, F, Rose, LM, Splansky, GL, Stolk, L, Uitterlinden, AG, Chanock, SJ, Crisponi, L, Demerath, EW, Murabito, JM, Ridker, PM, Stricker, BH & Hunter, DJ 2012, 'Reproductive aging-associated common genetic variants and the risk of breast cancer', Breast Cancer Research, vol. 14, no. 2, R54. https://doi.org/10.1186/bcr3155
    He C, Chasman DI, Dreyfus J, Hwang SJ, Ruiter R, Sanna S et al. Reproductive aging-associated common genetic variants and the risk of breast cancer. Breast Cancer Research. 2012 Mar 20;14(2). R54. https://doi.org/10.1186/bcr3155
    He, Chunyan ; Chasman, Daniel I. ; Dreyfus, Jill ; Hwang, Shih Jen ; Ruiter, Rikje ; Sanna, Serena ; Buring, Julie E. ; Fernández-Rhodes, Lindsay ; Franceschini, Nora ; Hankinson, Susan E. ; Hofman, Albert ; Lunetta, Kathryn L. ; Palmieri, Giuseppe ; Porcu, Eleonora ; Rivadeneira, Fernando ; Rose, Lynda M. ; Splansky, Greta L. ; Stolk, Lisette ; Uitterlinden, André G. ; Chanock, Stephen J. ; Crisponi, Laura ; Demerath, Ellen W. ; Murabito, Joanne M. ; Ridker, Paul M. ; Stricker, Bruno H. ; Hunter, David J. / Reproductive aging-associated common genetic variants and the risk of breast cancer. In: Breast Cancer Research. 2012 ; Vol. 14, No. 2.
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    title = "Reproductive aging-associated common genetic variants and the risk of breast cancer",
    abstract = "Introduction: A younger age at menarche and an older age at menopause are well established risk factors for breast cancer. Recent genome-wide association studies have identified several novel genetic loci associated with these two traits. However, the association between these loci and breast cancer risk is unknown.Methods: In this study, we investigated 19 and 17 newly identified single nucleotide polymorphisms (SNPs) from the ReproGen Consortium that have been associated with age at menarche and age at natural menopause, respectively, and assessed their associations with breast cancer risk in 6 population-based studies among up to 3,683 breast cancer cases and 34,174 controls in white women of European ancestry. In addition, we used these SNPs to calculate genetic risk scores (GRSs) based on their associations with each trait.Results: After adjusting for age and potential population stratification, two age at menarche associated SNPs (rs1079866 and rs7821178) and one age at natural menopause associated SNP (rs2517388) were associated with breast cancer risk (p values, 0.003, 0.009 and 0.023, respectively). The odds ratios for breast cancer corresponding to per-risk-allele were 1.14 (95{\%} CI, 1.05 to 1.24), 1.08 (95{\%} CI, 1.02 to 1.15) and 1.10 (95{\%} CI, 1.01 to 1.20), respectively, and were in the direction predicted by their associations with age at menarche or age at natural menopause. These associations did not appear to be attenuated by further controlling for self-reported age at menarche, age at natural menopause, or known breast cancer susceptibility loci. Although we did not observe a statistically significant association between any GRS for reproductive aging and breast cancer risk, the 4 th and 5 th highest quintiles of the younger age at menarche GRS had odds ratios of 1.14 (95{\%} CI, 1.01 to 1.28) and 1.13 (95{\%} CI, 1.00 to 1.27), respectively, compared to the lowest quintile.Conclusions: Our study suggests that three genetic variants, independent of their associations with age at menarche or age at natural menopause, were associated with breast cancer risk and may contribute modestly to breast cancer risk prediction; however, the combination of the 19 age at menarche or the 17 age at natural menopause associated SNPs did not appear to be useful for identifying a high risk subgroup for breast cancer.",
    author = "Chunyan He and Chasman, {Daniel I.} and Jill Dreyfus and Hwang, {Shih Jen} and Rikje Ruiter and Serena Sanna and Buring, {Julie E.} and Lindsay Fern{\'a}ndez-Rhodes and Nora Franceschini and Hankinson, {Susan E.} and Albert Hofman and Lunetta, {Kathryn L.} and Giuseppe Palmieri and Eleonora Porcu and Fernando Rivadeneira and Rose, {Lynda M.} and Splansky, {Greta L.} and Lisette Stolk and Uitterlinden, {Andr{\'e} G.} and Chanock, {Stephen J.} and Laura Crisponi and Demerath, {Ellen W.} and Murabito, {Joanne M.} and Ridker, {Paul M.} and Stricker, {Bruno H.} and Hunter, {David J.}",
    year = "2012",
    month = "3",
    day = "20",
    doi = "10.1186/bcr3155",
    language = "English",
    volume = "14",
    journal = "Breast Cancer Research",
    issn = "1465-5411",
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    TY - JOUR

    T1 - Reproductive aging-associated common genetic variants and the risk of breast cancer

    AU - He, Chunyan

    AU - Chasman, Daniel I.

    AU - Dreyfus, Jill

    AU - Hwang, Shih Jen

    AU - Ruiter, Rikje

    AU - Sanna, Serena

    AU - Buring, Julie E.

    AU - Fernández-Rhodes, Lindsay

    AU - Franceschini, Nora

    AU - Hankinson, Susan E.

    AU - Hofman, Albert

    AU - Lunetta, Kathryn L.

    AU - Palmieri, Giuseppe

    AU - Porcu, Eleonora

    AU - Rivadeneira, Fernando

    AU - Rose, Lynda M.

    AU - Splansky, Greta L.

    AU - Stolk, Lisette

    AU - Uitterlinden, André G.

    AU - Chanock, Stephen J.

    AU - Crisponi, Laura

    AU - Demerath, Ellen W.

    AU - Murabito, Joanne M.

    AU - Ridker, Paul M.

    AU - Stricker, Bruno H.

    AU - Hunter, David J.

    PY - 2012/3/20

    Y1 - 2012/3/20

    N2 - Introduction: A younger age at menarche and an older age at menopause are well established risk factors for breast cancer. Recent genome-wide association studies have identified several novel genetic loci associated with these two traits. However, the association between these loci and breast cancer risk is unknown.Methods: In this study, we investigated 19 and 17 newly identified single nucleotide polymorphisms (SNPs) from the ReproGen Consortium that have been associated with age at menarche and age at natural menopause, respectively, and assessed their associations with breast cancer risk in 6 population-based studies among up to 3,683 breast cancer cases and 34,174 controls in white women of European ancestry. In addition, we used these SNPs to calculate genetic risk scores (GRSs) based on their associations with each trait.Results: After adjusting for age and potential population stratification, two age at menarche associated SNPs (rs1079866 and rs7821178) and one age at natural menopause associated SNP (rs2517388) were associated with breast cancer risk (p values, 0.003, 0.009 and 0.023, respectively). The odds ratios for breast cancer corresponding to per-risk-allele were 1.14 (95% CI, 1.05 to 1.24), 1.08 (95% CI, 1.02 to 1.15) and 1.10 (95% CI, 1.01 to 1.20), respectively, and were in the direction predicted by their associations with age at menarche or age at natural menopause. These associations did not appear to be attenuated by further controlling for self-reported age at menarche, age at natural menopause, or known breast cancer susceptibility loci. Although we did not observe a statistically significant association between any GRS for reproductive aging and breast cancer risk, the 4 th and 5 th highest quintiles of the younger age at menarche GRS had odds ratios of 1.14 (95% CI, 1.01 to 1.28) and 1.13 (95% CI, 1.00 to 1.27), respectively, compared to the lowest quintile.Conclusions: Our study suggests that three genetic variants, independent of their associations with age at menarche or age at natural menopause, were associated with breast cancer risk and may contribute modestly to breast cancer risk prediction; however, the combination of the 19 age at menarche or the 17 age at natural menopause associated SNPs did not appear to be useful for identifying a high risk subgroup for breast cancer.

    AB - Introduction: A younger age at menarche and an older age at menopause are well established risk factors for breast cancer. Recent genome-wide association studies have identified several novel genetic loci associated with these two traits. However, the association between these loci and breast cancer risk is unknown.Methods: In this study, we investigated 19 and 17 newly identified single nucleotide polymorphisms (SNPs) from the ReproGen Consortium that have been associated with age at menarche and age at natural menopause, respectively, and assessed their associations with breast cancer risk in 6 population-based studies among up to 3,683 breast cancer cases and 34,174 controls in white women of European ancestry. In addition, we used these SNPs to calculate genetic risk scores (GRSs) based on their associations with each trait.Results: After adjusting for age and potential population stratification, two age at menarche associated SNPs (rs1079866 and rs7821178) and one age at natural menopause associated SNP (rs2517388) were associated with breast cancer risk (p values, 0.003, 0.009 and 0.023, respectively). The odds ratios for breast cancer corresponding to per-risk-allele were 1.14 (95% CI, 1.05 to 1.24), 1.08 (95% CI, 1.02 to 1.15) and 1.10 (95% CI, 1.01 to 1.20), respectively, and were in the direction predicted by their associations with age at menarche or age at natural menopause. These associations did not appear to be attenuated by further controlling for self-reported age at menarche, age at natural menopause, or known breast cancer susceptibility loci. Although we did not observe a statistically significant association between any GRS for reproductive aging and breast cancer risk, the 4 th and 5 th highest quintiles of the younger age at menarche GRS had odds ratios of 1.14 (95% CI, 1.01 to 1.28) and 1.13 (95% CI, 1.00 to 1.27), respectively, compared to the lowest quintile.Conclusions: Our study suggests that three genetic variants, independent of their associations with age at menarche or age at natural menopause, were associated with breast cancer risk and may contribute modestly to breast cancer risk prediction; however, the combination of the 19 age at menarche or the 17 age at natural menopause associated SNPs did not appear to be useful for identifying a high risk subgroup for breast cancer.

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