Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis

Dwek, M. 2019. Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis . International Journal of Epidemiology. 48 (3), pp. 795-806. doi:10.1093/ije/dyy201

TitleAssociations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis
TypeJournal article
AuthorsDwek, M.
Abstract

Background

In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear.

Methods

We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium.

Results

All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p  =  5.09  ×  10–4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p  =  4.02  ×  10–4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p  =  5.05  ×  10–19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p  =  9.22  ×  10–6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer.

Conclusions

We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.

KeywordsKeywords: Breast cancer, insulin, glucose, obesity, genetics, Mendelian randomization analysis
JournalInternational Journal of Epidemiology
Journal citation48 (3), pp. 795-806
ISSN0300-5771
Year2019
PublisherOxford University Press
Digital Object Identifier (DOI)doi:10.1093/ije/dyy201
Web address (URL)https://academic.oup.com/ije/advance-article/doi/10.1093/ije/dyy201/5113258?guestAccessKey=3a40190f-c24f-4334-b8cf-e95f3246cfc4
Publication dates
Published online01 Oct 2018
Published in printJun 2019

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Abstract B76 - An overview of the DietCompLyf study - a multicentre UK study to evaluate the role of diet, lifestyle and complementary medicine use on breast cancer recurrence
Swann, R., Perkins, A., Dahya, P., Woodside, J., Dutton, S., Robertson, C.E., Velentzis, L.S., Leathem, A. and Dwek, M. 2011. Abstract B76 - An overview of the DietCompLyf study - a multicentre UK study to evaluate the role of diet, lifestyle and complementary medicine use on breast cancer recurrence. National Cancer Research Institute (NCRI) Cancer Conference 2011. BT Convention Centre, Liverpool, UK 06 - 09 Nov 2011

Separation and characterization of different isoform populations of PSA in seminal fluid
Lines, A., Clarke, O., Dwek, M., Packer, S. and Edwards, R. 2011. Separation and characterization of different isoform populations of PSA in seminal fluid. American Association for Clinical Chemists Meeting. Atlanta, Georgia 15 - 19 Jul 2011

Abstract LB14 - Lectin microarray profilling of metastatic breast cancers
Fry, S., Afrough, B., Lomax-Browne, H., Timms, J.F., Velentzis, L.S. and Dwek, M. 2011. Abstract LB14 - Lectin microarray profilling of metastatic breast cancers. National Cancer Research Institute (NCRI) Cancer Conference 2011. BT Convention Centre, Liverpool, UK 06 - 09 Nov 2011

Breast cancer invasion is mediated by beta-N-acetylglucosaminidase (beta-NAG) and associated with a dysregulation in the secretory pathway of cancer cells
Ramessur, K.T., Greenwell, P., Nash, R. and Dwek, M. 2010. Breast cancer invasion is mediated by beta-N-acetylglucosaminidase (beta-NAG) and associated with a dysregulation in the secretory pathway of cancer cells. British Journal of Biomedical Science. 67 (4), pp. 189-196.

Revealing real-time cell surface interaction analysis: a focus on lectin - cell glycan interactions
Dwek, M. 2010. Revealing real-time cell surface interaction analysis: a focus on lectin - cell glycan interactions. Discovery-Summit. Majestic Barrière Hotel, Cannes, France 22nd – 24th March 2010

Revealing real-time cell surface interaction analysis: a focus on lectin - cell glycan interactions
Dwek, M. 2010. Revealing real-time cell surface interaction analysis: a focus on lectin - cell glycan interactions. Informa Life Sciences 6th Annual Next Generation Protein Therapeutics. Sheraton Brussels Hotel, Belgium 28th – 29th September 2010

GalNAc-recognition by lectins for cancer prognostication
Dwek, M. 2010. GalNAc-recognition by lectins for cancer prognostication. 105th Annual Meeting of the Anatomische Gesellschaft. Hamburg, Germany 29th March 2010

An evaluation of breast cancer cell line sialyltransferase expression levels and assessment of possible correlation with HPA lectin binding profiles
Blaszczak, E., Greenwell, G. and Dwek, M. 2010. An evaluation of breast cancer cell line sialyltransferase expression levels and assessment of possible correlation with HPA lectin binding profiles. Horizons in Molecular Biology: International PhD Student Symposium. Göttingen, Germany 27 - 30 Sep 2010

A sensitive assay to measure biomarker glycosylation demonstrates increased fucosylation of prostate specific antigen (PSA) in patients with prostate cancer compared with benign prostatic hyperplasia
Dwek, M., Jenks, A. and Leathem, A. 2010. A sensitive assay to measure biomarker glycosylation demonstrates increased fucosylation of prostate specific antigen (PSA) in patients with prostate cancer compared with benign prostatic hyperplasia. Clinica Chimica Acta. 411 (23-24), pp. 1935-1939. doi:10.1016/j.cca.2010.08.009

Cancer prognostication using a recombinant form of the lectin from Helix pomatia agglutinin
Dwek, M., Markiv, A. and Odell, M. 2009. Cancer prognostication using a recombinant form of the lectin from Helix pomatia agglutinin. Glycobiology. 19 (11), p. 1318. doi:10.1093/glycob/cwp135

UEA-1 enables discrimination between prostate specific antigen from patients with prostate cancer and benign prostatic hyperplasia
Dwek, M., Jenks, A. and Leathem, A. 2009. UEA-1 enables discrimination between prostate specific antigen from patients with prostate cancer and benign prostatic hyperplasia. Glycobiology. 19 (11), p. 1318. doi:10.1093/glycob/cwp135

Proteome analysis of metastatic colorectal cancer cells recognized by the lectin Helix pomatia agglutinin (HPA)
Saint-Guirons, J., Zeqiraj, E., Schumacher, U., Greenwell, P. and Dwek, M. 2007. Proteome analysis of metastatic colorectal cancer cells recognized by the lectin Helix pomatia agglutinin (HPA). Proteomics. 7 (22), pp. 4082-4089. doi:10.1002/pmic.200700434

Colorectal cancer – a sticky problem
Dwek, M. 2007. Colorectal cancer – a sticky problem. Oncology News. 2 (3), pp. 19-21.

Identification and elimination of false-positives in an ELISA-based system for qualitative assessment of glycoconjugate binding using a selection of plant lectins
Afrough, B., Dwek, M. and Greenwell, P. 2007. Identification and elimination of false-positives in an ELISA-based system for qualitative assessment of glycoconjugate binding using a selection of plant lectins. BioTechniques. 43 (4), pp. 458-462.

Predictors of axillary lymph node metastasis in breast cancer: a systematic review
Patani, N.R., Dwek, M. and Douek, M. 2007. Predictors of axillary lymph node metastasis in breast cancer: a systematic review. European Journal of Surgical Oncology. 33 (4), pp. 409-419. doi:10.1016/j.ejso.2006.09.003

A proteomic approach to identify the integrins α 6 and α V as HPA binding partners in the metastatic colorectal cancer cell line HT29
Saint-Guirons, J., Zeqiraj, E., Greenwell, P. and Dwek, M. 2006. A proteomic approach to identify the integrins α 6 and α V as HPA binding partners in the metastatic colorectal cancer cell line HT29. Molecular and Cellular Proteomics. 5 (10 (supplement)), p. S148.

Confocal microscopy for the identification of glycosylation changes associated with metastatic colorectal cancer
Zeqiraj, E., Saint-Guirons, J., Kerrigan, M.J.P. and Dwek, M. 2005. Confocal microscopy for the identification of glycosylation changes associated with metastatic colorectal cancer. The Molecular Biology of Colorectal Cancer. UBHT Education Centre, Bristol, UK 10 - 11 Mar 2005

The metabolic role of methymalonyl CoA mutase in Escherichia coli
Kannan, S.M., Dwek, M., Bucke, C. and Roy, I. 2005. The metabolic role of methymalonyl CoA mutase in Escherichia coli. Proceedings of Viteomics: structure and function of vitamins and cofactors. Cambridge, UK 2005

Structure/function of N-glycans
Dwek, M. 2005. Structure/function of N-glycans. in: Redei, G.P. (ed.) Encyclopedic dictionary of genetics, genomics, and proteomics. 2nd edition Hoboken, USA Wiley.

Glycoproteomics
Dwek, M. 2005. Glycoproteomics. in: Redei, G.P. (ed.) Encyclopedic dictionary of genetics, genomics, and proteomics. 2nd edition Hoboken, USA Wiley.

Breast cancer proteomics using 2-dimensional gel electrophoresis
Rawlings, S. and Dwek, M. 2004. Breast cancer proteomics using 2-dimensional gel electrophoresis. in: Brooks, S. and Harris, A. (ed.) Breast cancer research protocols New Jersey, USA Humana Press.

Harnessing changes in cellular glycosylation in new cancer treatment strategies
Dwek, M. and Brooks, S. 2004. Harnessing changes in cellular glycosylation in new cancer treatment strategies. Current Cancer Drug Targets. 4 (5), pp. 425-442.

Proteome analysis enables separate clustering of normal breast, benign breast and breast cancer tissues
Dwek, M. and Alaiya, A.A. 2003. Proteome analysis enables separate clustering of normal breast, benign breast and breast cancer tissues. British Journal of Cancer. 89 (2), pp. 305-307. doi:10.1038/sj.bjc.6601008

Glycoproteomics
Dwek, M. and Mills, P. 2003. Glycoproteomics. in: Redei, G.P. (ed.) Encyclopedic dictionary of genetics, genomics, and proteomics Chichester, UK Wiley.

Structure/function of N-glycans
Brooks, S. and Dwek, M. 2003. Structure/function of N-glycans. in: Redei, G.P. (ed.) Encyclopedic dictionary of genetics, genomics, and proteomics Chichester, UK Wiley.

Use of proteomic methodology for the characterization of human milk fat globular membrane proteins
Charlwood, J., Hanrahan, S., Tyldesley, R., Langridge, J., Dwek, M. and Camilleri, P. 2002. Use of proteomic methodology for the characterization of human milk fat globular membrane proteins. Analytical Biochemistry. 301 (2), pp. 314-324. doi:10.1006/abio.2001.5498

Current perspectives in cancer proteomics
Dwek, M. and Rawlings, S. 2002. Current perspectives in cancer proteomics. Molecular Biotechnology. 22 (2), pp. 139-152.

Functional and molecular glycobiology
Brooks, S., Dwek, M. and Schumacher, U. 2002. Functional and molecular glycobiology. Oxford, UK BIOS Scientific.

Proteome and glycosylation mapping identifies post-translational modifications associated with aggressive breast cancer
Dwek, M., Ross, H. and Leathem, A. 2001. Proteome and glycosylation mapping identifies post-translational modifications associated with aggressive breast cancer. Proteomics. 1 (6), pp. 756-63. doi:10.1002/1615-9861(200106)1:6<756::AID-PROT756>3.0.CO;2-X

Helix pomatia agglutinin lectin-binding oligosaccharides of aggressive breast cancer
Dwek, M., Ross, H., Streets, A., Brooks, S., Adam, E., Titcomb, A., Woodside, J., Schumacher, U. and Leathem, A. 2001. Helix pomatia agglutinin lectin-binding oligosaccharides of aggressive breast cancer. International Journal of Cancer. 95 (2), pp. 79-85. doi:10.1002/1097-0215(20010320)95:2<79::AID-IJC1014>3.0.CO;2-E

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