The genetic interplay between body mass index, breast size and breast cancer risk: a Mendelian randomization analysis.
Breast size
LDSC regression
Mendelian randomization
body mass index
breast cancer risk
genetic correlation
genetic epidemiology
Journal
International journal of epidemiology
ISSN: 1464-3685
Titre abrégé: Int J Epidemiol
Pays: England
ID NLM: 7802871
Informations de publication
Date de publication:
01 06 2019
01 06 2019
Historique:
accepted:
31
05
2019
pubmed:
28
6
2019
medline:
2
4
2020
entrez:
28
6
2019
Statut:
ppublish
Résumé
Evidence linking breast size to breast cancer risk has been inconsistent, and its interpretation is often hampered by confounding factors such as body mass index (BMI). Here, we used linkage disequilibrium score regression and two-sample Mendelian randomization (MR) to examine the genetic associations between BMI, breast size and breast cancer risk. Summary-level genotype data from 23andMe, Inc (breast size, n = 33 790), the Breast Cancer Association Consortium (breast cancer risk, n = 228 951) and the Genetic Investigation of ANthropometric Traits (BMI, n = 183 507) were used for our analyses. In assessing causal relationships, four complementary MR techniques [inverse variance weighted (IVW), weighted median, weighted mode and MR-Egger regression] were used to test the robustness of the results. The genetic correlation (rg) estimated between BMI and breast size was high (rg = 0.50, P = 3.89x10-43). All MR methods provided consistent evidence that higher genetically predicted BMI was associated with larger breast size [odds ratio (ORIVW): 2.06 (1.80-2.35), P = 1.38x10-26] and lower overall breast cancer risk [ORIVW: 0.81 (0.74-0.89), P = 9.44x10-6]. No evidence of a relationship between genetically predicted breast size and breast cancer risk was found except when using the weighted median and weighted mode methods, and only with oestrogen receptor (ER)-negative risk. There was no evidence of reverse causality in any of the analyses conducted (P > 0.050). Our findings indicate a potential positive causal association between BMI and breast size and a potential negative causal association between BMI and breast cancer risk. We found no clear evidence for a direct relationship between breast size and breast cancer risk.
Sections du résumé
BACKGROUND
Evidence linking breast size to breast cancer risk has been inconsistent, and its interpretation is often hampered by confounding factors such as body mass index (BMI). Here, we used linkage disequilibrium score regression and two-sample Mendelian randomization (MR) to examine the genetic associations between BMI, breast size and breast cancer risk.
METHODS
Summary-level genotype data from 23andMe, Inc (breast size, n = 33 790), the Breast Cancer Association Consortium (breast cancer risk, n = 228 951) and the Genetic Investigation of ANthropometric Traits (BMI, n = 183 507) were used for our analyses. In assessing causal relationships, four complementary MR techniques [inverse variance weighted (IVW), weighted median, weighted mode and MR-Egger regression] were used to test the robustness of the results.
RESULTS
The genetic correlation (rg) estimated between BMI and breast size was high (rg = 0.50, P = 3.89x10-43). All MR methods provided consistent evidence that higher genetically predicted BMI was associated with larger breast size [odds ratio (ORIVW): 2.06 (1.80-2.35), P = 1.38x10-26] and lower overall breast cancer risk [ORIVW: 0.81 (0.74-0.89), P = 9.44x10-6]. No evidence of a relationship between genetically predicted breast size and breast cancer risk was found except when using the weighted median and weighted mode methods, and only with oestrogen receptor (ER)-negative risk. There was no evidence of reverse causality in any of the analyses conducted (P > 0.050).
CONCLUSION
Our findings indicate a potential positive causal association between BMI and breast size and a potential negative causal association between BMI and breast cancer risk. We found no clear evidence for a direct relationship between breast size and breast cancer risk.
Identifiants
pubmed: 31243447
pii: 5523691
doi: 10.1093/ije/dyz124
pmc: PMC6659372
doi:
Substances chimiques
Receptors, Estrogen
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
781-794Subventions
Organisme : CIHR
Pays : Canada
Organisme : NCI NIH HHS
ID : U19 CA148065
Pays : United States
Organisme : Cancer Research UK
ID : C1287/A10118
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C1287/A16563
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C1287/A10710
Pays : United Kingdom
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of the International Epidemiological Association.
Références
Nat Genet. 2013 Apr;45(4):353-61, 361e1-2
pubmed: 23535729
J Natl Cancer Inst. 1996 Jun 5;88(11):756-8
pubmed: 8637031
JAMA Oncol. 2018 Nov 1;4(11):e181771
pubmed: 29931120
Nat Commun. 2014 Oct 24;5:5303
pubmed: 25342443
Nat Genet. 2016 Jul;48(7):709-17
pubmed: 27182965
PLoS Med. 2016 Aug 23;13(8):e1002105
pubmed: 27551723
Sci Rep. 2018 Jan 19;8(1):1201
pubmed: 29352164
J Plast Reconstr Aesthet Surg. 2014 Dec;67(12):1615-23
pubmed: 25456291
Eur J Cancer. 1991;27(2):131-5
pubmed: 1827274
Nature. 2017 Nov 2;551(7678):92-94
pubmed: 29059683
Int J Epidemiol. 2016 Jun;45(3):896-908
pubmed: 27427428
Nature. 2015 Feb 12;518(7538):197-206
pubmed: 25673413
Genet Epidemiol. 2013 Nov;37(7):658-65
pubmed: 24114802
Int J Cancer. 2006 Apr 15;118(8):2031-4
pubmed: 16284954
Ergonomics. 2017 Nov;60(11):1576-1585
pubmed: 28532249
Genet Epidemiol. 2016 May;40(4):304-14
pubmed: 27061298
PLoS Med. 2017 Jun 13;14(6):e1002314
pubmed: 28609445
Am J Obstet Gynecol. 1994 Jul;171(1):171-7
pubmed: 8030695
Eur J Cancer Prev. 1996 Oct;5(5):337-42
pubmed: 8972252
Am J Hum Biol. 2012 Mar-Apr;24(2):158-64
pubmed: 22287066
BMC Med Genet. 2012 Jun 30;13:53
pubmed: 22747683
Cancer Manag Res. 2018 Jan 18;10:143-151
pubmed: 29403312
Twin Res Hum Genet. 2010 Oct;13(5):450-4
pubmed: 20874466
Lancet. 2014 Aug 30;384(9945):755-65
pubmed: 25129328
Int J Epidemiol. 2017 Dec 1;46(6):1985-1998
pubmed: 29040600
Nat Genet. 2015 Apr;47(4):373-80
pubmed: 25751625
Nat Genet. 2015 Nov;47(11):1236-41
pubmed: 26414676
Elife. 2018 May 30;7:
pubmed: 29846171
Front Cardiovasc Med. 2018 May 28;5:51
pubmed: 29892602
Lancet. 2008 Feb 16;371(9612):569-78
pubmed: 18280327
Int J Obes Relat Metab Disord. 1997 Jun;21(6):432-8
pubmed: 9192225
Cancer Causes Control. 1999 Apr;10(2):115-8
pubmed: 10231159
Int J Epidemiol. 2015 Apr;44(2):512-25
pubmed: 26050253
Nat Genet. 2018 May;50(5):693-698
pubmed: 29686387
J Natl Cancer Inst. 2014 May 10;106(5):
pubmed: 24816206
Int J Cancer. 2009 Feb 1;124(3):698-712
pubmed: 18988226
N Engl J Med. 2007 Jan 18;356(3):227-36
pubmed: 17229950
Breast Cancer Res Treat. 2010 Oct;123(3):641-9
pubmed: 20711809