000			04073 am a22003493u 4500
042			_adc
100	1	0	_aHao, Yu _eauthor _92878
700	1	0	_aXiao, Jinyu _eauthor _92879
700	1	0	_aLiang, Yu _eauthor _92880
700	1	0	_aWu, Xueyao _eauthor _92881
700	1	0	_aXiao, Chenghan _eauthor _92882
700	1	0	_aZhang, Li _eauthor _92883
700	1	0	_aWang, Nan _eauthor _92884
700	1	0	_aZhao, Xunying _eauthor _92885
700	1	0	_aZhang, Haoyu _eauthor _92886
700	1	0	_aBurgess, Stephen _eauthor
700	1	0	_aKraft, Peter _eauthor _92887
700	1	0	_aLi, Jiayuan _eauthor _92888
700	1	0	_aJiang, Xia _eauthor _92889
245	0	0	_aReassessing the causal role of obesity in breast cancer susceptibility - a comprehensive multivariable Mendelian randomization investigating the distribution and timing of exposure
260			_c2022-07-15.
500			_a/pmc/articles/PMC7614158/
500			_a/pubmed/35848946
520			_aBACKGROUND: Previous Mendelian randomization (MR) studies on obesity and breast cancer (BC) risk adopted a small number of instrumental variables and mainly focused on crude total causal effects. We aim to investigate the independent causal effect of obesity-related exposures on breast cancer susceptibility, taking into consideration the distribution of fat, covering both early and late life. METHODS: Using an enlarged set of female-specific genetic variants associated with adult general (body mass index, BMI) and abdominal obesity (waist-to-hip ratio with and without adjusted for BMI, WHR and WHR(adj)BMI) as well as using sex-combined genetic variants of childhood obesity (childhood BMI), we performed a two-sample univariable MR (UVMR) to re-evaluate the total effect of each obesity exposure on BC overall (N(case) = 133,384, N(control) = 113,789). We further looked into its estrogen receptor (ER)-defined subtypes (N(ER+) = 69,501, N(ER−) = 21,468, N(control) = 105,974). Multivariable MR (MVMR) was applied to estimate the independent causal effect of each obesity-related trait on BC taking into account confounders as well as to investigate the independent effect of adult and childhood obesity taking into account their inter-correlation. RESULTS: In UVMR, significant protective effects of both adult BMI (OR = 0.89, 95%CI = 0.83-0.96) and childhood BMI (OR = 0.78, 95%CI = 0.70-0.87) were observed for BC overall. Comparable effects were found in ER+ and ER− subtypes. Similarly, genetically predicted adult WHR was also associated with a significantly decreased risk of BC overall (OR = 0.88, 95%CI = 0.80-0.98), restricting to ER+ subtype (OR = 0.88, 95%CI = 0.80-0.98). Conditional on childhood BMI, the effect of adult general obesity on BC overall attenuated to null (OR = 1.00, 95%CI = 0.90-1.10), while the effect of adult abdominal obesity attenuated to some extent (WHR: OR = 0.90, 95%CI = 0.82-0.98; WHR(adj)BMI: OR = 0.92, 95%CI = 0.86-0.99). On the contrary, an independent significant protective effect of childhood BMI was observed in BC overall, irrespective of adult measures (adjusted for adult BMI: OR = 0.86, 95%CI = 0.77-0.95; adjusted for adult WHR: OR = 0.86, 95%CI = 0.78-0.95; adjusted for adult WHR(adj)BMI: OR = 0.82, 95%CI = 0.75-0.90). CONCLUSIONS: While successfully replicating the inverse causal relationship between obesity-related exposures and risk of BC, our study demonstrated the protective effect of adult obesity to be largely (adult BMI) or partly (adult WHR or WHR(adj)BMI) attributed to childhood obesity. Our findings highlight an independent role of childhood obesity in affecting the risk of BC as well as the importance of taking into account the complex interplay underlying correlated exposures.
540			_a
540			_ahttps://creativecommons.org/licenses/by/4.0/This work is licensed under a CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/) International license.
546			_aen
690			_aArticle
655	7		_aText _2local
786	0		_nInt J Epidemiol
856	4	1	_uhttp://dx.doi.org/10.1093/ije/dyac143 _zConnect to this object online.
999			_c2132 _d2132