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Estimating the effect of lipids on IGF axis and subsequent breast cancer risk

By Vanessa Y Tan, Caroline J. Bull, Kalina M Biernacka, Alexander Teumer, Laura Corbin, Tom Dudding, Eleanor Sanderson, Qibin Qi, Robert Kaplan, Jerome Rotter, Nele Friedrich, Uwe Völker, Julia Mayerle, Claire M Perks, Jeffrey MP Holly, NJ Timpson

Posted 07 Jun 2020
medRxiv DOI: 10.1101/2020.06.04.20122630

Circulating lipids have been associated with breast cancer (BCa). This association may, in part, be due to an effect of lipids on insulin-like growth factors (IGFs), which have been reliably associated with BCa. In two-sample Mendelian randomization (MR) analyses, we found that low density lipoprotein (LDL-C) was associated with IGFBP-3 (beta: 0.08 SD; 95%CI: 0.02, 0.15; p=0.01, per SD increase in LDL-C) and IGFBP-3 was associated with postmenopausal BCa (OR: 1.09; 95%CI: 1.00, 1.19; p=0.05, per SD increase in IGFBP-3). We also found that triglycerides were associated with IGF-I (beta: -0.13 SD; 95%CI: -0.22, -0.03, per SD increase in triglycerides) and that IGF-I was associated with overall BCa (OR: 1.10; 95%CI: 1.02, 1.18, per SD increase in IGF-I). Taken together, these results suggest that IGFBP-3 may be a potential causal step between LDL-C and postmenopausal BCa and IGF-I a potential causal for triglycerides. Our two-step MR results build on evidence linking circulating lipids and IGFs with BCa, however, multivariable MR analyses are currently unable to support this relationship due to weak instruments.

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