Kelsey E. Johnson , Katherine M. Siewert , Derek Klarin, Scott M. Damrauer, Kyong-Mi Chang, Philip S. Tsao, Themistocles L. Assimes, Kara N. Maxwell, Benjamin F. Voight
A number of epidemiological and genetic studies have attempted to determine whether levels of circulating lipids are associated with risks of various cancers, including breast cancer (BC). However, it remains unclear whether a causal relationship exists between lipids and BC. If alteration of lipid levels also reduced risk of BC, this could present a target for disease prevention. This study aimed to assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein, HDL; low-density lipoprotein, LDL; triglycerides, TGs) with risk for BC using Mendelian randomization (MR).
Breast cancer (BC) is the second leading cause of death for women, motivating the need for a better understanding of its etiology and more effective treatments . Cholesterol is a known risk factor for multiple diseases that have reported associations with BC, including obesity, heart disease, and diabetes . However, it is unknown whether cholesterol plays a causal role in BC susceptibility.
Lipid GWAS summary statistics were obtained from the Million Veteran Program (MVP) (up to 215,551 European individuals)  and the Global Lipids Genetics Consortium (GLGC) (up to 188,577 genotyped individuals) . As additional exposures in multivariable MR analyses, we used BMI summary statistics from a meta-analysis of GWASs in up to 795,640 individuals and age at menarche summary statistics from a meta-analysis of GWASs in up to 329,345 women of European ancestry [17,23]. GWAS summary statistics from 122,977 BC cases and 105,974 controls were obtained from the Breast Cancer Association Consortium (BCAC) . The MVP received ethical and study protocol approval from the Veteran Affair Central Institutional Review Board in accordance with the principles outlined in the Declaration of Helsinki, and written consent was obtained from all participants. For the Willer and colleagues  and BCAC  data sets, we refer the reader to the primary GWAS manuscripts and their supplementary material for details on consent protocols for each of their respective cohorts. More details on these cohorts are in the S1 Text.
Using MR, we provide evidence that genetically elevated HDL and LDL levels are associated with increased risk for BC, supporting a causal hypothesis. Previous meta-analyses of observational studies of BC risk and lipids reported a negative association with HDL and no relationship with LDL [4,5], whereas individual studies have reported a positive relationship with HDL  or no relationship with HDL or LDL [45,46]. Our analyses help clarify these mixed results and infer a direction of effect, which is not possible in observational studies because of potential reverse causation. Furthermore, we find evidence of genome-wide genetic correlation between some lipid traits and BC and local genetic correlation at the ABO locus. Although some studies have found an association between blood group and BC risk , haplotype patterns indicate that ABO gene expression, not blood group, may be the causal mechanism . However, because of the pleiotropic nature of the ABO locus, it is unclear whether the BC association is caused by the lipid associations .
Citation: Johnson KE, Siewert KM, Klarin D, Damrauer SM, the VA Million Veteran Program, Chang K-M, et al. (2020) The relationship between circulating lipids and breast cancer risk: A Mendelian randomization study. PLoS Med 17(9): e1003302. https://doi.org/10.1371/journal.pmed.1003302
Academic Editor: Cosetta Minelli, Imperial College London, UNITED KINGDOM
Received: October 18, 2019; Accepted: August 10, 2020; Published: September 11, 2020
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Data Availability: The summary statistics for the MR instrumental variables are available in S1, S2 and S3 Tables. Genome-wide summary statistics are available from the Global Lipids Genetics Consortium (GLGC) at http://csg.sph.umich.edu/abecasis/public/lipids2013/ and the Breast Cancer Association Consortium (BCAC) at http://bcac.ccge.medschl.cam.ac.uk/bcacdata/oncoarray/oncoarray-and-combined-summary-result/gwas-summary-results-breast-cancer-risk-2017/. The Million Veterans Program (MVP) lipid GWAS results are available in dbGAP. The dbGAP accession number for MVP overall is phs001672.v3.p1. The accession numbers for the European-specific MVP data are TC: pha004834.1, LDL: pha004831.1, HDL: pha004828.1, and TG: pha004837.1. BMI summary statistics from Yengo et al. are available at https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files#2018_GIANT_and_UK_BioBank_Meta-analysis. Age of menarche summary statistics from Day et al are available at https://www.reprogen.org/data_download.html. The UK10K data utilized in the study cannot be shared publicly (per data use access agreement) but are available by Institutional Data Access request for researchers who meet the criteria for access at https://www.sanger.ac.uk/legal/DAA/MasterController.
Funding: This work was supported by the US National Institutes of Health (R01 DK101478 and HG010067 for BFV, T32 GM008216 for KEJ, T32 HG000046 for KMS) and a Linda Pechenik Montague Investigator award (to BFV). This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration and was supported by award #MVP000. This research was also supported by two additional Department of Veterans Affairs awards (I01-BX003362 [PST/KC], IK2-CX001780 [Damrauer]). This publication does not represent the views of the Department of Veterans Affairs or the United States Government. This study makes use of data generated by the UK10K Consortium, derived from samples from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Department of Twin Research and Genetic Epidemiology (DTR), the TWINSUK Cohort. A full list of the investigators who contributed to the generation of the data is available from www.UK10K.org. Funding for UK10K was provided by the Wellcome Trust under award WT091310. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: SMD declares research support to institution from Renalytix AI and a patent application filed by VA on drug repurposing for lipid reduction.
Abbreviations: ABCA1, ATP Binding Cassette Subfamily A Member 1; APOC, Apolipoprotein C1; APOE, Apolipoprotein E; BC, breast cancer; BCAC, Breast Cancer Association Consortium; BMI, body mass index; CETP, Cholesteryl Ester Transfer Protein; CI, confidence interval; ER, estrogen receptor; GLGC, Global Lipids Genetics Consortium; GWAS, genome-wide association study; HDL, high-density lipoprotein; HMGCR, 3-Hydroxy-3-Methylglutaryl-CoA Reductase; LCAT, Lecithin-Cholesterol Acyltransferase; LD, linkage disequilibrium; LDL, low-density lipoprotein; LDLR, LDL Receptor; LIPC, Lipase C, Hepatic Type; LIPG, Lipase G, Endothelial Type; LPA, Lipoprotein(A); MR, Mendelian randomization; MVP, Million Veteran Program; MYLIP, Myosin Regulatory Light Chain Interacting Protein; NPC1L1, NPC1-Like Intracellular Cholesterol Transporter 1; OR, odds ratio; PCSK9, Proprotein Convertase Subtilisin/Kexin Type 9; PLTP, Phospholipid Transfer Protein; SCARB1, Scavenger Receptor Class B Member 1; STROBE, Strengthening the Reporting of Observational Studies in Epidemiology; TC, total cholesterol; TG, triglyceride