The relationship between circulating lipids and breast cancer risk: A Mendelian randomization study


Autoři: Kelsey E. Johnson aff001;  Katherine M. Siewert aff002;  Derek Klarin aff003;  Scott M. Damrauer aff006;  ;  Kyong-Mi Chang aff006;  Philip S. Tsao aff009;  Themistocles L. Assimes aff009;  Kara N. Maxwell aff008;  Benjamin F. Voight aff006
Působiště autorů: Cell and Molecular Biology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America aff001;  Genomics and Computational Biology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America aff002;  Boston VA Healthcare System, Boston, Massachusetts, United States of America aff003;  Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America aff004;  Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America aff005;  Corporal Michael Crescenz VA Medical Center, Philadelphia, Pennsylvania, United States of America aff006;  Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff007;  Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff008;  VA Palo Alto Health Care System, Palo Alto, California, United States of America aff009;  Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America aff010;  Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff011;  Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff012;  Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff013
Vyšlo v časopise: The relationship between circulating lipids and breast cancer risk: A Mendelian randomization study. PLoS Med 17(9): e32767. doi:10.1371/journal.pmed.1003302
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003302

Souhrn

Background

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).

Methods and findings

Data from genome-wide association studies in up to 215,551 participants from the Million Veteran Program (MVP) were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on BC risk was evaluated using genetic data from the BCAC (Breast Cancer Association Consortium) based on 122,977 BC cases and 105,974 controls. Using MR, we observed that a 1-standard–deviation genetically determined increase in HDL levels is associated with an increased risk for all BCs (HDL: OR [odds ratio] = 1.08, 95% confidence interval [CI] = 1.04–1.13, P < 0.001). Multivariable MR analysis, which adjusted for the effects of LDL, TGs, body mass index (BMI), and age at menarche, corroborated this observation for HDL (OR = 1.06, 95% CI = 1.03–1.10, P = 4.9 × 10−4) and also found a relationship between LDL and BC risk (OR = 1.03, 95% CI = 1.01–1.07, P = 0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor (ER) status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for BCs (OR = 1.11, 95% CI = 1.06–1.16, P = 1.5 × 10−6), including locus-specific associations at ABCA1 (ATP Binding Cassette Subfamily A Member 1), APOE-APOC1-APOC4-APOC2 (Apolipoproteins E, C1, C4, and C2), and CETP (Cholesteryl Ester Transfer Protein). In addition, we found evidence that genetic variation at the ABO locus is associated with both lipid levels and BC. Through multiple statistical approaches, we minimized and tested for the confounding effects of pleiotropy and population stratification on our analysis; however, the possible existence of residual pleiotropy and stratification remains a limitation of this study.

Conclusions

We observed that genetically elevated plasma HDL and LDL levels appear to be associated with increased BC risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal of developing potential therapeutic strategies aimed at altering the cholesterol-mediated effect on BC risk.

Klíčová slova:

Breast cancer – Cancer risk factors – Genetic loci – Genetics – Cholesterol – Lipid analysis – Lipids – Lipoproteins


Zdroje

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