Associations of genetically proxied inhibition of HMG-CoA reductase, NPC1L1, and PCSK9 with breast cancer and prostate cancer

Breast Cancer Research

Huan Ding¹  Yu Wang²  Lulu Sun²  Fanghua Liu²  Yiming Jia²  Pinni Yang²  Yonghong Zhang²  Zhengbao Zhu³  Mengyao Shi³  Daoxia Guo⁴ 

[1] Department of Chronic Infectious Disease Control and Prevention, Wuxi Center for Disease Control and Prevention, Wuxi, China;Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, 199 Renai Road, Industrial Park District, 215123, Suzhou, Jiangsu Province, China;Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, 199 Renai Road, Industrial Park District, 215123, Suzhou, Jiangsu Province, China;Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA;Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, 199 Renai Road, Industrial Park District, 215123, Suzhou, Jiangsu Province, China;School of Nursing, Medical College of Soochow University, Suzhou, China;

关键词: LDL-C-lowering drug;    HMG-CoA reductase;    NPC1L1;    PCSK9;    Breast cancer;    Prostate cancer;   

DOI  :  10.1186/s13058-022-01508-0

来源: Springer

【 摘 要 】

BackgroundPreclinical and epidemiological studies indicate a potential chemopreventive role of low-density lipoprotein cholesterol (LDL-C) -lowering drugs in the risks of breast cancer and prostate cancer, but the causality remains unclear. We aimed to evaluate the association of genetically proxied inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, Niemann-Pick C1-Like 1 (NPC1L1), and proprotein convertase subtilisin/kexin type 9 (PCSK9) with risks of breast cancer and prostate cancer using a two-sample Mendelian randomization (MR) method.MethodsSingle-nucleotide polymorphisms (SNPs) in HMGCR, NPC1L1, and PCSK9 associated with LDL-C in a genome-wide association study (GWAS) meta-analysis from the Global Lipids Genetics Consortium (GLGC; up to 188,577 European individuals) were used to proxy inhibition of HMG-CoA reductase, NPC1L1, and PCSK9. Summary statistics with outcomes were obtained from a GWAS meta-analysis of the Breast Cancer Association Consortium (BCAC; 228,951 European females) and a Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL; 140,254 European males) consortium. SNPs were combined into multiallelic models and MR estimates representing lifelong inhibition of targets were generated using the inverse-variance weighted method.ResultsGenetically proxied inhibition of HMG-CoA reductase (OR: 0.84; 95% CI 0.74–0.95; P = 0.005) and NPC1L1 (OR: 0.72; 95% CI 0.58–0.90; P = 0.005) equivalent to a 1-mmol/L (38.7 mg/dL) reduction in LDL-C was associated with reduced breast cancer risk. There were no significant associations of genetically proxied inhibition of PCSK9 with breast cancer. In contrast, genetically proxied inhibition of PCSK9 (OR: 0.81; 95% CI 0.73–0.90; P < 0.001) but not HMG-CoA reductase and NPC1L1 was negatively associated with prostate cancer. In the secondary analysis, genetically proxied inhibition of HMG-CoA reductase (OR: 0.82; 95% CI 0.71–0.95; P = 0.008) and NPC1L1 (OR: 0.66; 95% CI 0.50–0.86; P = 0.002) was associated with estrogen receptor-positive breast cancer, whereas there was no association of HMG-CoA reductase and NPC1L1 with estrogen receptor-negative breast cancer.ConclusionsGenetically proxied inhibition of HMG-CoA reductase and NPC1L1 was significantly associated with lower odds of breast cancer, while genetically proxied inhibition of PCSK9 was associated with reduced risk of prostate cancer. Further randomized controlled trials are needed to confirm the respective roles of these LDL-C-lowering drugs in breast cancer and prostate cancer.

【 授权许可】

CC BY