Blood lipids, lipid-regulatory medications, and risk of bladder cancer: a Mendelian randomization study

Zhang Cheng; Fangdie Ye; Yingchun Liang; Chenyang Xu; Zheyu Zhang; Yuxi Ou; Xinan Chen; Xiyu Dai; Zezhong Mou; Weijian Li; Yiling Chen; Quan Zhou; Lujia Zou; Shanhua Mao; Haowen Jiang

doi:10.3389/fnut.2023.992608

Blood lipids, lipid-regulatory medications, and risk of bladder cancer: a Mendelian randomization study

Front Nutr. 2023 Dec 22:10:992608. doi: 10.3389/fnut.2023.992608. eCollection 2023.

Authors

Zhang Cheng^{1

2}, Fangdie Ye^{1

2}, Yingchun Liang^{1

2}, Chenyang Xu^{1

2}, Zheyu Zhang^{1

2}, Yuxi Ou^{1

2}, Xinan Chen^{1

2}, Xiyu Dai^{1

2}, Zezhong Mou^{1

2}, Weijian Li^{1

2}, Yiling Chen^{1

2}, Quan Zhou^{1

2}, Lujia Zou^{1

2}, Shanhua Mao^{1

2}, Haowen Jiang^{1

2

3}

Affiliations

¹ Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
² Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.
³ National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.

Abstract

Background: The influences of blood lipids and lipid-regulatory medications on the risk of bladder cancer have long been suspected, and previous findings remain controversial. We aimed to assess the causality between blood lipids or lipid-regulatory medications and bladder cancer susceptibility by means of a comprehensive Mendelian Randomization (MR) study.

Methods: Genetic proxies from genome-wide association studies (GWAS) of four blood lipid traits and lipid-lowering variants in genes encoding the targets of lipid-regulatory medications were employed. The largest ever GWAS data of blood lipids and bladder cancer involving up to 440,546 and 205,771 individuals of European ancestry were extracted from UK Biobank and FinnGen Project Round 6, respectively. A two-sample bidirectional MR study was performed using the inverse variance weighted as the main method. The heterogeneity, horizontal pleiotropy, MR Steiger, and leave-one-out analyses were also conducted as sensitivity tests.

Results: There was indicative evidence that genetically predicted low-density lipoprotein cholesterol (LDL-C) affected bladder cancer susceptibility based on 146 single nucleotide polymorphisms (SNPs) with an odds ratio (OR) of 0.776 (95% confidence interval [CI] = 0.625-0.965, p = 0.022). However, this result became non-significant after two SNPs that possibly drove the effect were removed as demonstrated by leave-one-out analysis. The reversed MR analysis suggested that bladder cancer could not affect serum lipid levels. No causal relationship was found between the lipid-lowering effect of lipid-regulatory medications (fibrates, probucol, statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors, and evinacumab) and the risk of bladder cancer. No heterogeneity or pleiotropy was found (all p > 0.05).

Conclusion: This MR study revealed for the first time, using the most recent and comprehensive GWAS data to date, that genetically predicted total cholesterol (TC) and the lipid-lowering effect of lipid-regulatory medications had no causal association with bladder cancer susceptibility. We also verified claims from early studies that low-density lipoprotein cholesterol (HDL-C), LDL-C, and triglyceride (TG) are not related to bladder cancer susceptibility either. The current study indicated that lipid metabolism may not be as important in the tumorigenesis of bladder cancer as previously believed.

Keywords: FinnGen; Mendelian randomization; UK Biobank; bladder cancer; blood lipids; lipid-regulatory medications.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the National Natural Science Foundation of P.R. of China (82373222), Leading Talent Program of Shanghai Municipal Health Commission (2022LJ008), and Medical Innovation Research Special Project of Science and Technology Commission of Shanghai Municipality (22Y21900200).