Association Between Genetically Proxied Lipid-Lowering Drug Targets and Renal Cell Carcinoma: A Mendelian Randomization Study.

Luyang Liu,Kexin Chen,Hongji Dai,Zhangyan Lyu,Chao Sheng

doi:10.3389/fnut.2021.755834

Luyang Liu, Kexin Chen + Show 3 more

Open Access

https://doi.org/10.3389/fnut.2021.755834

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Abstract

Observational studies suggested inconsistent associations between lipid-lowering drugs, such as statins, and renal cell carcinoma (RCC) risk. In a two-sample Mendelian randomization (MR) framework, we assessed the causal influence of lipid-lowering agents and circulating lipid traits on overall and sex-specific RCC risk. Genetic variants of six drug-target genes were selected to proxy the effects of low-density lipoprotein cholesterol (LDL-C) lowering therapies. Instrumental variables for circulating lipid traits were constructed from two large genome-wide association studies. We used endpoints for RCC from summary statistics of two studies [International Agency for Research on Cancer [IARC], N = 13,230; National Cancer Institute [NCI], N = 4,735]. The robustness of results was assessed through conventional MR sensitivity analyses. Overall, there was no significant association between genetically proxied HMG-CoA reductase (HMGCR) inhibition and RCC risk [Odds ratio [OR] = 1.42, 95% CI, 0.29–6.99]. In the sex-stratified analysis, we observed a positive association for genetically proxied drug targets with RCC risk. Specifically, genetically proxied proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition was associated with a higher risk of RCC in men [OR = 2.20 [95% CI, 1.24–3.89]], and the difference by sex was moderate. This study suggested genetically proxied inhibition of HMGCR was not associated with RCC risk, while genetically proxied PCSK9 inhibition might be associated with a higher risk of RCC in male.

Highlights

According to the estimates of cancer incidence and mortality reported by the International Agency for Research on Cancer (IARC), there were ∼430,000 new cases diagnosed with renal cell carcinoma (RCC) and 180,000 deaths worldwide in 2020 [1]
We performed drug-target Mendelian randomization (MR) analysis to investigate the association of genetically proxied hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), Niemann-Pick C1-Like 1 (NPC1L1, targets of ezetimibe), proprotein convertase subtilisin/kexin type 9 (PCSK9, target of evolocumab and alirocumab), Cholesteryl Ester Transfer Protein (CETP), low density lipoprotein receptor (LDLR), and Apolipoprotein B (APOB) inhibitors with overall and sexspecific RCC risk
Information of genetic variants in HMGCR, NPC1L1, PCSK9, LDLR, CETP, and APOB used to proxy the effect of drug-target genes were presented in Table 1 and Supplementary Table 1

Summary

Introduction

According to the estimates of cancer incidence and mortality reported by the International Agency for Research on Cancer (IARC), there were ∼430,000 new cases diagnosed with renal cell carcinoma (RCC) and 180,000 deaths worldwide in 2020 [1]. Primary prevention of RCC is necessary for reducing the disease burden. Clear cell RCC (ccRCC) is characterized by the accumulation of lipid droplets in the cytoplasm. Both fatty acid synthesis and lipid storage could promote the growth of ccRCC [3]. Observational studies suggested that dyslipidemia might be involved in the carcinogenesis of RCC [4]. A recent Mendelian randomization (MR) study that incorporated the largest published

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