AUTHOR=Li Honglin , Zhang Lei , Yang Feiran , Feng Xiaoteng , Fu Rong , Zhao Ruohan , Li Xiurong , Li Huijie 

TITLE=Lipid-lowering drugs affect lung cancer risk via sphingolipid metabolism: a drug-target Mendelian randomization study

JOURNAL=Frontiers in Genetics

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1269291

DOI=10.3389/fgene.2023.1269291

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> The causal relationship between lipid-lowering drug (LLD) use and lung cancer risk is controversial, and the role of sphingolipid metabolism in this effect remains unclear.</p><p><bold>Methods:</bold> Genome-wide association study data on low-density lipoprotein (LDL), apolipoprotein B (ApoB), and triglycerides (TG) were used to develop genetic instrumental variables (IVs) for LLDs. Two-step Mendelian randomization analyses were performed to examine the causal relationship between LLDs and lung cancer risk. The effects of ceramide, sphingosine-1-phosphate (S1P), and ceramidases on lung cancer risk were explored, and the proportions of the effects of LLDs on lung cancer risk mediated by sphingolipid metabolism were calculated.</p><p><bold>Results:</bold><italic>APOB</italic> inhibition decreased the lung cancer risk in ever-smokers via ApoB (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.70–0.92, <italic>p</italic> = 0.010), LDL (OR 0.82, 95% CI 0.71–0.96, <italic>p</italic> = 0.040), and TG (OR 0.63, 95% CI 0.46–0.83, <italic>p</italic> = 0.015) reduction by 1 standard deviation (SD), decreased small-cell lung cancer (SCLC) risk via LDL reduction by 1 SD (OR 0.71, 95% CI 0.56–0.90, <italic>p</italic> = 0.016), and decreased the plasma ceramide level and increased the neutral ceramidase level. <italic>APOC3</italic> inhibition decreased the lung adenocarcinoma (LUAD) risk (OR 0.60, 95% CI 0.43–0.84, <italic>p</italic> = 0.039) but increased SCLC risk (OR 2.18, 95% CI 1.17–4.09, <italic>p</italic> = 0.029) via ApoB reduction by 1 SD. <italic>HMGCR</italic> inhibition increased SCLC risk via ApoB reduction by 1 SD (OR 3.04, 95% CI 1.38–6.70, <italic>p</italic> = 0.014). The <italic>LPL</italic> agonist decreased SCLC risk via ApoB (OR 0.20, 95% CI 0.07–0.58, <italic>p</italic> = 0.012) and TG reduction (OR 0.58, 95% CI 0.43–0.77, <italic>p</italic> = 0.003) while increased the plasma S1P level. <italic>PCSK9</italic> inhibition decreased the ceramide level. Neutral ceramidase mediated 8.1% and 9.5% of the reduced lung cancer risk in ever-smokers via ApoB and TG reduction by <italic>APOB</italic> inhibition, respectively, and mediated 8.7% of the reduced LUAD risk via ApoB reduction by <italic>APOC3</italic> inhibition.</p><p><bold>Conclusion:</bold> We elucidated the intricate interplay between LLDs, sphingolipid metabolites, and lung cancer risk. Associations of <italic>APOB</italic>, <italic>APOC3</italic>, and <italic>HMGCR</italic> inhibition and <italic>LPL</italic> agonist with distinct lung cancer risks underscore the multifaceted nature of these relationships. The observed mediation effects highlight the considerable influence of neutral ceramidase on the lung cancer risk reduction achieved by <italic>APOB</italic> and <italic>APOC3</italic> inhibition.</p>