Abstract
BACKGROUND: Melanoma proliferation is partly attributed to dysregulated lipid metabolism. The effectiveness of lipid-lowering drugs in combating cutaneous melanoma (CM) is a subject of ongoing debate in both in vitro and clinical studies. METHOD: This study aims to evaluate the causal relationship between various lipid-lowering drug targets, namely 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR, targeted by statins), Proprotein convertase subtilisin/kexin type 9 (PCSK9, targeted by alirocumab and evolocumab), and Niemann-Pick C1-like 1 (NPC1L1, targeted by ezetimibe), and the outcomes of cutaneous melanoma. To mimic the effects of lipid-lowering drugs, we utilized two genetic tools: analysis of polymorphisms affecting the expression levels of drug target genes, and genetic variations linked to low-density lipoprotein cholesterol levels and drug target genes. These variations were sourced from genome-wide association studies (GWAS). We applied Summary-data-based Mendelian Randomization (SMR) and Inverse Variance Weighted Mendelian Randomization (IVW-MR) to gauge the effectiveness of these drugs. RESULTS: Our findings, with SMR results showing an odds ratio (OR) of 1.44 (95% CI: 1.08-1.92; P = 0.011) and IVW-MR results indicating an OR of 1.56 (95% CI: 1.10-2.23; P = 0.013), demonstrate a positive correlation between PCSK9 expression and increased risk of CM. However, no such correlations were observed in other analyses. CONCLUSION: The study concludes that PCSK9 plays a significant role in the development of CM, and its inhibition is linked to a reduced risk of the disease.