Genetically proxied inhibition of cholesterol-lowering drug targets and survival in HPV-positive and non-HPV driven head and neck cancer: a multicentre MR study.

Abstract

Cholesterol pathways may influence head and neck squamous cell carcinoma (HNSCC) progression, but evidence on prognosis is inconsistent. We used Mendelian randomization (MR) to test whether genetically proxied inhibition of major LDL-C-lowering drug targets and circulating lipid traits affects overall survival (OS) in HPV-positive and non-HPV driven HNSCC. We proxied lifelong LDL-C lowering using 55 cis-acting SNPs in HMGCR, NPC1L1, PCSK9, and LDLR from the updated 2021 Global Lipids Genetics Consortium, and instrumented circulating lipid traits. Two-sample MR estimated effects on OS in 4,869 multi-centre HNSCC cases (1,291 HPV-positive; 3,578 non-HPV driven) using minimally adjusted Cox models. Sensitivity analyses additionally adjusted for tumour stage and treatment, assessed collider bias using an external HNSCC incidence GWAS, and examined between-centre heterogeneity and colocalization. Using the updated GLGC 2021 instruments, genetically proxied HMGCR inhibition showed a directionally protective but non-significant association with OS in HPV-positive oropharyngeal HNSCC in the primary analysis (IVW HR=0.19, 95% CI 0.03-1.18; P=0.08), with directionally concordant weighted median results. No corresponding protective association was observed for HMGCR in non-HPV-driven disease (IVW HR=1.68, 95% CI 0.78-3.63; P=0.19). No clear evidence of association was observed for NPC1L1, PCSK9, LDLR, or circulating lipid traits in either HPV stratum. Colocalization did not support a shared causal variant. These analyses provide suggestive evidence that genetically proxied HMGCR inhibition may influence survival in HPV-positive oropharyngeal HNSCC. HMGCR-related pathways may be relevant to prognosis in HPV-positive oropharyngeal HNSCC, whereas clear survival effects of other cholesterol-lowering targets were not supported.