ArticleDiscover oncology2026
Mendelian randomization analysis reveals causal associations between HLA gene expression, inflammatory biomarkers, and non-small cell lung cancer risk.
Article in Discover oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundNon-small cell lung cancer (NSCLC) represents a major global health burden with complex genetic etiology. While observational studies have identified numerous potential risk factors, establishing causal relationships remains challenging due to confounding and reverse causation.
methodsWe conducted a comprehensive Mendelian randomization (MR) analysis to investigate causal relationships between circulating biomarkers, lung tissue gene expression levels, and NSCLC risk. The analysis employed three complementary MR methods: inverse variance weighted (IVW), MR Egger, and weighted median approaches. Genetic instruments were selected from 10 to 26 single nucleotide polymorphisms (SNPs) significantly associated with exposure variables. We validated key findings through quantitative real-time PCR (qRT-PCR) analysis in A549 and H1299 NSCLC cell lines. We examined multiple biomarkers including inflammatory mediators, immune-related proteins, and particularly focused on the HLA region within the major histocompatibility complex.
resultsAmong circulating biomarkers, thymic stromal lymphopoietin demonstrated a statistically significant positive association with increased NSCLC risk (OR: 1.240, 95% CI: 1.073–1.433, p = 0.003). Gene expression analysis identified 18 genes with significant causal associations (FDR < 0.05), revealing a complex pattern of protective and risk-associated effects. qRT-PCR validation in A549 and H1299 cell lines confirmed differential expression patterns, with protective genes (HLA-DQB2, GMPPA) showing lower expression and risk-associated genes (VDR, P4HTM) showing higher expression in cancer cells compared to normal bronchial epithelial cells. Notable protective genes included HLA-DQB2 (OR: 0.917), HLA-DRB9 (OR: 0.875), and GMPPA (OR: 0.697), while risk-associated genes included VDR (OR: 1.825), P4HTM (OR: 1.520), and multiple HLA variants. Regional association analysis of the HLA-DQB2 locus revealed extremely high significance levels (p-values > 10^-135) within the MHC region on chromosome 6.
conclusionsThis MR analysis provides robust genetic evidence for causal relationships between immune system regulation, inflammatory pathways, and NSCLC development, with experimental validation supporting the functional relevance of identified genetic associations.
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