Fig. 6: Novel HLA risk loci for HPV(-) oropharynx and oral cavity cancer.
From: Cross-ancestral GWAS identifies 29 variants across head and neck cancer subsites
Manhattan plots display all independent lead variants of risk for HPV(−)(cases = 1470; controls = 38,973) and OC (cases = 5578; controls =38,973) subsite. Variants highlighted under the significance threshold reached significance in later rounds; only the plot from the first round of stepwise logistic-regression analysis is shown here. Novel variants are highlighted in red; known variants are in grey. The horizontal red line reflects the HLA significance threshold (p < 2.4 × 10−6), adjusted using the Bonferroni correction. a HPV(-) oropharynx: The lead SNP, (b) rs1131212 (OR = 1.33, 95% CI:1.19,1.49, p = 5.33 × 10−7), causes an amino acid change from Gln to His at residue 94 located in the HLA-B protein binding pocket (PDB ID: 2BVP). This variant is in LD (r2 = 1) with 70Asn/Ser (OR = 1.32, 95% CI:1.18,1.47, p = 8.81 × 10−7). The right panel shows the comparable risk effects of the two related signals. The known SNP, (c) rs1264813 (OR = 1.37, 95% CI:1.22,1.55, p = 2.77 × 10−7), is in high LD (r2 = 0.77) with HLA-A*24 allele (OR = 1.34, 95% CI:1.18,1.52, p = 7.24 × 10−6) and shows comparable risk effects shown in right panel. d) Oral cavity: The lead SNP, rs9268925 (OR = 0.81, 95% CI: 0.75,0.87, p = 1.36 × 10−7), is highly correlated with a novel risk haplotype, DRB1*15:01-DQA1*01:02-DQB1*06:02 (OR = 0.8, 95% CI:0.73,0.86, p = 2.15 × 10−8), and has a similar risk effect, as shown in the right panel. Model accuracy difference (△BIC) between the original model in the presence of all independent lead variants and the model replacing the lead variant with a related amino acid residue, allele or haplotype, lower than 2 confer equivalent risk. This figure is created in BioRender. https://BioRender.com/98q9ivz. Source data are provided as a Source Data file.
