Nasopharyngeal carcinoma MHC region deep sequencing identifies HLA and novel non-HLA TRIM31 and TRIM39 loci

Despite pronounced associations of major histocompatibility complex (MHC) regions with nasopharyngeal carcinoma (NPC), causal variants underlying NPC pathogenesis remain elusive. Our large-scale comprehensive MHC region deep sequencing study of 5689 Hong Kong Chinese identifies eight independent NPC-associated signals and provides mechanistic insight for disrupted transcription factor binding, altering target gene transcription. Two novel protective variants, rs2517664 ( T rs2517664 = 4.6%, P = 6.38 × 10 −21 ) and rs117495548 ( G rs117495548 = 3.0%, P = 4.53 × 10 −13 ), map near TRIM31 and TRIM39 / TRIM39-RPP21 ; multiple independent protective signals map near HLA-B including a previously unreported variant, rs2523589 ( P = 1.77 × 10 −36 ). The rare HLA-B*07:05 allele (OR < 0.015, P = 5.83 × 10 −21 ) is absent in NPC, but present in controls. The most prevalent haplotype lacks seven independent protective alleles (OR = 1.56) and the one with additional Asian-specific susceptibility rs9391681 allele (OR = 2.66) significantly increased NPC risk. Importantly, this study provides new evidence implicating two non-human leukocyte antigen (HLA) genes, E3 ubiquitin ligases, TRIM31 and TRIM39 , impacting innate immune responses, with NPC risk reduction, independent of classical HLA class I/II alleles.