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

• Published in: Communications biology Vol. 3; no. 1; p. 759
• Main Authors: Ning, Lvwen, Ko, Josephine Mun-Yee, Yu, Valen Zhuoyou, Ng, Hoi Yan, Chan, Candy King-Chi, Tao, Lihua, Lam, Shiu-Yeung, Leong, Merrin Man-Long, Ngan, Roger Kai-Cheong, Kwong, Dora Lai-Wan, Lee, Anne Wing-Mui, Ng, Wai-Tong, Cheng, Ashley, Tung, Stewart, Lee, Victor Ho-Fun, Lam, Ka-On, Kwan, Chung-Kong, Li, Wing-Sum, Yau, Stephen, Bei, Jin-Xin, Lung, Maria Li
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.12.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 45/23; 631/208/69; 631/250/248; 631/67/69; 692/699/67/1536; 82/51; 82/80; Alleles; Antigens; Association analysis; Biology; Biomedical and Life Sciences; Epstein-Barr virus; Haplotypes; Histocompatibility antigen HLA; Immune response; Innate immunity; Life Sciences; Major histocompatibility complex; Nasopharyngeal carcinoma; Ubiquitin; Ubiquitin-protein ligase; Hong Kong China; China
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-020-01487-y

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. Here the authors report a major histocompatibility complex (MHC) association analysis for nasopharyngeal carcinoma in Chinese individuals from Hong Kong, finding 8 independent associated loci associated with lower risk for developing nasopharyngeal carcinoma. Two non-human leukocyte antigen (HLA) genes are E3 ubiquitin ligases, TRIM31 and TRIM39 , having a role in the innate immune response and implicating the importance of host Epstein-Barr virus interactions in this cancer.