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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 (Trs2517664 = 4.6%, P = 6.38 × 10-21) and rs117495548 (Grs117495548 = 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.

Citation

Lvwen Ning, Josephine Mun-Yee Ko, Valen Zhuoyou Yu, Hoi Yan Ng, Candy King-Chi Chan, Lihua Tao, Shiu-Yeung Lam, Merrin Man-Long Leong, Roger Kai-Cheong Ngan, Dora Lai-Wan Kwong, Anne Wing-Mui Lee, Wai-Tong Ng, Ashley Cheng, Stewart Tung, Victor Ho-Fun Lee, Ka-On Lam, Chung-Kong Kwan, Wing-Sum Li, Stephen Yau, Jin-Xin Bei, Maria Li Lung. Nasopharyngeal carcinoma MHC region deep sequencing identifies HLA and novel non-HLA TRIM31 and TRIM39 loci. Communications biology. 2020 Dec 11;3(1):759

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PMID: 33311639

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