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

• DOI: 10.1038/s42003-020-01487-y
• Publication Date: 2020-12-11T11:20:56Z
• Authors: Lvwen Ning; Josephine Mun-Yee Ko; Valen Zhuoyou Yu; Hoi Yan Ng; Candy King-Chi Chan; Lihua Tao; Shiu-Yeung Lam; Merrin Man-Long L...; Roger Kai-Cheong ...; 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
• Keywords: Male; QH301-705.5; Polymorphism, Single Nucleotide; Article; Genetic Heterogeneity; 03 medical and health sciences; INDEL Mutation; HLA Antigens; Humans; Genetic Predisposition to Disease; Genetic Testing; Biology (General); Alleles; Aged; 0303 health sciences; Nasopharyngeal Carcinoma; Histocompatibility Antigens Class I; Genetic Variation; High-Throughput Nucleotide Sequencing; Middle Aged; 3. Good health; Amino Acid Substitution; Haplotypes; Case-Control Studies; Female; Genome-Wide Association Study

AbstractDespite 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 nearTRIM31andTRIM39/TRIM39-RPP21; multiple independent protective signals map nearHLA-Bincluding a previously unreported variant, rs2523589 (P = 1.77 × 10−36). The rareHLA-B*07:05allele (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,TRIM31andTRIM39, impacting innate immune responses, with NPC risk reduction, independent of classical HLA class I/II alleles.