Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study.
Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study.
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DOI：
10.1016/s1470-2045(16)30148-6
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发表时间：
2016-09
期刊：
影响因子：
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通讯作者：
Bei JX
中科院分区：
文献类型：
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作者：
Li Z;Xia Y;Feng LN;Chen JR;Li HM;Cui J;Cai QQ;Sim KS;Nairismägi ML;Laurensia Y;Meah WY;Liu WS;Guo YM;Chen LZ;Feng QS;Pang CP;Chen LJ;Chew SH;Ebstein RP;Foo JN;Liu J;Ha J;Khoo LP;Chin ST;Zeng YX;Aung T;Chowbay B;Diong CP;Zhang F;Liu YH;Tang T;Tao M;Quek R;Mohamad F;Tan SY;Teh BT;Ng SB;Chng WJ;Ong CK;Okada Y;Raychaudhuri S;Lim ST;Tan W;Peng RJ;Khor CC;Bei JX
鼻型结外自然杀伤 T 细胞淋巴瘤 (NKTCL) 是一种罕见的侵袭性恶性肿瘤，主要发生在亚洲和拉丁美洲人群中。尽管 Epstein-Barr 病毒感染是已知的危险因素，但其他危险因素和 NKTCL 的发病机制尚不清楚。我们的目的是确定影响 NKTCL 个体风险的常见遗传变异。我们对来自中国南方广东省的 189 名结外 NKTCL、鼻型（WHO 分类标准；病例）患者和 957 名对照者进行了全基因组关联研究。我们在四个独立的病例对照系列中验证了我们的研究结果，包括来自广东省的 75 例病例和来自香港的 296 例对照，来自广东省的 65 例病例和 983 例对照，来自北京（中国北部）的 125 例病例和 1110 例对照，以及来自新加坡的 60 例病例和 2476 例对照。我们使用插补和条件逻辑回归分析来精细绘制关联。我们还对复制系列和整个数据集进行了荟萃分析。在映射到 6 号染色体上 II 类 MHC 区域的 51 个单核苷酸多态性 (SNP) 中观察到超过全基因组显着性阈值 (p<5 × 10−8) 的关联，其中 rs9277378（位于 HLA-DPB1）与 NKTCL 易感性具有最强关联（p=4·21 × 10−19，优势比 [OR] 1·84 [95% CI） 1·61–2·11]整个数据集的荟萃分析）。基于估算的跨 II 类 MHC 区域的精细作图表明，HLA-DPB1 肽结合沟边缘接近完全连锁不平衡的四个氨基酸残基 (Gly84-Gly85-Pro86-Met87) 可以解释 rs9277378*A 风险等位基因与 NKTCL 易感性之间的大部分关联（OR 2∙38，单倍型的 p 值） 2∙32 × 10−14)。这种关联不同于 MHC 与 Epstein-Barr 病毒感染的关联。据我们所知，这是第一次在全基因组范围内注意到赋予 NKTCL 风险的遗传变异。这一发现强调了 HLA-DP 抗原呈递在 NKTCL 发病机制中的重要性。
Extranodal natural killer T-cell lymphoma (NKTCL), nasal type, is a rare and aggressive malignancy that occurs predominantly in Asian and Latin American populations. Although Epstein-Barr virus infection is a known risk factor, other risk factors and the pathogenesis of NKTCL are not well understood. We aimed to identify common genetic variants affecting individual risk of NKTCL. We did a genome-wide association study of 189 patients with extranodal NKTCL, nasal type (WHO classification criteria; cases) and 957 controls from Guangdong province, southern China. We validated our findings in four independent case-control series, including 75 cases from Guangdong province and 296 controls from Hong Kong, 65 cases and 983 controls from Guangdong province, 125 cases and 1110 controls from Beijing (northern China), and 60 cases and 2476 controls from Singapore. We used imputation and conditional logistic regression analyses to fine-map the associations. We also did a meta-analysis of the replication series and of the entire dataset. Associations exceeding the genome-wide significance threshold (p<5 × 10−8) were seen at 51 single-nucleotide polymorphisms (SNPs) mapping to the class II MHC region on chromosome 6, with rs9277378 (located in HLA-DPB1) having the strongest association with NKTCL susceptibility (p=4·21 × 10−19, odds ratio [OR] 1·84 [95% CI 1·61–2·11] in meta-analysis of entire dataset). Imputation-based fine-mapping across the class II MHC region suggests that four aminoacid residues (Gly84-Gly85-Pro86-Met87) in near-complete linkage disequilibrium at the edge of the peptide-binding groove of HLA-DPB1 could account for most of the association between the rs9277378*A risk allele and NKTCL susceptibility (OR 2∙38, p value for haplotype 2∙32 × 10−14). This association is distinct from MHC associations with Epstein-Barr virus infection. To our knowledge, this is the first time that a genetic variant conferring an NKTCL risk is noted at genome-wide significance. This finding underlines the importance of HLA-DP antigen presentation in the pathogenesis of NKTCL.