Fine-mapping the MHC region in Asian populations identified novel variants modifying susceptibility to lung cancer
Fine-mapping the MHC region in Asian populations identified novel variants modifying susceptibility to lung cancer
复制标题
对亚洲人群 MHC 区域进行精细绘制，发现了改变肺癌易感性的新变异。
DOI：
10.1016/j.lungcan.2017.08.016
复制
发表时间：
2017-10-01
期刊：
影响因子：
5.3
通讯作者：
Shen, Hongbing
中科院分区：
文献类型：
--
作者：
Qin, Na;Wang, Cheng;Shen, Hongbing
目的：多态性主要组织相容性复合体（MHC）在免疫系统中起着至关重要的作用，并导致多种癌症的易感性。在最近的全基因组关联研究中，已经确定了一些肺癌相关的MHC基因变异;然而，因果变异仍不清楚。Materials and Methods：在本研究中，我们进行了一项大规模的肺癌精细定位研究，在MHC区域的13,945个无关的亚洲人寻找潜在的因果变异。我们以最近建立的泛亚洲样本组为参照，对8个HLA基因进行了估算HLA-A、HLA-B、HLA-C、HLA-DRB 1、HLA-DQA 1、HLA-DQB 1、HLA-DPA 1和HLA-DPB 1）。我们发现了一个单核苷酸多态性，rs 12333226（OR = 1.41，P = 3.97 × 10（-7）），HLA-DRB 1位点5个氨基酸多态性（OR = 0.89，P = 7.51 × 10（-6）-8.57 × 10（-6））和一个二位数经典HLA等位基因HLA-A*11（OR = 0.87，P = 9.68 × 10（-6））与肺癌的危险性强相关。Rs 12333226是HLA-A和HLA-H在外周血单核细胞中表达的数量性状位点，对肺癌的危险性有影响，尤其是在年轻人群中。HLA-DR β 1位置10、16和25驱动了一个报告的SNP rs 2395185的作用。肽位置分析确定了其他肺癌易感性氨基酸位置，包括HLA-DR β 1位置30和11（P-综合= 6.11 x 10（-5）和6.91 x 10（-5）），HLA-DQa 147和76（P-综合= 3.96 × 10（-4）和1.41 × 10（-2））和HLA-A 152（P-综合= 4.86 × 10（-4））。大多数肽的位置位于肽结合槽，似乎影响抗原呈递。所有现有的和新的变异解释了约2.37%的表型变异，而21.10%是由于在本study.Conclusion中确定的变异：我们确定了7个新的双等位基因变异和5个多态性氨基酸位点的HLA-DR β 1，HLA-DQa 1，和HLA-A，赋予肺癌的风险。这一发现为HLA I类和II类分子对肺癌易感性的实质性贡献提供了证据。
Objectives: The polymorphic major histocompatibility complex (MHC) plays a vital role in the immune system and drives predisposition to multiple cancers. A number of lung cancer-related genetic variants in the MHC have been identified in recent genome-wide association studies; however, the causal variants remain unclear.Materials and methods: In the present study, we conducted a large-scale fine-mapping study of lung cancer in the MHC region of 13,945 unrelated Asian individuals to search for potential causal variants. We used the recently constructed Pan-Asian panel as the reference and imputed eight HLA genes (HLA-A, HLC-B, HLA-C, HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1) using SNP2HLA software.Results: We identified one single nucleotide polymorphism, rs12333226 (OR = 1.41, P = 3.97 x 10(-7)), five HLA amino acid polymorphisms in HLA-DRB1 (OR = 0.89, P = 7.51 x 10(-6)-8.57 x 10(-6)), and one two-digit classic HLA allele HLA-A*11 (OR = 0.87, P = 9.68 x 10(-6)) that were strongly associated with the risk of lung cancer. Rs12333226 was an expression quantitative trait locus of HLA-A and HLA-H in circulating monocytes, and exerted effect on lung cancer risk especially in the younger. HLA-DR beta 1 positions 10, 16, and 25 drove the effect of one reported SNP rs2395185. The peptide position analysis identified additional lung cancer susceptibility amino acid positions, including HLA-DR beta 1 position 30 and 11 (P-omnibus = 6.11 x 10(-5) and 6.91 x 10(-5)), HLA-DQa1 47 and 76 (P-omnibus = 3.96 x 10(-4) and 1.41 x 10(-2)) and HLA-A 152 (P-omnibus = 4.86 x 10(-4)). Most of the peptide positions were located in the peptide-binding grooves and seemed to affect antigen presentation. All the existing and novel variants explained approximately 2.37% of the phenotypic variances, while 21.10% was attributed to the variants identified in this study.Conclusion: We identified seven novel bi-allelic variants and five polymorphic amino acid positions in HLA-DR beta 1, HLA-DQa1, and HLA-A that confer a risk of lung cancer. This finding provides evidence for the substantial contributions of HLA class I and II molecules to lung cancer susceptibility.