中国汉族人群MHC区域与胃癌易感性的关联

李倩; 颜财旺; 靳光付

doi:10.16462/j.cnki.zhjbkz.2021.09.002

中国汉族人群MHC区域与胃癌易感性的关联

doi: 10.16462/j.cnki.zhjbkz.2021.09.002

211166 南京，南京医科大学公共卫生学院流行病学系

基金项目:

国家自然科学基金 81872702

国家自然科学基金 82003534

江苏省自然科学基金 BK20200674

详细信息

通讯作者:
靳光付, E-mail: guangfujin@njmu.edu.cn

中图分类号: R181;R735.2
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- 被引次数: 0
出版历程
- 收稿日期: 2021-08-13
- 修回日期: 2021-08-25
- 网络出版日期: 2021-10-23
- 刊出日期: 2021-09-10

Association between MHC region and gastric cancer susceptibility in Han Chinese

Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing 211166, China

Funds:

National Natural Science Foundation of China 81872702

National Natural Science Foundation of China 82003534

National Natural Science Foundation of Jiangsu Province BK20200674

More Information

Corresponding author: JIN Guang-fu, E-mail: guangfujin@njmu.edu.cn

摘要

摘要: 目的探讨主要组织相容性复合体(major histocompatibility complex, MHC)区域遗传变异与胃癌易感性的关联。方法采用病例对照研究设计，以中国汉族人群MHC参考数据集为参照，利用SNP2HLA v1.0.3软件对MHC区域进行基因型填补；应用Logistic回归分析模型鉴定MHC区域中与胃癌易感性存在关联的遗传变异；基于公共数据库，通过系统功能注释探索MHC区域内的易感基因和功能性遗传变异。结果本研究发现，rs2517714为MHC区域与胃癌发生风险独立关联的遗传位点(OR=1.13, P=2.70×10^-8)；功能注释显示位于HLA-A基因外显子区域的氨基酸多态性位点及单核苷酸多态性(single nucleotide polymorphism, SNP)可能会影响HLA-A蛋白稳定性；同时，非编码区的功能性遗传变异rs9295829可能通过影响所在区域增强子活性，从而远程调控HLA-A基因表达，共同影响易感基因HLA-A的功能。结论 MHC区域致病性遗传变异通过影响易感基因HLA-A功能，从而影响胃癌易感性。
- 胃癌 /
- 全基因组关联研究 /
- 精细定位 /
- 主要组织相容性复合体 /
- HLA-A
Abstract: Objective To investigate the association between genetic variants in the major histocompatibility complex (MHC) region and gastric cancer (GC) susceptibility. Methods Based on a case-control study, MHC region was imputed with SNP2HLA v1.0.3 software by using the Han-MHC database as a reference panel. Logistic regression analysis model was used to identify the independent genetic loci associated with GC susceptibility in the MHC region. Functional annotation of the MHC region was based on online public databases and performed to find the susceptibility gene and potential functional variants. Results We found that rs2517714 was the only independent association signal associated with GC risk in the MHC region (OR=1.13, P=2.70×10^-8). The results of functional annotation showed that HLA amino acid polymorphisms and single nucleotide polymorphisms (SNPs) located in the exon region of HLA-A may affect the stability of HLA-A protein. The SNP rs9295829 located in a non-coding region could remotely regulate the expression of HLA-A by affecting enhancer activity. Conclusion Functional genetic variations in the MHC region may affect the function of the susceptibility gene HLA-A to modulate GC susceptibility.
- Gastric cancer /
- Genome-wide association study /
- Fine mapping /
- Major histocompatibility complex /
- HLA-A

HTML全文

图 1 MHC区域遗传变异与胃癌发生风险关联的区域图

注：横坐标代表染色体位置，纵坐标代表关联P值的负对数，绿色虚线代表Bonferroni多重校正界值。

Figure 1. Regional association plots of MHC loci independently associated with GC risk

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图 2 功能性位点和易感基因的功能注释结果

Figure 2. Functional annotation results of potential functional variant and susceptibility gene

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表 1 预测可影响蛋白稳定性和功能的遗传变异

Table 1. Genetic variants predicted to affect protein stability and function

遗传变异	OR(95% CI)值^a	P值^a	r²值^b	氨基酸改变	预测结果
AA_A_142_30019177_T	1.13(1.08~1.18)	6.24×10^-8	0.93	异亮氨酸(I)>苏氨酸(T)	有害变异
AA_A_145_30019186_H	1.13(1.08~1.18)	6.24×10^-8	0.93	精氨酸(R)>组氨酸(H)	有害变异
AA_A_107_30019072_W	1.12(1.08~1.17)	9.85×10^-8	0.90	甘氨酸(G)>色氨酸(W)	有害变异
AA_A_184_30019881_A	1.12(1.07~1.16)	1.58×10^-7	0.85	脯氨酸(P)>丙氨酸(A)	有害变异
AA_A_62_30018696_G	1.12(1.07~1.17)	2.38×10^-7	0.89	谷氨酰胺(Q)>甘氨酸(G)	有害变异
AA_A_127_30019132_K	1.10(1.06~1.15)	2.21×10^-6	0.65	天冬酰胺(N)>赖氨酸(K)	有害变异
rs1059516	1.13(1.08~1.18)	6.24×10^-8	0.90	异亮氨酸(ATC)>苏氨酸(ACC)	有害变异
rs1059520	0.89(0.85~0.93)	6.24×10^-8	0.90	精氨酸(CGC)>组氨酸(CAC)	有害变异
rs1136702	0.89(0.85~0.93)	9.85×10^-8	0.85	甘氨酸(CGG)>色氨酸(CTG)	有害变异
rs1136741	1.12(1.07~1.16)	1.70×10^-7	0.84	脯氨酸(CCC)>丙氨酸(CGC)	有害变异
注：^a采用固定效应模型对6项GWAS研究进行Meta分析；^b在中国汉族人群MHC区域参考基因组数据集中与rs2517714之间的连锁不平衡。

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表 2 与rs2517714存在高度LD且具有调控活性的11个遗传变异功能注释

Table 2. Functional annotations of 11 variants in strong LD with the lead variant rs2517714

遗传变异	OR(95% CI)值^a	P值^a	r²值^b	dbSNP注释	调控活性^c	RegulomeDB评分	CADD评分	3DSNP评分	GWAVA评分
rs2523763	0.91(0.88~0.95)	1.35×10^-5	0.63	基因间	E	3a	9.15	56.22	0.25
rs2734987	1.10(1.05~1.14)	8.48×10^-6	0.63	基因间	E	3a	10.06	58.08	0.24
rs2734903	0.90(0.86~0.94)	3.98×10^-7	0.73	基因上游	E/P	2a	10.28	144.14	0.36
rs9260124	0.90(0.86~0.94)	3.98×10^-7	0.78	内含子	P	4	10.36	207.05	0.28
rs17885299	0.89(0.85~0.93)	2.38×10^-7	0.86	内含子	P	4	10.26	105.92	0.28
rs9260145	1.11(1.07~1.16)	4.85×10^-7	0.79	内含子	E/P	3a	13.84	135.27	0.32
rs17882350	0.89(0.85~0.93)	1.05×10^-7	0.87	内含子	P	3a	14.64	139.97	0.40
rs9260149	1.11(1.07~1.16)	4.85×10^-7	0.79	内含子	P	4	10.94	138.15	0.35
rs9260152	0.90(0.86~0.94)	4.85×10^-7	0.79	内含子	P	4	10.04	139.98	0.36
rs9393984	0.89(0.85~0.93)	1.27×10^-7	0.79	基因间	E	4	9.90	207.12	0.55
rs9295829	1.11(1.06~1.16)	2.19×10^-6	0.76	内含子	E/P	1b	11.38	201.66	0.41
注：^a采用固定效应模型对6项GWAS研究进行Meta分析；^b在中国汉族人群MHC区域参考基因组数据集中与rs2517714之间的连锁不平衡；^c E代表具有增强子活性，P代表具有启动子活性。

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参考文献(25)

[1]	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. DOI: 10.3322/caac.21660.
[2]	Guan Z, Song B, Liu F, et al. TGF-beta induces HLA-G expression through inhibiting miR-152 in gastric cancer cells[J]. J Biomed Sci, 2015, 22: 107. DOI: 10.1186/s12929-015-0177-4.
[3]	Dutta N, Gupta A, Mazumder DN, et al. Down-regulation of locus-specific human lymphocyte antigen class Ⅰ expression in Epstein-Barr virus-associated gastric cancer: implication for viral-induced immune evasion[J]. Cancer, 2006, 106(8): 1685-1693. DOI: 10.1002/cncr.21784.
[4]	Kelly A, Trowsdale J. Genetics of antigen processing and presentation[J]. Immunogenetics, 2019, 71(3): 161-170. DOI: 10.1007/s00251-018-1082-2.
[5]	Jin G, Lv J, Yang M, et al. Genetic risk, incident gastric cancer, and healthy lifestyle: a meta-analysis of genome-wide association studies and prospective cohort study[J]. Lancet Oncol, 2020, 21(10): 1378-1386. DOI: 10.1016/S1470-2045(20)30460-5.
[6]	Jin G, Ma H, Wu C, et al. Genetic variants at 6p21.1 and 7p15.3 are associated with risk of multiple cancers in Han Chinese[J]. Am J Hum Genet, 2012, 91(5): 928-934. DOI: 10.1016/j.ajhg.2012.09.009.
[7]	Shi Y, Hu Z, Wu C, et al. A genome-wide association study identifies new susceptibility loci for non-cardia gastric cancer at 3q13.31 and 5p13.1[J]. Nat Genet, 2011, 43(12): 1215-1218. DOI: 10.1038/ng.978.
[8]	Yan C, Zhu M, Ding Y, et al. Meta-analysis of genome-wide association studies and functional assays decipher susceptibility genes for gastric cancer in Chinese populations[J]. Gut, 2020, 69(4): 641-651. DOI: 10.1136/gutjnl-2019-318760.
[9]	Gutierrez-Achury J, Zhernakova A, Pulit SL, et al. Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease[J]. Nat Genet, 2015, 47(6): 577-578. DOI: 10.1038/ng.3268.
[10]	Hu X, Deutsch AJ, Lenz TL, et al. Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk[J]. Nat Genet, 2015, 47(8): 898-905. DOI: 10.1038/ng.3353.
[11]	Sharp SA, Rich SS, Wood AR, et al. Development and Standardization of an Improved Type 1 Diabetes Genetic Risk Score for Use in Newborn Screening and Incident Diagnosis[J]. Diabetes Care, 2019, 42(2): 200-207. DOI: 10.2337/dc18-1785.
[12]	Abnet CC, Freedman ND, Hu N, et al. A shared susceptibility locus in PLCE 1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma[J]. Nat Genet, 2010, 42(9): 764-767. DOI: 10.1038/ng.649.
[13]	Zhou F, Cao H, Zuo X, et al. Deep sequencing of the MHC region in the Chinese population contributes to studies of complex disease[J]. Nat Genet, 2016, 48(7): 740-746. DOI: 10.1038/ng.3576.
[14]	Jia X, Han B, Onengut-Gumuscu S, et al. Imputing amino acid polymorphisms in human leukocyte antigens[J]. PLoS One, 2013, 8(6): e64683. DOI: 10.1371/journal.pone.0064683.
[15]	Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans[J]. Bioinformatics, 2010, 26(17): 2190-2191. DOI: 10.1093/bioinformatics/btq340.
[16]	Tang Z, Li C, Kang B, et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses[J]. Nucleic Acids Res, 2017, 45(W1): W98-W102. DOI: 10.1093/nar/gkx247.
[17]	Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data[J]. Nucleic Acids Res, 2010, 38(16): e164. DOI: 10.1093/nar/gkq603.
[18]	Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels[J]. Bioinformatics, 2015, 31(16): 2745-2747. DOI: 10.1093/bioinformatics/btv195.
[19]	Teng L, He B, Wang J, et al. 4DGenome: a comprehensive database of chromatin interactions[J]. Bioinformatics, 2015, 31(15): 2560-2564. DOI: 10.1093/bioinformatics/btv158.
[20]	Jin F, Li Y, Dixon JR, et al. A high-resolution map of the three-dimensional chromatin interactome in human cells[J]. Nature, 2013, 503(7475): 290-294. DOI: 10.1038/nature12644.
[21]	Gonzalez-Galarza FF, Mccabe A, Santos E, et al. Allele frequency net database (AFND) 2020 update: gold-standard data classification, open access genotype data and new query tools[J]. Nucleic Acids Res, 2020, 48(D1): D783-D788. DOI: 10.1093/nar/gkz1029.
[22]	Niens M, Jarrett RF, Hepkema B, et al. HLA-A02 is associated with a reduced risk and HLA-A01 with an increased risk of developing EBV⁺ Hodgkin lymphoma[J]. Blood, 2007, 110(9): 3310-3315. DOI: 10.1182/blood-2007-05-086934.
[23]	Salter RD, Norment AM, Chen BP, et al. Polymorphism in the alpha 3 domain of HLA-A molecules affects binding to CD8[J]. Nature, 1989, 338(6213): 345-347. DOI: 10.1038/338345a0.
[24]	Rudolph MG, Stanfield RL, Wilson IA. How TCRs bind MHCs, peptides, and coreceptors[J]. Annu Rev Immunol, 2006, 24: 419-466. DOI: 10.1146/annurev.immunol.23.021704.115658.
[25]	Kwak Y, Koh J, Park Y, et al. Differential prognostic impact of CD8⁺ T cells based on human leucocyte antigen I and PD-L1 expression in microsatellite-unstable gastric cancer[J]. Br J Cancer, 2020, 122(9): 1399-1408. DOI: 10.1038/s41416-020-0793-y.