基于全外显子测序分析CES1和MUC5B基因多态性与乙酸甲酯中毒关联性  

Analyzing the association between polymorphism of CES1 and MUC5B genes and methyl acetate poisoning by whole exome sequencing

作　　者：吴家韵 吴志佳 农骐郢 赵娜[2] 秦亦如 黄永顺[2] WU Jiayun;WU Zhijia;NONG Qiying;ZHAO Na;QIN Yiru;HUANG Yongshun(School of Public Health,Guangdong Pharmaceutical University,Guangzhou,Guangdong 510006,China;不详)

机构地区：[1]广东药科大学公共卫生学院,广东广州510006 [2]广东省职业病防治院,广东广州510300 [3]南方医科大学公共卫生学院,广东广州510515

出　　处：《中国职业医学》2023年第4期386-393,共8页China Occupational Medicine

基　　金：广东省医学科学技术研究基金(A2022013,A2023048);广东省职业病防治院重点科研课题青年项目(Z2022-11);广州市基础研究计划(2023A04J2471)。

摘　　要：目的通过全外显子测序检测和分析乙酸甲酯中毒患者易感基因。方法采用判断抽样方法,选择2例职业性急性重度乙酸甲酯中毒患者及与其处于同一工种、同一工位、工作时间相似的直系亲属各1人作为研究对象,采集周围静脉血进行全外显子测序;将测序数据与公共基因组数据库进行对比以筛选变异位点,找出与乙酸甲酯中毒相关的基因位点,进行可疑致病突变基因注释与解读。结果全外显子测序结果显示,乙酸甲酯中毒患者与直系亲属对照间存在40个差异基因,包括80个单核苷酸多态性与8个插入缺失标记;其中,关联性较强的基因为羧酸酯酶1(CES1)和黏蛋白(MUC)5B。乙酸甲酯中毒患者CES1的基因位点发生c.248C>T(p.Ser83Leu)杂合突变,MUC5B的基因位点发生c.6635C>T(p.Thr2212Met)和c.7685C>T(p.Thr2562Met)的杂合突变,均为错义突变。经构建蛋白质-蛋白质相互作用网络,获得证据等级较高的11对交互作用,所涉及的基因包括赖氨酸甲基转移酶2C、含E3泛素蛋白连接酶2的HECT和RLD结构域、中性粒细胞胞质因子1、还原型烟酰胺腺嘌二核苷酸磷酸氧化酶3、C末端结合蛋白2、锌指蛋白717、FSHD区域基因2家族成员C、FSHD区域基因1、MUC4、MUC6、MUC5B和MUC12。结论乙酸甲酯中毒患者基因位点CES1与MUC5B基因多态性可能与乙酸甲酯中毒的发生发展机制存在联系。Objective To detect and analyze the susceptibility genes of methyl acetate poisoning in patients by whole exome sequencing.Methods Two patients with occupational acute severe methyl acetate poisoning and their first-degree relatives who work in the same occupation and position with similar working hours were selected as the research subjects by judgment sampling method.Peripheral blood was collected for whole exome sequencing.The sequencing data was compared with the public genome database to screen the mutation sites and find out the gene sites related to methyl acetate poisoning.The suspected pathogenic mutation genes were annotated and interpreted.Results The results of whole exome sequencing showed that there were 40 differential genes between the patients with methyl acetate poisoning and their first-degree relatives,including 80 single nucleotide polymorphisms and eight Indel with specific marker sequence index.Among these,the genes with strong correlation were carboxyesterase 1(CES1)and mucin(MUC)5B.The CES1 gene loci c.248C>T(p.Ser83Leu)heterozygous mutations,MUC5B gene loci c.6635C>T(p.Thr2212Met)and c.7685C>T(p.Thr2562Met)heterozygous mutations in patients with methyl acetate poisoning were detected.They were missense mutations.By constructing a proteinprotein interaction network,a total of 11 pairs of interactions with high levels of evidence were identified,involving genes such as lysine methyltransferase 2C,HECT and RLD domains containing E3 ubiquitin protein ligase 2,neutrophil cytoplasmic factor 1,nicotinamide adenine dinucleotide phosphate oxidase 3,C-terminal binding protein 2,zinc finger protein 717,FSHD region gene 2 family member C,FSHD region gene 1,MUC4,MUC6,MUC5B,and MUC12.Conclusion The polymorphism of CES1 and MUC5B genes may be related to the occurrence and development of methyl acetate poisoning in patients.

关 键 词：乙酸甲酯 急性中毒 职业中毒 全外显子测序 蛋白组学 差异基因 

分 类 号：R135.1[医药卫生—劳动卫生]