载脂蛋白A5基因突变在高三酰甘油血症性急性胰腺炎患者中的致病性分析  

Pathogenic analysis of apolipoprotein A5 gene variants in patients with hypertriglyceridemia-associated acute pancreatitis

作　　者：濮娜 杨琦 李刚 Pu Na;Yang Qi;Li Gang(Department of Critical Care Medicine,Eastern Theater General Hospital of the Chinese People's Liberation Army(Jinling Hospital,Affiliated Hospital of Medical School,Nanjing University),Nanjing 210000,China)

机构地区：[1]中国人民解放军东部战区总医院(南京大学医学院附属金陵医院)重症医学科,南京210000

出　　处：《中华胰腺病杂志》2025年第1期16-23,共8页Chinese Journal of Pancreatology

基　　金：江苏省自然科学基金(BK20231506);南京大学附属金陵医院临床专项课题(22LCYY-QH3)。

摘　　要：目的探讨载脂蛋白A5(APOA5)基因突变在高三酰甘油血症性急性胰腺炎(HTG-AP)患者中的分布特征及致病性分析。方法收集2018年6月至2020年6月间东部战区总医院重症急性胰腺炎中心495例HTG-AP患者的临床资料,应用二代测序(NGS)技术对HTG-AP患者进行全外显子序列分析,筛查APOA5突变位点,应用Sanger测序进行验证。通过突变率检索、保守性分析、致病性预测等生物信息学方法预测相关突变位点的功能。通过蛋白3D结构建模,进一步分析突变蛋白的结构与功能变化。结果495例HTG-AP患者中275例(55.78%)携带APOA5基因外显子突变,包括2个常见错义突变c.457G>A(杂合突变100例、纯合突变13例,突变率22.83%)、c.553G>T(杂合突变111例、纯合突变31例,突变率28.69%),13个罕见突变(均为杂合突变)。62例(12.5%)妊娠期急性胰腺炎(APIP)患者中,37例(58.06%)携带APOA5基因突变,其中25例(67.57%)为错义突变c.553G>T携带者,其中1例为移码突变c.230dupT(p.Ser78fs)与c.553G>T(p.Gly185Cys)构成的复合杂合突变。生物信息学预测c.230dupT位点为可能致病性突变,c.553G>T为潜在致病突变。蛋白三维结构模型分析提示,p.Ser78fs突变体为明确功能丧失型(LoF)突变,p.Gly185Cys错义突变体为潜在LoF突变。结论APOA5基因在中国HTG-AP患者中突变率较高,APOA5基因缺陷与妊娠等因素的叠加作用是HTG-APIP发病及复发的重要病因。ObjectiveTo analyze the distribution features and pathogenicity of apolipoprotein A5(APOA5)gene variants in patients with hypertriglyceridemia-associated acute pancreatitis(HTG-AP).MethodsClinical data of 495 patients with HTG-AP in severe acute pancreatitis center of Eastern Theater General Hospital were collected.Next generation sequencing was performed to analyze the whole exonic regions to screen APOA5 gene variants in patients with HTP-AP.Sanger sequencing was used for validation.Bioinformative methods including mutation search,conservative analysis and pathogenicity were used to predict the functions of related mutations.3D structural modeling were further used to evaluate the structure and function of potential mutated protein.ResultsOf 495 HTG-AP patients,275 patients(55.78%)carried APOA5 exomic variants,including 2 common missense polymorphisms as c.457G>A(100 heterozygotes and 13 homozygotes,with a prevalence of 22.83%),and c.553G>T(111 heterozygotes and 31 homozygotes,with a prevalence of 28.69%),as well as 13 rare APOA5 variants(all heterozygotes).In particular,62 cases of enrolled patients were those suffering acute pancreatitis in pregnancy(APIP),and among them 37 carriers(58.06%)of APOA5 variants were found.Furthermore,25(67.57%)of the APIPs carrying c.553G>T missense polymorphism,and among them 1 patient was compound with a novel APOA5 frame-shift variant c.230dupT(p.S78Efs).As bioinformatics predicted,the frame-shift variant c.230dupT was probably pathogenic and missense variant c.553G>T had potential pathogenecity,whereas the 3D-modeling of protein structure suggested that the p.Ser78fs shifting was clearly loss-of-function(LoF),and the p.Gly185Cys substitution was potential LoF.ConclusionsThe current study indicates that prevalence of APOA5 gene deficiency is found in HTG-AP patients,and the interaction between APOA5 gene deficiency and pregnancy plays an important role in the development and recurrence of HTG-APIP.

关 键 词：急性胰腺炎 高三酰甘油血症 载脂蛋白A类 基因突变 

分 类 号：R576[医药卫生—消化系统]