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Abstract：
OBJECTIVE: To study the role of gene mutations in the development of severe hypertriglyceridemia (HTG) in patients with hyperlipidemic acute pancreatitis (HLAP), especially different apolipoprotein A5 (APOA5) mutations.
METHODS: Whole-exome sequencing was performed on 163 patients with HLAP and 30 patients with biliary acute pancreatitis (BAP). The pathogenicity of mutations was then assessed by combining clinical information, predictions of bioinformatics programs, information from multiple gene databases, and residue location and conservation. The pathogenic mutations of APOA5 were visualized using the software.
RESULTS: 1. Compared with BAP patients, pathogenic mutations of APOA5 were frequent in HLAP patients; among them, the heterozygous mutation of p.G185C was the most common. 2. All six pathogenic mutations of APOA5 identified in this study (p.S35N, p.D167V, p.G185C, p.K188I, p.R223C, and p.H182fs) were positively correlated with severe HTG; they were all in the important domains of apolipoprotein A-V (apoA-V). Residue 223 is strictly conserved in multiple mammals and is located in the lipoprotein lipase (LPL)-binding domain (Pro215-Phe261). When Arg 223 is mutated to Cys 223, the positive charge of this residue is reduced, which is potentially destructive to the binding function of apoA-V to LPL. 3. Four new APOA5 mutations were identified, namely c.563A > T, c.667C > T, c.788G > A, and c.544_545 insGGTGC.
CONCLUSIONS: The pathogenic mutations of APOA5 were specific to the patients with HLAP and severe HTG in China, and identifying such mutations had clinical significance in elucidating the etiology and subsequent treatment.
METHODS: Whole-exome sequencing was performed on 163 patients with HLAP and 30 patients with biliary acute pancreatitis (BAP). The pathogenicity of mutations was then assessed by combining clinical information, predictions of bioinformatics programs, information from multiple gene databases, and residue location and conservation. The pathogenic mutations of APOA5 were visualized using the software.
RESULTS: 1. Compared with BAP patients, pathogenic mutations of APOA5 were frequent in HLAP patients; among them, the heterozygous mutation of p.G185C was the most common. 2. All six pathogenic mutations of APOA5 identified in this study (p.S35N, p.D167V, p.G185C, p.K188I, p.R223C, and p.H182fs) were positively correlated with severe HTG; they were all in the important domains of apolipoprotein A-V (apoA-V). Residue 223 is strictly conserved in multiple mammals and is located in the lipoprotein lipase (LPL)-binding domain (Pro215-Phe261). When Arg 223 is mutated to Cys 223, the positive charge of this residue is reduced, which is potentially destructive to the binding function of apoA-V to LPL. 3. Four new APOA5 mutations were identified, namely c.563A > T, c.667C > T, c.788G > A, and c.544_545 insGGTGC.
CONCLUSIONS: The pathogenic mutations of APOA5 were specific to the patients with HLAP and severe HTG in China, and identifying such mutations had clinical significance in elucidating the etiology and subsequent treatment.
摘要：
目的：研究基因突变在高脂血症性急性胰腺炎（HLAP）患者严重高甘油三酯血症（HTG）发展中的作用。特别是不同的载脂蛋白A5（APOA5）突变。
方法：对163例HLAP患者和30例胆源性急性胰腺炎（BAP）患者进行全外显子组测序。然后通过结合临床信息评估突变的致病性，生物信息学项目的预测，来自多个基因数据库的信息，以及残留物的位置和保护。使用该软件可视化APOA5的致病突变。
结果：1.与BAP患者相比，APOA5的致病突变在HLAP患者中常见；其中，p.G185C的杂合突变最为常见。2.在这项研究中确定了APOA5的所有六个致病性突变（p。S35N,p.D167V,p.G185C,p.K188I,p.R223C,和p.H182fs）与重度HTG呈正相关；它们都在载脂蛋白A-V（apoA-V）的重要结构域中。残基223在多种哺乳动物中严格保守，位于脂蛋白脂肪酶（LPL）结合域（Pro215-Phe261）中。当Arg223突变为Cys223时，该残基的正电荷减少，这可能会破坏apoA-V与LPL的结合功能。3.发现了四个新的APOA5突变，即c.563A>T，c.667C>T，c.788G>A，和c.544_545inSGTGC。
结论：APOA5的致病突变在中国HLAP和重度HTG患者中具有特异性。鉴定这些突变对阐明病因和后续治疗具有临床意义。
方法：对163例HLAP患者和30例胆源性急性胰腺炎（BAP）患者进行全外显子组测序。然后通过结合临床信息评估突变的致病性，生物信息学项目的预测，来自多个基因数据库的信息，以及残留物的位置和保护。使用该软件可视化APOA5的致病突变。
结果：1.与BAP患者相比，APOA5的致病突变在HLAP患者中常见；其中，p.G185C的杂合突变最为常见。2.在这项研究中确定了APOA5的所有六个致病性突变（p。S35N,p.D167V,p.G185C,p.K188I,p.R223C,和p.H182fs）与重度HTG呈正相关；它们都在载脂蛋白A-V（apoA-V）的重要结构域中。残基223在多种哺乳动物中严格保守，位于脂蛋白脂肪酶（LPL）结合域（Pro215-Phe261）中。当Arg223突变为Cys223时，该残基的正电荷减少，这可能会破坏apoA-V与LPL的结合功能。3.发现了四个新的APOA5突变，即c.563A>T，c.667C>T，c.788G>A，和c.544_545inSGTGC。
结论：APOA5的致病突变在中国HLAP和重度HTG患者中具有特异性。鉴定这些突变对阐明病因和后续治疗具有临床意义。
