Abstract
BACKGROUND AND AIMS: 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.