Abstract：
Severe hypertriglyceridemia is a pathological condition caused by genetic factors alone or in combination with environmental factors, sometimes leading to acute pancreatitis (AP). In this study, exome sequencing and biochemical analyses were performed in 4 patients with hypertriglyceridemia complicated by obesity or diabetes with a history of AP or decreased post-heparin LPL mass. In a patient with a history of AP, SNP rs199953320 resulting in LMF1 nonsense mutation and APOE rs7412 causing apolipoprotein E2 were both found in heterozygous form. Three patients were homozygous for APOA5 rs2075291, and one was heterozygous. ELISA and Western blot analysis of the serum revealed the existence of apolipoprotein A-V in the lipoprotein-free fraction regardless of the presence or absence of rs2075291; furthermore, the molecular weight of apolipoprotein A-V was different depending on the class of lipoprotein or lipoprotein-free fraction. Lipidomics analysis showed increased serum levels of sphingomyelin and many classes of glycerophospholipid; however, when individual patients were compared, the degree of increase in each class of phospholipid among cases did not coincide with the increases seen in total cholesterol and triglycerides. Moreover, phosphatidylcholine, lysophosphatidylinositol, and sphingomyelin levels tended to be higher in patients who experienced AP than those who did not, suggesting that these phospholipids may contribute to the onset of AP. In summary, this study revealed a new disease-causing gene mutation in LMF1, confirmed an association between overlapping of multiple gene mutations and severe hypertriglyceridemia, and suggested that some classes of phospholipid may be involved in the pathogenesis of AP.
摘要：
严重的高甘油三酯血症是由遗传因素单独或与环境因素联合引起的病理状况，有时导致急性胰腺炎（AP）。在这项研究中,我们对4例合并肥胖或糖尿病的高甘油三酯血症患者进行了外显子组测序和生化分析,这些患者有AP病史或肝素后LPL质量下降.有AP病史的患者,导致LMF1无义突变的SNPrs19995320和导致载脂蛋白E2的APOErs7412均以杂合形式发现。3例患者为APOA5rs2075291纯合，1例为杂合。血清的ELISA和Westernblot分析显示，无论是否存在rs2075291，无脂蛋白部分中都存在载脂蛋白A-V；此外，载脂蛋白A-V的分子量因脂蛋白类别或无脂蛋白组分而异.脂质组学分析显示鞘磷脂和许多种类的甘油磷脂的血清水平升高；然而，当个体患者进行比较时，病例中各类磷脂的增加程度与总胆固醇和甘油三酯的增加不一致.此外，磷脂酰胆碱，溶血磷脂酰肌醇，经历过AP的患者的鞘磷脂水平往往高于未经历AP的患者，这表明这些磷脂可能有助于AP的发作。总之,这项研究揭示了LMF1中一种新的致病基因突变，证实了多个基因突变的重叠与严重的高甘油三酯血症之间的关联，提示某些磷脂可能与AP的发病机制有关。
