背景:严重的高甘油三酯血症可由编码与富含甘油三酯的脂蛋白代谢有关的蛋白质的基因中的致病变体引起。在这方面的关键蛋白质是脂蛋白脂酶(LPL),其水解这些脂蛋白中的甘油三酯。另一种重要的蛋白是糖基磷脂酰肌醇锚定的高密度脂蛋白结合蛋白1(GPIHBP1),其将LPL转运至内皮细胞的腔侧。
目的:我们的目的是在459名血清甘油三酯水平≥20mmol/l的连续无关受试者中确定高甘油三酯血症的遗传原因。从1998年到2021年,这些患者被转诊进行分子遗传检测。此外,我们想研究GPIHBP1自身抗体是否也是高甘油三酯血症的原因.
方法:编码LPL的基因的分子遗传分析,GPIHBP1,载脂蛋白C2,脂肪酶成熟因子1和载脂蛋白A5以及载脂蛋白E基因分型,在所有459例患者中进行。在进行分子遗传测试后约9年,从132名患者中获得血清以测量GPIHBP1自身抗体。
结果:在459例患者中有4例(0.9%)发现了单基因病因,9例(2.0%)患者由于载脂蛋白E2纯合性而出现脂蛋白血症。132名(0.8%)患者中有一名患有GPIHBP1自身抗体综合征。
结论:只有0.9%的患者患有单基因高甘油三酯血症,只有0.8%患有GPIHBP1自身抗体综合征。后一个数字很可能被低估,因为血清样本是在首次发现高甘油三酯血症大约九年后获得的。需要在临床医学中实施GPIHBP1自身抗体的测量以确保采取适当的治疗行动。
BACKGROUND: Severe hypertriglyceridemia can be caused by pathogenic variants in genes encoding proteins involved in the metabolism of triglyceride-rich lipoproteins. A key protein in this respect is lipoprotein lipase (LPL) which hydrolyzes triglycerides in these lipoproteins. Another important protein is glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) which transports LPL to the luminal side of the endothelial cells.
OBJECTIVE: Our objective was to identify a genetic cause of hypertriglyceridemia in 459 consecutive unrelated subjects with levels of serum triglycerides ≥20 mmol/l. These patients had been referred for molecular genetic testing from 1998 to 2021. In addition, we wanted to study whether GPIHBP1 autoantibodies also were a cause of hypertriglyceridemia.
METHODS: Molecular genetic analyses of the genes encoding LPL, GPIHBP1, apolipoprotein C2, lipase maturation factor 1 and apolipoprotein A5 as well as apolipoprotein E genotyping, were performed in all 459 patients. Serum was obtained from 132 of the patients for measurement of GPIHBP1 autoantibodies approximately nine years after molecular genetic testing was performed.
RESULTS: A monogenic cause was found in four of the 459 (0.9%) patients, and nine (2.0%) patients had dyslipoproteinemia due to homozygosity for apolipoprotein E2. One of the 132 (0.8%) patients had GPIHBP1 autoantibody syndrome.
CONCLUSIONS: Only 0.9% of the patients had monogenic hypertriglyceridemia, and only 0.8% had GPIHBP1 autoantibody syndrome. The latter figure is most likely an underestimate because serum samples were obtained approximately nine years after hypertriglyceridemia was first identified. There is a need to implement measurement of GPIHBP1 autoantibodies in clinical medicine to secure that proper therapeutic actions are taken.