Guay Simon-Pierre, Paquette Martine, Taschereau Amélie, Desgagné Véronique, Bouchard Luigi, Bernard Sophie, Baass Alexis
Genetic Dyslipidemias Clinic of the Montreal Clinical Research Institute, Montréal, Québec, Canada; Department of Pediatric, Division of Medical Genetics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
Genetic Dyslipidemias Clinic of the Montreal Clinical Research Institute, Montréal, Québec, Canada.
Clin Biochem. 2025 Jan;135:110873. doi: 10.1016/j.clinbiochem.2025.110873. Epub 2025 Jan 3.
Familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS) are the two main causes of severe hypertriglyceridemia (sHTG). FCS is a rare autosomal recessive form of sHTG, whereas MCS is mainly polygenic in nature with both common and rare variants accumulating and leading to sHTG. However, 30 to 50% of MCS patients have no identified genetic cause of sHTG. DNA methylation (DNAm) is a non-traditional heritable factor known to be associated with triglyceride (TG) levels. The aim of this study is to determine if DNAm level at three candidate genes for hypertriglyceridemia (ABCG1, CPT1A and SREBF1) could contribute to sHTG in MCS patients.
A total of 114 MCS and 20 FCS patients were included in this retrospective study. DNAm levels were measured at ABCG1 (cg06500161), CPT1A (cg00574958), and SREBF1 (cg11024682) gene loci using pyrosequencing of bisulfite-treated DNA.
DNAm levels at ABCG1, CPT1A and SREBF1 were significantly associated with TG levels or minimal TG levels in MCS patients. Prevalence of patients with at least 2 loci with DNAm levels into the top tertile of DNAm associated with hypertriglyceridemia was significantly higher in MCS patients with genetically undefined sHTG compared to MCS patients with polygenic sHTG and FCS patients (57 % vs. 24 % vs. 0 %, respectively; p < 0.0001).
This study suggests for the first time that DNAm could contribute to sHTG in MCS patients. It suggests that further studies of epivariations may contribute to better understand the clinical heterogeneity seen in MCS patients.
家族性乳糜微粒血症综合征（FCS）和多因素乳糜微粒血症综合征（MCS）是严重高甘油三酯血症（sHTG）的两个主要病因。FCS是一种罕见的常染色体隐性sHTG形式，而MCS本质上主要是多基因的，常见和罕见变异的积累导致sHTG。然而，30%至50%的MCS患者尚未确定sHTG的遗传病因。DNA甲基化（DNAm）是一种已知与甘油三酯（TG）水平相关的非传统遗传因素。本研究的目的是确定高甘油三酯血症的三个候选基因（ABCG1、CPT1A和SREBF1）处的DNAm水平是否会导致MCS患者出现sHTG。
本回顾性研究共纳入114例MCS患者和20例FCS患者。使用亚硫酸氢盐处理的DNA焦磷酸测序法，测量ABCG1（cg06500161）、CPT1A（cg00574958）和SREBF1（cg11024682）基因位点的DNAm水平。
MCS患者中，ABCG1、CPT1A和SREBF1的DNAm水平与TG水平或最低TG水平显著相关。与多基因sHTG的MCS患者和FCS患者相比，遗传原因不明的sHTG的MCS患者中，至少有2个位点的DNAm水平处于与高甘油三酯血症相关的DNAm最高三分位数的患者比例显著更高（分别为57%、24%和0%；p<0.0001）。
本研究首次表明DNAm可能导致MCS患者出现sHTG。这表明对表观变异的进一步研究可能有助于更好地理解MCS患者中观察到的临床异质性。
