DNA methylation levels may contribute to severe hypertriglyceridemia in multifactorial chylomicronemia syndrome.

Background And Aims: 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.

Methods: 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.

Results: 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).

Conclusion: 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.