Rare Variants in Triglycerides-Related Genes Increase Pancreatitis Risk in Multifactorial Chylomicronemia Syndrome

Abstract

Context Severe hypertriglyceridemia (fasting triglycerides (TG) concentration ≥ 10 mmol/L) can be caused by multifactorial chylomicronemia syndrome (MCS) or familial chylomicronemia syndrome (FCS). Both conditions are associated with an increased risk of acute pancreatitis. The clinical differences between MCS patients with or without a rare variant in TG-related genes have never been studied. Objectives To compare the clinical and biochemical characteristics of FCS, positive-MCS patients and negative-MCS patients, as well as to investigate the predictors of acute pancreatitis in MCS patients. Methods All patients referred at the clinic for severe hypertriglyceridemia underwent genetic testing for the 5 canonical genes involved in TG metabolism (LPL, APOC2, GPIHBP1, APOA5, and LMF1) using next-generation sequencing. Results A total of 53 variant negative-MCS, 22 variant positive-MCS and 28 FCS subjects were included in this retrospective cross-sectional study. A significant difference was observed in the prevalence of pancreatitis (9%, 41% and 61%) and multiple pancreatitis (6%, 23% and 46%) in the negative-MCS, the positive-MCS and the FCS groups, respectively (P<0.0001). Predictors of pancreatitis among MCS subjects included the presence of a rare variant, lower apolipoprotein B, as well as a higher GGT, maximal TG value and fructose consumption. Conclusion We observed that the MCS individuals who carried a rare variant have an intermediate phenotype between FCS and negative-MCS subjects. Since novel molecules such as the antisense oligonucleotide against APOC3 mRNA showed high efficacy in reducing TG levels in patients with multifactorial chylomicronemia, identification of higher-risk MCS patients that would benefit from additional treatment is primordial.

Case Report: Genetic Analysis of PEG-Asparaginase Induced Severe Hypertriglyceridemia in an Adult With Acute Lymphoblastic Leukaemia

“…Recently, it has been hypothesised that severe hypertriglyceridemia could be more frequently caused by the coexistence of rare variants in genes recognized in FCS, as well as by the presence of common or rare variants currently not recognized in the metabolism of triglycerides. This condition has been named multifactorial chylomicronaemia syndrome (MCS) ( Dron and Hegele, 2020 ; Paquette et al, 2021 ). MCS represents a predisposing condition which could expose the patients to a 4 times greater risk of developing severe hypertriglyceridemia ( Dron et al, 2019 ).…”

The Evolving Story of Multifactorial Chylomicronemia Syndrome

“…For example, in the French Canadian population, there exists an enrichment in two LPL variants [p.(Gly215Glu) and p.(Pro234Leu)]. Accordingly, the reported prevalence of MCS patients carrying a rare variant in this population is higher than expected in Caucasian patients ( 30 , 40 ).…”

“…Echoing the findings of Paquette et al ( 24 ), others found significantly lower concentrations of total cholesterol ( 25 ), HDL-C ( 25 – 27 ), and LDL-C ( 26 , 27 ) in FCS patients compared with MCS patients. Importantly, the apolipoprotein B (apoB) concentration in FCS patients was also found to be significantly lower than in MCS patients, with minimal overlap between groups ( 28 , 30 ). Indeed, apoB cutoffs between 0.75 and 0.9 g/L have been proposed in order to differentiate FCS patients from MCS patients ( 28 , 31 ).…”

“…Although there is now a better understanding of the clinical and biochemical differences between FCS and MCS patients, the phenotype heterogeneity among MCS patients remains poorly studied. In a recent publication, the clinical differences between MCS patients with (positive-MCS) vs. without (negative-MCS) a rare deleterious variant in the five canonical genes involved in TG metabolism have been studied for the first time ( 30 ). The main observation of this study is that the positive-MCS group ( n = 22) had an intermediate phenotype severity between the FCS ( n = 28) and negative-MCS ( n = 53) groups.…”

Hypertriglyceridaemia: Contemporary management of a neglected cardiovascular risk factor

“…A recent study also showed that MCM patients with a rare heterozygote variant of LPL appear to have an intermediate risk of developing pancreatitis with an intermediate phenotype between MCM patients without rare variants and FCS patients; potentially enabling identification of higher-risk MCS patients who would benefit from additional treatment 14 .…”