Hypertriglyceridemia (hyperTG) is a common dyslipidemia with a significant genetic component, especially the severe form of hyperTG. Severe hyperTG is defined clinically as triglyceride (TG) concentration ≥ 10 mmol/L [1] and is present in around 1 in 400 North American adults [2]. Severe hyperTG is often caused by the accumulation of chylomicrons in circulation, a condition known as chylomicronemia syndrome [1]. Two main clinical presentations of chylomicronemia syndrome have been described: familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS) [3,4]. FCS is a rare monogenic autosomal recessive form of chylomicronemia syndrome caused by bi-allelic pathogenic variants (PVs) in the five canonical TG-related metabolism genes: LPL, APOC2, GPIHBP1, APOA5 and LMF1 [3,5]. Whereas FCS represents only 3% of chylomicronemia syndromes, MCS is much more frequent and represents most cases [3,4,6].

Chylomicronemia syndrome is associated with an increased risk of life-threatening acute pancreatitis [3,4,6]. HyperTG-induced acute pancreatitis is known to be associated with higher mortality and morbidity compared to other forms of acute pancreatitis [7]. FCS is associated with a higher risk of acute pancreatitis compared to MCS, but the vast majority of hyperTG-induced acute pancreatitis are observed in MCS patients due to its larger prevalence [3,8]. The risk of acute pancreatitis in MCS patients is highly heterogeneous and few predictors have been identified [[8], [9], [10], [11], [12]]. Although the most consistent risk factor of acute pancreatitis in MCS remains the maximal TG concentration, this risk factor alone is insufficient to explain the difference in interindividual risk for acute pancreatitis in this population [8].

MCS occurs mainly when both a genetic susceptibility and secondary factors are present and compromise TG metabolism [3,4,6]. Genetic components of MCS include both the presence of rare heterozygous PVs in TG-related metabolism genes as well as the extreme accumulation of common single nucleotide polymorphisms (SNPs) in hyperTG susceptibility genes [13,14]. Extreme accumulation of common SNPs can be established by using a TG-polygenic risk score (PRS) [13,14]. Indeed, Dron et al. previously showed that severe hyperTG was mainly polygenic in nature, with higher prevalence of PVs and high TG-PRS in individuals with severe hyperTG than in a control population [13]. Interestingly, our team previously showed that the presence of a heterozygous PV in one of the TG-related metabolism genes was a significant predictor of acute pancreatitis in MCS [8]. More recently, Deshotels et al. showed that both the presence of heterozygous PVs in a TG-related metabolism gene and high TG-PRS in a cohort of patients with mild to severe hyperTG was associated with a higher risk of acute pancreatitis compared to those without a PV and with a low TG-PRS [15]. However, the impact of an extreme TG-PRS on the risk of acute pancreatitis in patients with MCS remains unknown. The objective of our study was therefore to determine if the risk of acute pancreatitis is similar amongst MCS patients with different molecular causes of severe hyperTG.