Severe hypertriglyceridemia (hyperTG) is defined clinically as fasting triglycerides (TG) levels ≥ 10 mmol/L1. Severe hyperTG is often caused by the accumulation of chylomicrons in the circulation, a condition known as chylomicronemia syndrome1. Chylomicronemia syndrome is a relatively common metabolic condition in North America population, with an estimated prevalence around 1:10002, 3, 4, 5, 6, 7. However, it is likely underreported, and the prevalence will probably increase in context of the current epidemy of obesity and type 2 diabetes1,4.

Both genetic and environmental factors are known to influence the development of chylomicronemia syndrome1,4. Familial chylomicronemia syndrome (FCS) is a rare monogenic autosomal recessive form of chylomicronemia syndrome with a prevalence of 1 per million8,9. FCS is caused by bi-allelic pathogenic variants in one of the five canonical genes involved in TG metabolism: LPL, APOC2, GPIHBP1, APOA5 and LMF17. FCS represents only up to 3% of the chylomicronemia syndrome8,9. The multifactorial chylomicronemia syndrome (MCS) is much more frequent and represents the vast majority of chylomicronemia syndrome. MCS occurs mainly when both a genetic susceptibility and secondary factors are present and compromise TG metabolism, such as hypothyroidism, unhealthy diet, obesity, uncontrolled diabetes, alcohol intake or some medications4,8,9.

Chylomicronemia syndrome is associated with an increased risk of life-threatening acute pancreatitis, as well as related complications such as chronic pancreatitis and exocrine and endocrine pancreatic insufficiency4,8,9. The vast majority of hyperTG-induced acute pancreatitis are caused by MCS. However, the risk of acute pancreatitis in MCS patients is highly heterogeneous and few predictors have been identified in the last decades11, 12, 13, 14. Our group previously showed that the presence of a rare variant in TG metabolism-related genes, a maximal TG value >40 mmol\L, a gamma-glutamyl transferase (GGT) level >45 U/L, an apolipoprotein B (apoB) level <1 g/L and a fructose consumption >4% of total energy intake were predictor of pancreatitis in MCS patients11. Nevertheless, the independent contribution of these factors explaining the differences in interindividual risk for pancreatitis still remain to be clarified.

Genetic factors are known to influence the risk of pancreatitis15, 16, 17, 18, 19. Both rare and common genetic variants involved in genes associated with trypsinogen activation have been associated with risk of acute or chronic pancreatitis. Recent genome-wide association studies also showed that single nucleotide polymorphisms (SNPs) within PRSS1, SPINK1, PRSS2, CTRC, CLDN2/MORC4, CTRB1/2, TWIST2 and ABCG5/8 gene locus were associated with the risk of pancreatitis15, 16, 17, 18, 19. Rosendahl et al. previously showed that individual carrying more than two common SNPs in pancreatitis candidate genes were more prone to develop alcoholic chronic pancreatitis15. It was also recently suggested that the accumulation of common variants in TG metabolism-related genes, estimated with a polygenic risk score (PRS), could potentially explain, at least partially, the pancreatitis risk in severe hypertriglyceridemia19,20. However, the role of common genetic determinants of pancreatitis itself in MCS remains unclear. The objective of our study was therefore to determine if a pancreatitis-PRS could be a predictor of acute pancreatitis in MCS patients.