Pancreatitis Polygenic Risk Score is Associated with Acute Pancreatitis in Multifactorial Chylomicronemia Syndrome

Abstract

Study Funding

This work was supported by the Cardiometabolic Health, Diabetes and Obesity Research Network (CMDO) from Le Fonds de recherche du Québec (FRQS). Luigi Bouchard received a Senior Research Scholar from the FRQS and is a member of the FRQS-Centre Hospitalier

Background/Synopsis

The most common cause of severe hypertriglyceridemia is multifactorial chylomicronemia syndrome (MCS). MCS is associated with an increased risk of acute pancreatitis (AP), but the risk is highly heterogenous between patients. The maximal concentration of triglycerides (TG) and the presence of a heterozygous rare pathogenic variant in a TG-related metabolism gene are known predictors of AP in MCS patients. Previous genome-wide association studies identified pancreatitis susceptibility genes. However, no study has assessed whether the accumulation of common variants in these pancreatitis susceptibility genes could help predict the risk of AP in MCS patients.

Objective/Purpose

To determine if a weighted polygenic risk score (PRS) including common variants in known pancreatitis susceptibility genes is associated with AP in MCS patients.

Methods

A total of 114 patients MCS underwent gene sequencing for the five canonical genes involved in TG metabolism (LPL, APOA5, APOC2, GPIHBP1, and LMF1). In addition, we genotyped eight single nucleotide polymorphisms (SNPs) in genes previously associated with pancreatitis (ABCG8, CLDN2, CTRB1/2, CTRC, PRSS1, PRSS2, SPINK1, and TWIST2). A weighted PRS was calculated to account for the phenotypic effect of each SNP locus.

Results

A high pancreatitis-PRS score (defined as ≥ 0.44 and representing the median PRS score) was associated with a 2.94-fold increased risk of AP (p=0.02) among patients with MCS. The association between the pancreatitis-PRS and AP remained statistically significant after correction for known predictors of acute pancreatitis, including age, sex, body mass index, diabetes, the maximal TG concentration and the presence of a heterozygous pathogenic rare variant in a TG-related metabolism gene (p=0.04). MCS patients with a high pancreatitis - PRS and heterozygous for a pathogenic rare variant in a TG metabolism-related gene had a 9.50-fold increased risk of AP (p=0.001), compared to those with a low-PRS and no pathogenic variant.

Conclusions

This is the first study to show that the accumulation of common variants in known pancreatitis susceptibility genes is associated with AP in MCS patients. MCS patients with both a high pancreatitis-PRS score and a heterozygous pathogenic rare variant in a TG-related metabolism gene have higher risk of AP, similar to what is seen in monogenic form of severe hypertriglyceridemia. Genetic testing, including both rare and common variants, could help clinicians to identify MCS patients who may be at higher risk of acute pancreatitis and who may benefit from precision medicine.