Acute pancreatitis risk in multifactorial chylomicronemia syndrome depends on the molecular cause of severe hypertriglyceridemia

Simon-Pierre Guay; Martine Paquette; Amélie Taschereau; Lysanne Girard; Véronique Desgagné; Luigi Bouchard; Sophie Bernard; Alexis Baass

doi:10.1016/j.atherosclerosis.2024.117489

Acute pancreatitis risk in multifactorial chylomicronemia syndrome depends on the molecular cause of severe hypertriglyceridemia

Atherosclerosis. 2024 Feb 27:117489. doi: 10.1016/j.atherosclerosis.2024.117489. Online ahead of print.

Authors

Simon-Pierre Guay¹, Martine Paquette², Amélie Taschereau³, Lysanne Girard³, Véronique Desgagné⁴, Luigi Bouchard⁵, Sophie Bernard², Alexis Baass⁶

Affiliations

¹ Genetic Dyslipidemias Clinic of the Montreal Clinical Research Institute, Montréal, Québec, Canada; Department of Medicine, Division of Endocrinology, Université de Montréal, Montréal, Québec, Canada.
² Genetic Dyslipidemias Clinic of the Montreal Clinical Research Institute, Montréal, Québec, Canada.
³ Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
⁴ Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada; Clinical Department of Laboratory Medicine, Centre Intégré Universitaire de Santé et de Services Sociaux (CIUSSS) Du Saguenay-Lac-Saint-Jean - Hôpital de Chicoutimi, Saguenay, Québec, Canada.
⁵ Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada; Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
⁶ Genetic Dyslipidemias Clinic of the Montreal Clinical Research Institute, Montréal, Québec, Canada; Department of Medicine, Divisions of Experimental Medicine and Medical Biochemistry, McGill University, Montréal, Québec, Canada. Electronic address: Alexis.Baass@ircm.qc.ca.

PMID: 38448342
DOI: 10.1016/j.atherosclerosis.2024.117489

Abstract

Background and aims: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia (hyperTG) associated with an increased risk of acute pancreatitis (AP). Severe hyperTG is mainly polygenic in nature, either caused by the presence of heterozygous pathogenic variants (PVs) in TG-related metabolism genes or by accumulation of common variants in hyperTG susceptibility genes. This study aims to determine if the risk of AP is similar amongst MCS patients with different molecular causes of severe hyperTG.

Methods: This study included 114 MCS patients who underwent genetic testing for PVs in TG-related metabolism genes and 16 single nucleotide polymorphisms (SNPs) in hyperTG susceptibility genes. A weighted TG-polygenic risk score (TG-PRS) was calculated. A TG-PRS score ≥ 90th percentile was used to define a high TG-PRS.

Results: Overall, 66.7% of patients had severe hyperTG of polygenic origin. MCS patients with only a PV and those with both a PV and high TG-PRS were more prone to have maximal TG concentration ≥ 40 mmol/L (OR 5.33 (1.55-18.36); p = 0.008 and OR 5.33 (1.28-22.25); p = 0.02), as well as higher prevalence of AP (OR 3.64 (0.89-14.92); p = 0.07 and OR 11.90 (2.54-55.85); p = 0.002) compared to MCS patients with high TG-PRS alone.

Conclusions: This is the first study to show that MCS caused by a high TG-PRS and a PV is associated with higher risk of AP, similar to what is seen in the monogenic form of severe hyperTG. This suggests that determining the molecular cause of severe hyperTG could be useful to stratify the risk of pancreatitis in MCS.

Keywords: Acute pancreatitis; Multifactorial chylomicronemia syndrome; Polygenic risk score; Rare pathogenic variants; Severe hypertriglyceridemia.