ORF30-05 - Stratifying Severe Hypertriglyceridemia: Genetic Spectrum of Multifactorial Chylomicronemia and Implications for APOC3-Targeted Therapy

Background: Severe hypertriglyceridemia (HTG) is defined as fasting triglyceride (TG) > 885 mg/dL (>10 mmol/L). Patients with severe HTG are sometimes presumed to have familial chylomicronemia syndrome (FCS) – an ultrarare autosomal recessive condition, resulting from biallelic loss-of-function variants in genes involved in intravascular lipolysis. However, only a minority of patients with severe HTG have FCS. Most instead have multifactorial chylomicronemia syndrome (MCS). A subgroup of MCS patients is refractory to treatment and resembles FCS clinically. We stratified a severe HTG cohort to characterize the genotypic spectrum of MCS, evaluate clinical tools to differentiate MCS from FCS, and identify the MCS subgroup most likely to benefit from novel APOC3-targeted therapy.

Methods: This single-center retrospective study included 193 adults with severe HTG from London, ON, Canada. Subjects underwent targeted exome sequencing and were stratified as FCS (biallelic pathogenic variants [PV]) or MCS based on a monoallelic (heterozygous) PV, risk variant (RV), or variant of unknown significance (VUS). Refractory MCS was defined as those with persistent TG >10 mmol/L despite treatment.

Results: Of 193 patients with severe HTG, 11 (5.7%) had genetically confirmed FCS. Of the total MCS group of 182 individuals, 16 (8.8%) had a heterozygous PV, 107 (58.7%) had >1 RVs, 7 (3.8%) had a heterozygous VUS, 6 (3.1%) had undiagnosed familial partial lipodystrophy, and 46 (25.3%) had no identifiable cause, confirming the heterogeneous nature of MCS. FCS patients had higher clinical scores (Moulin score 12.4 ± 1.9, North American FCS [NAFCS] score 76.9 ± 17.0) compared to all MCS subgroups, of whom none had a mean Moulin score ≥10 or NAFCS score ≥50. FCS patients had significantly higher mean TG levels and acute pancreatitis (AP) history than MCS patients overall. 16 individuals (8.3%) had refractory MCS, and were evenly distributed across all MCS subgroups. Mean TG levels were comparable in FCS versus refractory MCS patients (44.2 ± 12.1 vs 39.0 ± 20.1 mmol/L, not significant [NS]). AP history trended non-significantly higher in FCS versus refractory MCS (81.8% vs 56.3%, p = 0.23, NS).

Conclusion: In our severe HTG cohort, we found that: 1) only a small proportion had FCS; 2) MCS was etiologically heterogeneous, with minimal clinical differences between subgroups; 3) clinical scoring systems could differentiate between genetically confirmed FCS and MCS, supporting their utility; 4) a subgroup of 8.3% of refractory MCS patients were distributed evenly among MCS subgroups; and 5) refractory MCS patients exhibited peak TG levels and AP rates comparable to FCS patients, suggesting they might potentially benefit from APOC3-targeted therapy to reduce AP-related morbidity and mortality.