👤 Manon Fantino

Severe hypertriglyceridemia (fasting triglycerides [TG] concentration ≥10 mmol/L) can be caused by multifactorial chylomicronemia syndrome (MCS) or familial chylomicronemia syndrome (FCS). Both conditions are associated with an increased risk of acute pancreatitis. The clinical differences between MCS patients with or without a rare variant in TG-related genes have never been studied. To compare the clinical and biochemical characteristics of FCS, positive-MCS patients, and negative-MCS patients, as well as to investigate the predictors of acute pancreatitis in MCS patients. All patients referred at the clinic for severe hypertriglyceridemia underwent genetic testing for the 5 canonical genes involved in TG metabolism (LPL, APOC2, GPIHBP1, APOA5, and LMF1) using next-generation sequencing. A total of 53 variant negative-MCS, 22 variant positive-MCS and 28 FCS subjects were included in this retrospective cross-sectional study. A significant difference was observed in the prevalence of pancreatitis (9%, 41%, and 61%) and multiple pancreatitis (6%, 23%, and 46%) in the negative-MCS, the positive-MCS, and the FCS groups, respectively (P < 0.0001). Predictors of pancreatitis among MCS subjects included the presence of a rare variant, lower apolipoprotein B, as well as higher gamma-glutamyl transferase, maximal TG value, and fructose consumption. We observed that the MCS individuals who carried a rare variant have an intermediate phenotype between FCS and negative-MCS subjects. Since novel molecules such as the antisense oligonucleotide against APOC3 mRNA showed high efficacy in reducing TG levels in patients with multifactorial chylomicronemia, identification of higher-risk MCS patients who would benefit from additional treatment is essential. Show less

The rs964184 variant in the ZPR1 gene has been associated with blood lipids and cardiovascular disease risk in the general population through genome-wide association study, but its effect in patients with familial hypercholesterolemia (FH) has never been studied. The objectives of the present study are to investigate the effect of the rs964184 SNP on blood lipids and on the risk of incident myocardial infarction (MI) in patients with FH. This study included 725 patients with genetically confirmed FH. The MI events that occurred throughout the lifespan until the last medical visit were included. The median observation period was 50 years. An exome chip genotyping method (Illumina) was used to impute the rs964184 genotype. Among the 725 patients, 190 individuals carried one risk allele G (CG genotype), whereas 15 patients were carriers of the GG genotype. A significant difference in circulating triglycerides was observed between the 3 groups (1.33 [1.03-1.73] vs 1.46 [1.09-2.11] vs 1.56 [1.07-2.42] mmol/L, for the CC, CG, and GG carriers, respectively, P = .004 for the analysis of variance). The ZPR1 SNP rs964184 was significantly associated with MI even after correction for classical cardiovascular risk factors (hazard ratio 5.68, 95% confidence interval 2.40-13.45, P = .00008). The cardiovascular risk in patients with FH is highly heterogeneous, and this study suggests that the rs964184 variant of the ZPR1 gene represents one of the important modulating factors. Show less