Both low-fat and low-carbohydrate diets reduce triglyceride concentration in subjects with multifactorial chylomicronemia syndrome: a randomized crossover study.

Multifactorial chylomicronemia syndrome (MCS) is a complex disease including a genetic component and the presence of lifestyle-related risk factors. We hypothesized that, in subjects with MCS, there would be a greater decrease in plasma triglycerides (TG) with a low-fat (F) diet than with a low-carbohydrate (C) diet. In secondary analyses, we tested the effect of both diets on TG concentration according to the presence or absence of a rare variant in the LPL gene. This randomized crossover dietary intervention included 12 adult subjects with MCS. Subjects followed 2 isocaloric diets, low-C (C, 35%; F, 45%) and low-F (F, 20%; C, 60%), in random order. Each diet lasted 3 weeks, followed by a 6-hour test meal. Diets were separated by a 2-week washout period. TG concentration in fasting subjects decreased by 55% during low-F diet (P = .002) and by 48% during low-C diet (P = .005). The difference between the 2 diets was not significant. However, we observed a more pronounced decrease in TG concentration (65% ± 17%) with the low-F diet compared with the low-C diet (46% ± 31%) (P = .06) in subjects carrying a rare variant in the LPL gene. This is the first study to show that dietary intervention is effective in MCS subjects. In addition, we highlighted the importance of the genetic profile in the choice of treatment by suggesting that subjects with a rare variant of the LPL gene have a greater reduction of TG concentration with a low-F diet than with a low-C diet.

Paternal inheritance predicts earlier cardiovascular event onset in patients with familial hypercholesterolemia.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a genetic disease, with an autosomal codominant inheritance, predisposing to premature atherosclerotic cardiovascular disease (ASCVD). Paternal or maternal inheritance of the FH-causing mutation may affect the FH phenotype in offspring, but the effect of the genetic transmission on cardiovascular disease risk remains to be established. The aim of the present study is to compare the incidence of cardiovascular events between patients with maternal vs paternal inheritance of familial hypercholesterolemia. METHODS: We prospectively studied 725 genetically-confirmed FH patients (33,805 person-years), including 268 with maternal inheritance and 321 with paternal inheritance of the mutation. ASCVD was defined as angina, myocardial infarction, coronary angioplasty, coronary bypass surgery, claudication, peripheral angioplasty, peripheral arterial surgery, transient ischemic attack, stroke, carotid endarterectomy and CV death. Cox-proportional hazard models and Kaplan-Meier analysis were used to compare the two groups. RESULTS: Before 50 years of age, paternal inheritance of FH was associated with a 1.5-fold increased risk for ASCVD, as compared to maternal inheritance (HR 1.59, 95% CI 1.11-2.28, p = 0.01). This association remained significant after adjusting for confounding factors (HR 1.49, 95% CI 1.00-2.23, p = 0.05). The age of first ASCVD event was also significantly lower in the paternal inheritance group (42 years) than in the maternal inheritance group (46 years), p = 0.02. CONCLUSIONS: This study suggests that paternal inheritance of the FH-causing mutation was associated with an earlier cardiovascular event onset compared to maternal inheritance. The mechanisms behind these findings remain to be established.

ANKS1A genotype predicts cardiovascular events in patients with familial hypercholesterolemia.

BACKGROUND: The rs17609940 variant of the ANKS1A gene has been associated with coronary artery disease (CAD) risk in genome-wide association studies (GWAS), but no study has yet replicated this association in familial hypercholesterolemia (FH) population. OBJECTIVE: The aim of this study is to validate the association between the rs17609940 genotype and incident major adverse cardiovascular events (MACE) in a cohort of genetically-confirmed FH patients. METHODS: This association study includes 725 genetically-confirmed FH patients with a median observation period of 50 years (33 805 person-years). MACE were defined as either myocardial infarction (MI), stroke, coronary revascularization, hospital admission for unstable angina and cardiovascular disease (CVD) death. The rs17609940 genotype was imputed with an imputation quality of 0.831 following an exome chip genotyping method (Illumina). RESULTS: The cohort comprised 469 subjects with GG genotype, 218 subjects with CG genotype and 38 subjects with CC genotype. All baseline characteristics were balanced between the three groups. The CC genotype of rs17609940 was associated with a significant lower risk of incident MACE compared to GG and GC carriers in a recessive model (HR 0.30, 95% CI 0.11-0.82, p=0.02). Even after correction for confounding cardiovascular risk factors, the association between the ANKS1A polymorphism and incident MACE remained strongly significant. CONCLUSIONS: We demonstrated that the rs17609940 SNP of the ANKS1A gene is associated with the risk of incident MACE in FH subjects. The exact mechanism underlying this association remains to be clarified.

Rare Variants in Triglycerides-Related Genes Increase Pancreatitis Risk in Multifactorial Chylomicronemia Syndrome.

CONTEXT: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Montreal-FH-SCORE Predicts Coronary Artery Calcium Score in Patients With Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a monogenic disease characterized by a high concentration of low-density lipoprotein cholesterol. This population is considered to be at high cardiovascular risk; however, disease evolution remains heterogeneous among individuals. The coronary artery calcium (CAC) score is currently the best predictor of incidental major cardiovascular events in primary prevention in the general population. Few studies have described the CAC score in FH populations. METHODS: The objective of our study was to determine the predictors of the CAC score in FH patients. We retrospectively studied FH patients followed at the Montreal Clinical Research Institute (IRCM) Lipid Clinic who had a cardiac scan for CAC score, using the Agatston method, between 2013 and 2019. RESULTS: Final analysis included 62 FH patients. Mean age was 48 ± 14 years old, and 48% were men. Overall, 25 patients had a CAC score of 0 (40%), and 37 patients had a nonzero CAC score (60%). Sex, age, Montreal-FH-SCORE (MFHS), waist circumference, and statin exposure in years were significant predictors (P ≤ 0,05) of a nonzero CAC score in a univariate model. MFHS was the only factor that remained significant in a multivariate model (odds ratio 1.34, 95% confidence interval 1.11-1.61, P = 0.002). CONCLUSIONS: In conclusion, we found that MFHS, which includes traditional cardiovascular risk factors, was a predictor of a nonzero CAC score in FH patients. This finding suggests that MFHS may play a role in determining the cardiovascular risk and therefore the intensity of treatment in FH patients.

CONTEXTE: L'hypercholestérolémie familiale (HF) est une maladie monogénique caractérisée par une forte concentration de cholestérol des lipoprotéines de basse densité. La population touchée est considérée comme étant exposée à un risque cardiovasculaire élevé; toutefois, l'évolution de la maladie demeure hétérogène d'une personne à l'autre. À l'heure actuelle, le score calcique coronaire (SCC) est le meilleur outil prédictif de manifestations cardiovasculaires majeures fortuites en prévention primaire dans la population générale. Peu d'études ont décrit le SCC dans des populations atteintes de HF. MÉTHODOLOGIE: L'objectif de notre étude était de déterminer les facteurs prédictifs du SCC chez les patients atteints de HF. Nous avons étudié de façon rétrospective des patients atteints de HF qui étaient suivis à la clinique de lipides de l'Institut de recherches cliniques de Montréal (IRCM) et chez qui le score SCC avait été mesuré pendant un examen de tomodensitométrie cardiaque, au moyen de la méthode d'Agatston, entre 2013 et 2019. RÉSULTATS: L'analyse finale a porté sur 62 patients atteints de HF. L'âge moyen était de 48 ± 14 ans et la proportion d'hommes était de 48 %. Dans l'ensemble, 25 patients avaient un SCC de 0 (40 %) et 37, un SCC différent de zéro (60 %). Le sexe, l'âge, le score MFHS (Montreal-FH-SCORE), le tour de taille et le nombre d'années d'exposition aux statines ont été des facteurs prédictifs significatifs (p ≤ 0,05) d'un SCC différent de zéro dans un modèle à une variable. Le score MFHS est le seul facteur qui est demeuré significatif dans un modèle à plusieurs variables (rapport de cotes : 1,34; intervalle de confiance à 95 % : 1,11 à 1,61; p = 0,002). CONCLUSIONS: En conclusion, nous avons observé que le score MFHS, qui englobe les facteurs classiques de risque cardiovasculaire, était un facteur prédictif d'un SCC différent de zéro chez les patients atteints de HF. Cette observation semble indiquer que le score MFHS pourrait jouer un rôle dans la détermination du risque cardiovasculaire et, par conséquent, dans l'intensité du traitement chez les patients atteints de HF.

The ZPR1 genotype predicts myocardial infarction in patients with familial hypercholesterolemia.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.