👤 Carlos O Mendivil

Familial chylomicronemia syndrome (FCS) is an ultra-rare disorder associated with pathogenic variants in genes implicated in chylomicron metabolism such as LPL, APOA5, APOC2, GPIHBP1, and LMF1. Patients with FCS have severe hypertriglyceridemia complicated with recurrent episodes of pancreatitis. Volanesorsen is a treatment option for such patients. However, this treatment is not approved or available in all countries. To present the real-life evidence of clinical response to volanesorsen in patients with FCS in Colombia. All patients treated with volanesorsen in Colombia as of June 25, 2024, were included. After informed consent, relevant clinical and laboratory data were obtained through review of clinical charts and records from the volanesorsen patient support program. Ten patients with FCS and treated with volanesorsen were included. Most cases were caused by variants in LPL. A total of 90% of cases had at least 1 episode of pancreatis, the mean number of pancreatitis episodes was 5. Median follow-up was 56.5 weeks (IQR 38.3-82.3). The median highest plasma triglyceride (TG) level before treatment was 3111 mg/dL (IQR 1738-3810), while the median lowest TG level after treatment was 493 mg/dL (IQR 147-812). The mean percent decreases in plasma TG at months 1, 3, 6, and 12 were 53.6%, 59.7%, 51.5%, and 40.5%, respectively. There were no new pancreatitis episodes after initiation of volanesorsen treatment. Side effects were consistent with those reported in clinical trials. Real-life data of volanesorsen treatment for FCS in Colombia demonstrate efficacy and safety similar to pivotal clinical trials. Show less

Familial chylomicronemia syndrome (FCS) is an autosomal recessive disorder that affects approximately 1 to 10 individuals per million and is caused by variants in the genes encoding for the lipoprotein lipase (LPL) enzyme. In addition to its heterogeneous clinical presentation, FCS is characterized by a higher risk of life-threatening, recurrent acute pancreatitis and type 3 diabetes. Since available evidence on FCS in Latin America is limited, there is a clear need for a consensus document that provides relevant recommendations to guide the management of suspected cases and optimize disease diagnosis across the region. A panel of specialists from Latin America with extensive experience in the diagnosis of chylomicronemia was invited to participate in the creation of this document. The modified Delphi technique was used to reach group consensus through multiple rounds of questionnaires using statistical techniques and controlled feedback. Results and discussion: Seventeen recommendations on diagnosis of FCS were generated. This consensus reflects the collaborative efforts of Latin American scientific societies and is essential to suspect and diagnose FCS. The organizations that support this document, including Sociedad Argentina de Lípidos, Federación Argentina de Sociedades de Endocrinología, Fundación Bioquímica Argentina, Corporación Grupo Chileno de Trabajo en Ateroesclerosis, Asociación Colombiana de Endocrinología, Diabetes y Metabolismo, Departamento de Aterosclerose da Sociedade Brasileira de Cardiología, and Sociedad Mexicana de Nutrición y Endocrinología, are a robust support network that might aid the adoption of these recommendations in local healthcare systems. Show less

The genetic substrate of severe hypertriglyceridemia (sHTG) in Latin America is insufficiently understood. To identify genetic variants in genes related to triglyceride (TG) metabolism among adults with sHTG from Colombia. In individuals with plasma TG ≥ 880 mg/dL at least once in their lifetime, we amplified and sequenced all exons and intron/exon boundaries of the genes LPL, APOC2, APOA5, GPIHBP1 and LMF1. For each variant we ascertained its location, zygosity, allelic frequency and pathogenicity classification according to American College of Medical Genetics (ACMG) criteria. The study included 166 participants (62% male, mean age 50 years), peak TG levels ranged between 894 and 11,000 mg/dL. We identified 92 variants: 19 in LPL, 7 in APOC2, 11 in GPIHBP1, 38 in LMF1, and 17 in APOA5. Eighteen of these variants had not been reported. We identified a new pathogenic variant in LMF1 (c.41C>A; p.Ser14*), a new likely pathogenic variant in LMF1 (c.1527 C > T; p.Pro509=, also expressed as c.1447C>T; p.Gln483*), and a known pathogenic variant in LMF1 (c.779G>A; p.Trp260*). Four participants were heterozygous for variant c.953A>G; p.Asn318Ser in LPL, a known risk factor for hypertriglyceridemia. Participants with variants of unknown significance (VUS) in LMF1 had significantly higher peak TG than those with VUS in other genes. Peak TG were 4317 mg/dL in participants with a history of pancreatitis, and 1769 mg/dL in those without it (p = 0.001). Our study identified variants associated with sHTG among Latinos, and showed that genetic variation in LMF1 may be frequently associated with sHTG in this population. Show less

Dietary fats influence gene expression and several metabolic pathways. Therefore, it is crucial to study the role of personal genotypes in the interaction between fat consumption and cardiometabolic markers. This research aimed to determine the interaction of the rs708272 polymorphism of Show less

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive metabolic disorder that causes extremely elevated plasma triglyceride levels, with limited therapeutic options. Volanesorsen is an antisense oligonucleotide approved for its treatment. A 24-year-old woman with genetically diagnosed FCS secondary to a pathogenic variant in Show less

Dyslipidemias are known risk factors for chronic diseases. Precision nutrition interventions are designed according to characteristics, such as diet, phenotype, and genotype. This systematic review aims to define a panel of genetic variants associated with lipid abnormalities that could be later used in nutrigenetic intervention studies. A systematic review is conducted following the PRISMA-P. Studies published from January 2010 to December 2020 in English language and humans are included from PubMed and ScienceDirect databases. Articles that demonstrate a strong association between polymorphisms (single nucleotide variation) of genes involved in lipid metabolism and increased risk for dyslipidemia are included. A total of 3031 articles are screened, but only 51 articles fulfill the inclusion criteria. The genes included are FABP2, MTTP related to CM synthesis and secretion; LPL, LIPC involved in triglyceride hydrolysis; CETP, APOA1, LCAT, ABCA1, and APOA5 related to lipoprotein metabolism, and APOE, LDLR, SCARB1, APOC3 involved in lipid clearance. In this systematic review, genetic variants related to chylomicron synthesis, triglyceride hydrolysis, lipoprotein metabolism, and lipid clearance demonstrate a strong association with lipid abnormalities, which can be used to design precision nutrition interventions that may help to prevent and treat dyslipidemia effectively. Show less

The functionality of high-density lipoproteins (HDL) is a better cardiovascular risk predictor than HDL concentrations. One of the key elements of HDL functionality is its apolipoprotein composition. Lecithin-cholesterol acyl transferase (LCAT) and cholesterol-ester transfer protein (CETP) are enzymes involved in HDL-mediated reverse cholesterol transport. This study assessed the concentration and activity of LCAT and CETP in HDL subspecies defined by their content of apolipoproteins E (apoE) and C-III (apoC-III) in humans. Eighteen adults (ten women and eight men, mean age 55.6, BMI 26.9 Kg/m HDL without apoE or apoC-III was the predominant HDL subtype. The size distribution of HDL was very similar in all the four apolipoprotein-defined subtypes. LCAT was most abundant in E-C- HDL (3.58 mg/mL, 59.6% of plasma LCAT mass), while HDL with apoE or apoC-III had much less LCAT (19.8, 12.2 and 8.37% of plasma LCAT respectively for E + C-, E-C+ and E + C+). LCAT mass was lower in E + C- HDL relative to E-C- HDL, but LCAT activity was similar in both fractions, signaling a greater activity-to-mass ratio associated with the presence of apoE. Both CETP mass and CETP activity showed only slight variations across HDL subspecies. There was an inverse correlation between plasma LCAT activity and concentrations of both E-C+ pre-beta HDL (r = - 0.55, P = 0.017) and E-C- alpha 1 HDL (r = - 0.49, P = 0.041). Conversely, there was a direct correlation between plasma CETP activity and concentrations of E-C+ alpha 1 HDL (r = 0.52, P = 0.025). The presence of apoE in small HDL is correlated with increased LCAT activity and esterification of plasma cholesterol. These results favor an interpretation that LCAT and apoE interact to enhance anti-atherogenic pathways of HDL. Show less

Subspecies of HDL contain apolipoprotein E (apoE) and/or apoCIII. Both proteins have properties that could affect HDL metabolism. The relation between HDL metabolism and risk of coronary heart disease (CHD) is not well understood. Eighteen participants were given a bolus infusion of [D3]L-leucine to label endogenous proteins on HDL. HDL was separated into subspecies containing apoE and/or apoCIII and then into 4 sizes. Metabolic rates for apoA-I in HDL subspecies and sizes were determined by interactive modeling. The concentrations of apoE in HDL that contain or lack apoCIII were measured in a prospective study in Denmark including 1,949 incident CHD cases during 9 years. HDL containing apoE but not apoCIII is disproportionately secreted into the circulation, actively expands while circulating, and is quickly cleared. These are key metabolic steps in reverse cholesterol transport, which may protect against atherosclerosis. ApoCIII on HDL strongly attenuates these metabolic actions of HDL apoE. In the epidemiological study, the relation between HDL apoE concentration and CHD significantly differed depending on whether apoCIII was present. HDL apoE was associated significantly with lower risk of CHD only in the HDL subspecies lacking apoCIII. ApoE and apoCIII on HDL interact to affect metabolism and CHD. ApoE promotes metabolic steps in reverse cholesterol transport and is associated with lower risk of CHD. ApoCIII, when coexisting with apoE on HDL, abolishes these benefits. Therefore, differences in metabolism of HDL subspecies pertaining to reverse cholesterol transport are reflected in differences in association with CHD. Clinicaltrials.gov NCT01399632. This work was supported by NIH grant R01HL095964 to FMS and by a grant to the Harvard Clinical and Translational Science Center (8UL1TR0001750) from the National Center for Advancing Translational Science. Show less