Browsing by Autor "Mateo Amaya-Montoya"

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8293 The Genetic Landscape of Severe Hypertriglyceridemia in a Multiracial Latino Population
(Endocrine Society, 2024) Carlos O. Mendivil; Kathalina Puerto-Baracaldo; Mateo Amaya-Montoya; Gustavo Adolfo Parra-Serrano; Diana C Prada-Robles; Sergio Serrano‐Gómez; Lilliana María Giraldo; María Carolina Fragozo-Ramos; Verónica Tangarife; Germán Camilo Giraldo
Abstract Disclosure: C.O. Mendivil: None. K. Puerto-Baracaldo: None. M. Amaya-Montoya: None. G. Parra-Serrano: None. D.C. Prada-Robles: None. S. Serrano-Gómez: None. L.M. Restrepo Giraldo: None. M.C. Fragozo-Ramos: None. V. Tangarife: None. G. Giraldo-González: None. C.A. Builes-Barrera: None. M.S. Naranjo-Vanegas: None. A. Gómez-Aldana: None. J.P. Llano: None. N. Gil-Ochoa: None. L.D. Nieves-Barreto: None. P.V. Gaete: None. M. Pérez-Mayorga: None. Background: Severe hypertriglyceridemia (sHTG) increases the risk of life-threatening acute pancreatitis and several other conditions. Primary sHTG is often due to mutations in LPL, the gene encoding lipoprotein lipase, but may also result from mutations in genes for the proteins involved in LPL folding (LMF-1), transport (GPIHBP-1), polymerization (ApoA-V) or activation (apoC-II). Rare biallelic pathogenic mutations in these genes result in Familial Chylomicronemia Syndrome (FCS), while heterozygous mutations manifest as Multifactorial Chylomicronemia Syndrome (MCS). Plasma TG in these two conditions overlap. The genetic makeup of Latin Americans is quite particular, with intermixing of genetic pools of European, Native American, and African origin. Despite this, data on the genetic basis of HTG in Latin American populations are extremely scarce. We aimed to identify the most frequent genetic variants in these “canonical” sHTG genes in patients with sHTG from Colombia, South America. Methods: We studied individuals who had plasma TG&gt;=880 mg/dL at least once in their lifetime. We extracted from them blood, plasma, and leukocyte DNA, and collected clinical information. We amplified by PCR all the exons and intron/exon boundaries of LPL, APOC2, APOA5, GPIHBP1 and LMF1, sequenced the amplicons using capillary (Sanger)-based methodology, and performed bioinformatic analyses of the sequences. For each identified variant we ascertained its location (intronic, exonic or splice site), zygosity, whether it had been described previously, described allelic frequency (when applicable), and pathogenicity classification according to American College of Medical Genetics (ACMG) criteria, which we verified manually. Results: The study included 166 participants (62% male, mean age 50, mean BMI 27.0 Kg/m2, 20.6% had diabetes), peak TG levels ranged between 900 and 11,000 mg/dL. We identified 91 individual variants in the 166 patients. Eighteen of these variants had never been reported before (three in LPL, one in APOC2, three in GPIHBP1, eight in LMF1 and three in APOA5), highlighting the importance of ethnic diversity in studies of genetic causes of human metabolic alterations. We detected a known probably pathogenic variant in LPL (c.953A&gt;G == p.Asn318Ser), a new pathogenic nonsense mutation in LMF1 (c.41C&gt;A p.Ser14*), a new probably pathogenic mutation in LMF1 (c.1527 C&gt;T == p.Pro509Pro), and a known pathogenic mutation in LMF1 (c.779G&gt;A == p.Trp260Ter). In addition, we found in this phenotypically enriched sample a large number (23) of variants of undetermined significance as of the date the study execution was finished. Conclusion: Our results reveal a wide repertoire of plausible genetic causes for sHTG in a Latin American population and unveil LMF1 as a potential major player in the etiology of sHTG in people of Latino ethnicity. Presentation: 6/1/2024
ApoE and apoC-III-defined HDL subtypes: A descriptive study of their LCAT and CETP content and activity
(2020) Mateo Amaya-Montoya; Jairo A Pinzón-Cortés; Lina S Silva-Bermúdez; Daniel Ruiz-Manco; Maria C. Pérez-Matos; Mario A. Jiménez-Mora; Carlos O. Mendivil
<title>Abstract</title> Background High-density lipoproteins (HDL) in plasma are strongly and negatively associated with cardiovascular risk, yet interventions to raise HDL have not improved cardiovascular outcomes. HDL functionality and heterogeneity may hold the clue to this paradox. The apolipoprotein composition of HDL may be an important determinant of their functionality. Lecithin-cholesterol acyl transferase (LCAT) and cholesterol-ester transfer protein (CETP) are key enzymes for HDL-mediated reverse cholesterol transport. We assessed the distribution and activity of LCAT and CETP in HDL subspecies defined by their content of apolipoproteins E (apoE) and C-III (apoC-III) in humans. Methods We isolated in adult humans of both sexes (mean age 55.6, BMI 26.9 Kg/m2, HbA1c 5.4%), four subspecies of HDL containing respectively: No apoE and no apoC-III (E-C-), apoE but not apoC-III (E+C-), apoC-III but no apoE (E-C+) and both apoE and apoC-III (E+C+). In each HDL subspecies, we measured LCAT and CETP concentration and activity using immunoenzymatic and fluorometric methods. Additionally, we determined the size distribution of HDL in each apolipoprotein-defined fraction using non-denaturing electrophoresis and anti-ApoA-I western blot. Results Similar to previous studies, HDL in the E-C- fraction was the predominant subtype. The size distribution of HDL was very similar across all four apolipoprotein-defined fractions. 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+). Despite a much lower LCAT mass, LCAT activity in E+C- HDL was comparable to that in E-C- HDL. Both CETP mass and CETP activity showed only slight variations across HDL subspecies. There was an inverse correlation between plasma LCAT activity and 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 E-C+ alpha 1 HDL and CETP activity in plasma (r=0.52, p=0.025). Conclusions Our results suggest that LCAT activity in humans is influenced by the presence of small interchangeable apolipoproteins. The presence of apoE in small HDL is correlated with increased LCAT activity and esterification of plasma cholesterol.
ApoE and apoC-III-defined HDL subtypes: A descriptive study of their LCAT and CETP content and activity
(2020) Mateo Amaya-Montoya; Jairo A Pinzón-Cortés; Lina S Silva-Bermúdez; Daniel Ruiz-Manco; Maria C. Pérez-Matos; Mario A. Jiménez-Mora; Carlos O. Mendivil
<title>Abstract</title> Background High-density lipoproteins (HDL) functionality predicts cardiovascular risk better than HDL concentrations. The apolipoprotein composition of HDL may be a determinant of their function. Lecithin-cholesterol acyl transferase (LCAT) and cholesterol-ester transfer protein (CETP) are key enzymes for HDL-mediated reverse cholesterol transport. We assessed the distribution and activity of LCAT and CETP in HDL subspecies defined by their content of apolipoproteins E (apoE) and C-III (apoC-III) in humans. Methods We isolated in 18 adult humans of both sexes (mean age 55.6, BMI 26.9 Kg/m2, HbA1c 5.4%), four subspecies of HDL containing respectively: No apoE and no apoC-III (E-C-), apoE but not apoC-III (E+C-), apoC-III but no apoE (E-C+) and both apoE and apoC-III (E+C+). In each HDL subspecies, we measured LCAT and CETP concentration and activity using immunoenzymatic and fluorometric methods. Additionally, we determined the size distribution of HDL in each apolipoprotein-defined fraction using non-denaturing electrophoresis and anti-ApoA-I western blot. Results Similar to previous studies, HDL in the E-C- fraction was the predominant subtype. The size distribution of HDL was very similar across all four apolipoprotein-defined fractions. 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 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 E-C+ alpha 1 HDL and CETP activity in plasma (r=0.52, p=0.025). Conclusions Our results suggest that LCAT activity in humans is influenced by the presence of small interchangeable apolipoproteins. The presence of apoE in small HDL is correlated with increased LCAT activity and esterification of plasma cholesterol.
ApoE and apoC-III-defined HDL subtypes: A descriptive study of their lecithin cholesterol acyl transferase and cholesteryl ester transfer protein content and activity
(Research Square (United States), 2020) Mateo Amaya-Montoya; Jairo A Pinzón-Cortés; Lina S Silva-Bermúdez; Daniel Ruiz-Manco; Maria C. Pérez-Matos; Mario A. Jiménez-Mora; Carlos O. Mendivil
Abstract Background 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. Methods Eighteen adults (ten women and eight men, mean age 55.6, BMI 26.9 Kg/m 2 , HbA1c 5.4%) were studied. HDL from each participant were isolated and divided into four subspecies containing respectively: No apoE and no apoC-III (E-C-), apoE but not apoC-III (E+C-), apoC-III but no apoE (E-C+) and both apoE and apoC-III (E+C+). The concentration and enzymatic activity of LCAT and CETP were measured within each HDL subspecies using immunoenzymatic and fluorometric methods. Additionally, the size distribution of HDL in each apolipoprotein-defined fraction was determined using non-denaturing electrophoresis and anti-apoA-I western blotting. Results 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). Conclusions 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.
Genetic variants in triglyceride metabolism genes among individuals with hypertriglyceridemia in Colombia
(Elsevier BV, 2024) Kathalina Puerto-Baracaldo; Mateo Amaya-Montoya; Gustavo Adolfo Parra-Serrano; Diana C Prada-Robles; Sergio Serrano‐Gómez; Lina M. Restrepo-Giraldo; María Carolina Fragozo-Ramos; Verónica Tangarife; Germán Camilo Giraldo; Carlos Alfonso Builes Barrera