Analyses of familial chylomicronemia syndrome in Pereira, Colombia 2010-2020: a cross-sectional study.

BACKGROUND AND AIM: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive metabolic disorder caused by mutations in genes involved in chylomicron metabolism. On the other hand, multifactorial chylomicronemia syndrome (MCS) is a polygenic disorder and the most frequent cause of chylomicronemia, which results from the presence of multiple genetic variants related to chylomicron metabolism, in addition to secondary factors. Indeed, the genetic determinants that predispose to MCS are the presence of a heterozygous rare variant or an accumulation of several SNPs (oligo/polygenic). However, their clinical, paraclinical, and molecular features are not well established in our country. The objective of this study was to describe the development and results of a screening program for severe hypertriglyceridemia in Colombia. METHODS: A cross-sectional study was performed. All patients aged >18 years with triglyceride levels ≥500 mg/dL from 2010 to 2020 were included. The program was developed in three stages: 1. Review of electronic records and identification of suspected cases based on laboratory findings (triglyceride levels ≥500 mg/dL); 2. Identification of suspected cases based on laboratory findings that also allowed us to exclude secondary factors; 3. Patients with FCS scores <8 were excluded. The remaining patients underwent molecular analysis. RESULTS: In total, we categorized 2415 patients as suspected clinical cases with a mean age of 53 years, of which 68% corresponded to male patients. The mean triglyceride levels were 705.37 mg/dL (standard deviation [SD] 335.9 mg/dL). After applying the FCS score, 2.4% (n = 18) of patients met the probable case definition and underwent a molecular test. Additionally, 7 patients had unique variants in the APOA5 gene (c.694 T > C; p. Ser232Pro) or in the GPIHBP1 gene (c.523G > C; p. Gly175Arg), for an apparent prevalence of familial chylomicronemia in the consulting population of 0.41 per 1.000 patients with severe HTG measurement. No previously reported pathogenic variants were detected. CONCLUSION: This study describes a screening program for the detection of severe hypertriglyceridemia. Although we identified seven patients as carriers of a variant in the APOA5 gene, we diagnosed only one patient with FCS. We believe that more programs of these characteristics should be developed in our region, given the importance of early detection of this metabolic disorder.

Investigation of associations between apolipoprotein A5 and C3 gene polymorphisms with plasma triglyceride and lipid levels.

OBJECTIVE: The aim of this study was to determine frequency and associations between APOA5 c.56C>G, -1131T>C, c.553G>T, and APOC3 -482C>T and SstI gene polymorphisms with hypertriglyceridemia. METHODS: Under a case-control study model, 135 hypertriglyceridemic and 178 normotriglyceridemic control participants were recruited. Polymerase chain reaction and restriction fragment length polymorphism methods were utilized for genotyping. Statistical calculations were performed by comparing allele and genotype frequencies between groups. Clinical characteristics were compared between groups and intra-group genotypes. RESULTS: APOC3 gene -482C>T and SstI polymorphic genotypes and allele frequencies were significantly higher in hypertriglyceridemic group (genotype frequencies, p=0.035, p=0.028, respectively). Regression analysis under unadjusted model confirmed that APOC3 -482C>T and SstI polymorphisms were significantly contributing to have hypertriglyceridemia (p=0.02, odds ratio [OR]=1.831 (95% confidence interval [CI] 1.095-3.060); p=0.04, OR=1.812 (1.031-3.183), respectively). APOA5 c.56C>G was in complete linkage disequilibrium with APOA5 c.553G>T polymorphism (D'=1). CONCLUSION: For the first time in a population sample from Turkey, among the five polymorphisms of APOA5 and APOC3 genes investigated, APOC3 -482C>T and SstI polymorphisms were associated with elevated serum TG levels, while APOA5 c.56C>G, -1131T>C, and c.553G>T polymorphisms were not.

Association of rs662799 and rs5070 genetic polymorphisms with hypertriglyceridemia and atherogenic dyslipidemia in pediatric patients in Southeast Mexico.

BACKGROUND AND AIMS: Triglycerides are the initiators of the metabolic changes that lead to atherogenic dyslipidemia (AD). The APOA5 and APOA1 genes are involved in the response and metabolism of serum lipids and lipoproteins, where single nucleotide polymorphisms (SNP) rs662799 (promoter region) and rs5070 (intronic region) have been associated with the susceptibility to dyslipidemia. Until now, few studies evaluate the association of these polymorphisms with the presentation of hypertriglyceridemia and AD among Mexican children. Therefore, the objective was to determine the association between rs662799 and rs5070 with hypertriglyceridemia and AD in a pediatric population of southeastern Mexico. MATERIALS AND METHODS: A case-control analysis was performed including 268 infants aged 2-16 years, anthropometric, clinical variables, and serum lipid profiles were analyzed. DNA was extracted from blood samples and genotyping of polymorphisms was executed with the TaqMan SNP genotyping assay. Allele and genotypic frequencies were calculated. For genetic association analysis, logistic regression models were fitted according to models of inheritance. RESULTS: The SNP rs662799 (C) was significantly associated with hypertriglyceridemia in the overdominant model (OR=3.89, p=0.001) and AD in the dominant model (OR=4.01, p=0.001). The SNP rs5070 (T) has a protective effect against hypertriglyceridemia in the additive risk model (OR=0.68, p=0.03). CONCLUSION: Polymorphism rs662799 was significantly associated with cases of hypertriglyceridemia and AD in minors in southeastern Mexico. On the other hand, rs5070 polymorphism was not associated with cases of hypertriglyceridemia or AD.

Association of MARC1, ADCY5, and BCO1 Variants with the Lipid Profile, Suggests an Additive Effect for Hypertriglyceridemia in Mexican Adult Men.

Epidemiological studies have reported that the Mexican population is highly susceptible to dyslipidemia. The MARC1, ADCY5, and BCO1 genes have recently been involved in lipidic abnormalities. This study aimed to analyze the association of single nucleotide polymorphisms (SNPs) rs2642438, rs56371916, and rs6564851 on MARC1, ADCY5, and BCO1 genes, respectively, with the lipid profile in a cohort of Mexican adults. We included 1900 Mexican adults from the Health Workers Cohort Study. Demographic and clinical data were collected through a structured questionnaire and standardized procedures. Genotyping was performed using a predesigned TaqMan assay. A genetic risk score (GRS) was created on the basis of the three genetic variants. Associations analysis was estimated using linear and logistic regression. Our results showed that rs2642438-A and rs6564851-A alleles had a risk association for hypertriglyceridemia (OR = 1.57, p = 0.013; and OR = 1.33, p = 0.031, respectively), and rs56371916-C allele a trend for low HDL-c (OR = 1.27, p = 0.060) only in men. The GRS revealed a significant association for hypertriglyceridemia (OR = 2.23, p = 0.022). These findings provide evidence of an aggregate effect of the MARC1, ADCY5, and BCO1 variants on the risk of hypertriglyceridemia in Mexican men. This knowledge could represent a tool for identifying at-risk males who might benefit from early interventions and avoid secondary metabolic traits.

Síndrome de quilomicronemia familiar: experiencia pediátrica en Argentina / Familial chylomicronemia syndrome: pediatric experience in Argentina

El síndrome de quilomicronemia familiar (SQF) es unaenfermedad autosómica recesiva rara, con una prevalencia1:200 000 - 1:1 000 000, y se caracteriza por quilomicronemiaen ayunas y niveles muy elevados de triglicéridos (> 880 mg/dl). LPL es el gen más frecuentemente afectado, luego APOC2,GPIHBP1, APOA5 y LMF1; todos ellos comprometen la función de la lipoproteinlipasa endotelial. El SQF suele presentarseen la infancia con dolor abdominal recurrente, xantomaseruptivos, retraso del crecimiento, pancreatitis y, en ocasiones,asintomático. El tratamiento convencional es la restriccióndietética de grasas. Se muestra el resultado clínico de 20 pacientes pediátricoscon SQF reclutados de 4 hospitales en Argentina.

Familial chylomicronemia syndrome (FCS) is a rare autosomalrecessive disease, prevalence 1:200,000 - 1:1,000,000, andis characterized by fasting chylomicrons and very hightriglycerides > 880 mg/dl. LPL is the most frequentlyaffected gene, then APOC2, GPIHBP1, APOA5, LMF1, all ofthem compromising the function of lipoproteinlipase. FCScommonly presents in childhood with recurrent abdominalpain, eruptive xanthomas, failure to thrive, pancreatitis, andsometimes asymptomatic. The conventional treatment isdietetic fat restriction. The clinical outcome of 20 pediatric patients with FCS recruited from 4 hospitals in Argentina is reported.

[Familial chylomicronemia syndrome: pediatric experience in Argentina]. / Síndrome de quilomicronemia familiar: experiencia pediátrica en Argentina.

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disease, prevalence 1:200,000 - 1:1,000,000, and is characterized by fasting chylomicrons and very high triglycerides > 880 mg/dl. LPL is the most frequently affected gene, then APOC2, GPIHBP1, APOA5, LMF1, all of them compromising the function of lipoproteinlipase. FCS commonly presents in childhood with recurrent abdominal pain, eruptive xanthomas, failure to thrive, pancreatitis, and sometimes asymptomatic. The conventional treatment is dietetic fat restriction. The clinical outcome of 20 pediatric patients with FCS recruited from 4 hospitals in Argentina is reported.

El síndrome de quilomicronemia familiar (SQF) es una enfermedad autosómica recesiva rara, con una prevalencia 1:200 000 - 1:1 000 000, y se caracteriza por quilomicronemia en ayunas y niveles muy elevados de triglicéridos (> 880 mg/ dl). LPL es el gen más frecuentemente afectado, luego APOC2, GPIHBP1, APOA5 y LMF1; todos ellos comprometen la función de la lipoproteinlipasa endotelial. El SQF suele presentarse en la infancia con dolor abdominal recurrente, xantomas eruptivos, retraso del crecimiento, pancreatitis y, en ocasiones, asintomático. El tratamiento convencional es la restricción dietética de grasas. Se muestra el resultado clínico de 20 pacientes pediátricos con SQF reclutados de 4 hospitales en Argentina.

Severe hypertriglyceridemia secondary to splice-site and missense variants in LMF1 in three patients from Ecuador.

Rare pathogenic variants in the LMF1 gene, which encodes lipase maturation factor 1, are a minor cause of familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia. In this report we present three adult patients, all of them born and raised in Quito, Ecuador, with severe hypertriglyceridemia secondary to biallelic LMF1 variants. In two of the three cases (patients 1 and 3), the presentation was acute pancreatitis secondary to plasma triglycerides well above 10 mmol/L. The other case (patient 2) was a sibling of one of the initial patients, who was asymptomatic but markedly hypertriglyceridemic. Next-generation sequencing revealed a homozygous splice-site variant in exon 6 of LMF1 in patients 1 and 2 (c.897G>A, p.Gln299=), and a homozygous missense variant in exon 2 of LMF1 in patient 3 (c.233T>C, p.Leu78Pro). The finding of two disease-causing variants in three patients from the same location raises the question of whether LMF1 may be a more prevalent cause of severe hypertriglyceridemia among Latin-American patients.

Biochemical, Clinical, and Genetic Characteristics of Mexican Patients with Primary Hypertriglyceridemia, Including the First Case of Hyperchylomicronemia Syndrome Due to GPIHBP1 Deficiency.

Primary hypertriglyceridemia (PHTG) is characterized by a high concentration of triglycerides (TG); it is divided between familial hyperchylomicronemia syndrome and multifactorial chylomicronemia syndrome. In Mexico, hypertriglyceridemia constitutes a health problem in which the genetic bases have been scarcely explored; therefore, our objective was to describe biochemical-clinical characteristics and variants in the APOA5, GPIHBP1, LMF1, and LPL genes in patients with primary hypertriglyceridemia. Thirty DNA fragments were analyzed using PCR and Sanger sequencing in 58 unrelated patients. The patients' main clinical-biochemical features were hypoalphalipoproteinemia (77.6%), pancreatitis (18.1%), and a TG median value of 773.9 mg/dL. A total of 74 variants were found (10 in APOA5, 16 in GPIHBP1, 34 in LMF1, and 14 in LPL), of which 15 could be involved in the development of PHTG: 3 common variants with significative odds and 12 heterozygous rare pathogenic variants distributed in 12 patients. We report on the first Mexican patient with hyperchylomicronemia syndrome due to GPIHBP1 deficiency caused by three variants: p.R145*, p.A154_G155insK, and p.A154Rfs*152. Moreover, eleven patients were heterozygous for the rare variants described as causing PHTG and also presented common variants of risk, which could partially explain their phenotype. In terms of findings, two novel genetic variants, c.-40_-22del LMF1 and p.G242Dfs*10 LPL, were identified.

Contribution of APOA5, APOC3, CETP, ABCA1 and SIK3 genetic variants to hypertriglyceridemia development in Mexican HIV-patients receiving antiretroviral therapy.

OBJECTIVE: To investigate the impact of single nucleotide polymorphisms (SNPs) from APOA5, APOC3, CETP, ATP binding cassette transporter A1 and SIK3 genes in the development of hypertriglyceridemia in HIV patients under antiretroviral therapy. MATERIAL AND METHODS: A case-control study was developed. Leukocytic genomic DNA was extracted and genotyping for SNPs rs662799, rs964184, rs5128, rs2854116, rs2854117, rs3764261, rs4149310, rs4149267 and rs139961185 was performed by real time-PCR using TaqMan allelic discrimination assays, in Mexican mestizo patients with HIV infection, with hypertriglyceridemia (>1.7 mmol/L) under antiretroviral therapy. Genetic variants were also investigated in a control group of normolipidemic HIV patients (≤ 1.7 mmol/L). Haplotypes and gene interactions were analyzed. RESULTS: A total of 602 HIV patients were genotyped (316 cases and 286 controls). Age and antiretroviral regimen based on protease inhibitors were associated with hypertriglyceridemia (P = 0.0001 and P = 0.0002. respectively). SNP rs964184 GG genotype in APOA5 gene exhibited the highest association with hypertriglyceridemia risk (OR, 3.2, 95% CI, 1.7-5.8, P = 0.0001); followed by SNP rs139961185 in SIK3 gene (OR = 2.3; (95% CI, 1.1-4.8; P = 0.03 for AA vs. AG genotype; and APOC3 rs5128 GG genotype, (OR, 2.2; 95% CI, 1.1-4.9; P = 0.04) under codominant models. These associations were maintained in the adjusted analysis by age and protease inhibitors based antiretroviral regimens. CONCLUSIONS: This study reveals an association between rs964184 in APOA5; rs5128 in APOC3 and rs139961185 in SIK3 and high triglyceride concentrations in Mexican HIV-patients receiving protease inhibitors. These genetic factors may influence the adverse effects related to antiretroviral therapy.

Familial hypertriglyceridemia: an entity with distinguishable features from other causes of hypertriglyceridemia.

BACKGROUND: Familial hypertriglyceridemia (FHTG) is a partially characterized primary dyslipidemia which is frequently confused with other forms hypertriglyceridemia. The aim of this work is to search for specific features that can help physicians recognize this disease. METHODS: This study included 84 FHTG cases, 728 subjects with common mild-to-moderate hypertriglyceridemia (CHTG) and 609 normotriglyceridemic controls. All subjects underwent genetic, clinical and biochemical assessments. A set of 53 single nucleotide polymorphisms (SNPs) previously associated with triglycerides levels, as well as 37 rare variants within the five main genes associated with hypertriglyceridemia (i.e. LPL, APOC2, APOA5, LMF1 and GPIHBP1) were analyzed. A panel of endocrine regulatory proteins associated with triglycerides homeostasis were compared between the FHTG and CHTG groups. RESULTS: Apolipoprotein B, fibroblast growth factor 21(FGF-21), angiopoietin-like proteins 3 (ANGPTL3) and apolipoprotein A-II concentrations, were independent components of a model to detect FHTG compared with CHTG (AUC 0.948, 95%CI 0.901-0.970, 98.5% sensitivity, 92.2% specificity, P < 0.001). The polygenic set of SNPs, accounted for 1.78% of the variance in triglyceride levels in FHTG and 6.73% in CHTG. CONCLUSIONS: The clinical and genetic differences observed between FHTG and CHTG supports the notion that FHTG is a unique entity, distinguishable from other causes of hypertriglyceridemia by the higher concentrations of insulin, FGF-21, ANGPTL3, apo A-II and lower levels of apo B. We propose the inclusion of these parameters as useful markers for differentiating FHTG from other causes of hypertriglyceridemia.

Contribution of genetic, biochemical and environmental factors on insulin resistance and obesity in Mexican young adults.

Overweight/obesity, dyslipidemias, hypertension and hyperglycemia are strongly related to non-communicable diseases (NCD) in which genetic and environmental factors interact with each other. The Mexican population exhibit a genetic disposition to metabolic syndrome, type 2 diabetes, as well as many forms of dyslipidemia. This study aimed to determine the association between biochemical, genetic and environmental factors in the development of metabolic syndrome (MS), obesity and insulin resistance (IR) in Mexican young adults. Young women and men (n=6750 between 19.3±2.3 years old) participated in a health promotion program from the Autonomous University of Querétaro, México (SU-Salud program). A sub-sample of 665 participants was taken for the determination of single nucleotide polymorphisms (SNP) rs964184 (APOAV), rs9282541 (ABCA1) and rs1260326 (GCKR), using QuantStudio 12K Flex Real-Time PCR System. For the multivariate analysis, a multiple logistic regression was performed. A prevalence of 22% of overweight and 7% of obesity was determined. The main metabolic risk factors were low levels of HDL-C (30%), IR (19%), and a high level of triglycerides (15%). The main factors associated with IR were body fat percentage and triglycerides; SNP for the ABCA1 gene was related to MS, obesity and low HDL-C; SNP for GCKR gene was related to high fasting glycemia, while APOAV SNP was related with MS, hypertriglyceridemia and low HDL-C. Our findings show that the Mexican genetic predisposition to NCD affects young adults, who can suffer MS, obesity and IR. Public health strategies must focus on prevention actions from an early age.

Gene variants in AKT1, GCKR and SOCS3 are differentially associated with metabolic traits in Mexican Amerindians and Mestizos.

Amerindian ancestry appears to be a risk factor for metabolic diseases (MetD), making Mexicans an ideal population to better understand the genetic architecture of metabolic health. In this study, we determine the association of genetic variants previously reported with metabolic entities, in two Mexican populations, including the largest sample of Amerindians reported to date. We investigated the association of eigth single-nucleotide polymorphisms (SNPs) in AKT1, GCKR, and SOCS3 genes with different metabolic traits in 1923 Mexican Amerindians (MAs) belonging to 57 ethnic groups, and 855 Mestizos (MEZs). The allele frequency of 7/8 SNPs showed significant differences between MAs and MEZs. Interestingly, some alleles were monomorphic in particular ethnic groups, and highly frequent in other ones. With the exception of GCKR rs1260326T, as expected, all SNP frequencies in the MEZ population had intermediate values between its two main ancestral populations (MAs and Iberian populations in Spain [IBS]). We detected ethnic differences in linkage disequilibrium patterns and haplotype structure between MAs and MEZs, possibly due to the high genetic heterogeneity in these populations. Remarkably, AKT1 was associated with hypertension in MEZs, but not in MAs. GCKR was associated with protection against type 2 diabetes (T2D) in MAs, and with hypertriglyceridemia and protection against low HDL Cholesterol (HDL-C) levels in MEZs. The CAT haplotype in SOCS3 was associated with metabolic syndrome (MetS) in MEZs, and correlated with protection against high blood pressure (HBP) and risk for high waist circumference and T2D in MAs. Our results show differential genetic associations with metabolic traits between MAs and MEZs, possibly due to the differences in genetic structure between these Mexican populations.

A Common Variation in the Caveolin 1 Gene Is Associated with High Serum Triglycerides and Metabolic Syndrome in an Admixed Latin American Population.

BACKGROUND: The caveolin 1 (CAV1) gene has been associated with metabolic traits in animal models and human cohorts. Recently, a prevalent variant in CAV1 has been found to be related to metabolic syndrome in Hispanics living in North America. Since Hispanics represent an admixed population at high risk for cardiovascular diseases, in this study a Latin American population with a similar genetic background was assessed. OBJECTIVE: To analyze a genetic association between CAV1 and metabolic traits in an admixed Latin American population. METHODS: A cross-sectional study was carried out with adults from the Colombian Caribbean Coast, selected in urban clusters and work places through a stratified sampling to include diverse ages and socioeconomic groups. Blood pressure and waist circumference were registered. Serum concentrations of glucose, triglycerides, and high-density lipoprotein cholesterol were measured from an 8-hr fasting whole-blood sample. Two previously analyzed CAV1 single nucleotide polymorphisms were genotyped (rs926198 and rs11773845). A logistic regression model was applied to estimate the associations. An admixture adjustment was performed through a Bayesian model. RESULTS: A total of 605 subjects were included. rs11773845 was associated with hypertriglyceridemia [odds ratio (OR) = 1.33, p = 0.001] and the metabolic syndrome (OR = 1.53, p = 0.02). When admixture adjustment was performed these genetic associations preserved their statistical significance. There were no significant associations between rs926198 and metabolic traits. CONCLUSIONS: The CAV1 variation rs11773845 was found to be consistently associated with high serum triglycerides and the metabolic syndrome. This is the first report of a relationship between CAV1 variants and serum triglycerides in Latin America.

HHIPL-1 (rs2895811) gene polymorphism is associated with cardiovascular risk factors and cardiometabolic parameters in Mexicans patients with myocardial infarction.

Several studies have reported the role of hedgehog interacting protein-like 1 (HHIPL-1) in different pathologies, including cardiovascular disease. The aim of the present study was to analyze the association of HHIPL-1 (rs2895811) polymorphism with myocardial infarction (MI), cardiometabolic parameters, and traditional cardiovascular risk factors in the Mexican population. The polymorphism was genotyped using a TaqMan assay in 1023 patients with MI and 1105 controls. A similar distribution of the polymorphism was observed between studied groups. However, in patients group, the C allele was associated with a decreased risk of developing hypertriglyceridemia (OR = 0.757, Padditive = 0.030, OR = 0.685, Pdominant = 0.020, OR = 0.691, Pcodominant1 = 0.030), metabolic syndrome (OR = 0.746, Padditive = 0.030, OR = 0.647, Pdominant = 0.005, OR = 0.670, Pheterozygote = 0.015, OR = 0.637, Pcodominant1 = 0.005), and insulin resistance (OR = 0.681, Pdominant = 0.045). The results suggest that HHIPL-1 rs2895811 polymorphism is associated with cardiometabolic parameters in Mexican patients with MI.

Frequency of common polymorphisms in Caveolin 1 (CAV1) gene in adults with high serum triglycerides from Colombian Caribbean Coast / Frecuencia de polimorfismos comunes en el gen de Caveolina 1 (CAV1) en adultos con hipertrigliceridemia en el Caribe Colombiano

Abstract Background: Caveolin 1 gene (CAV1) has been associated with insulin resistance, metabolic syndrome and hypertension in humans. Also, it has been related to high serum triglycerides in rodents, however there is little evidence of this relation in humans. Aim: To describe frequencies of common variations in CAV1 in adults with high serum triglycerides. Methods: A case-control study was carried out with adults from Colombian Caribbean Coast. A whole blood sample was employed to measure serum concentrations of triglycerides, glucose, total cholesterol and HDLc. Six common Single Nucleotide Polymorphism (SNP) in CAV1 were genotyped (rs926198, rs3779512, rs10270569, rs11773845, rs7804372 and rs1049337). Allelic and genotypic frequencies were determined by direct count and Hardy-Weinberg Equilibrium (HWE) was assessed. Case and control groups were compared with null-hypothesis tests. Results: A total of 220 cases and 220 controls were included. For rs3779512 an excess in homozygotes frequency was found within case group (40.4% (GG), 41.3% (GT) and 18.1% (TT); Fis=0.13, p=0.03). Another homozygotes excess among case group was found in rs7804372 (59.5% (TT), 32.3% (TA) and 8.2% (AA); Fis= 0.12, p= 0.04). In rs1049337, cases also showed an excess in homozygotes frequency (52.7% (CC), 35.0% (CT) and 12.3% (TT); Fis= 0.16, p= 0.01). Finally, for rs1049337 there were differences in genotype distribution between case and control groups (p <0.05). Conclusion: An increased frequency of homozygote genotypes was found in subjects with high serum triglycerides. These findings suggest that minor alleles for SNPs rs3779512, rs7804372 and rs1049337 might be associated to higher risk of hypertriglyceridemia.

Resumen Introducción: En humanos, el gen Caveolina 1 (CAV1) ha sido asociado con resistencia a la insulina, síndrome metabólico e hipertensión. Además, ha sido relacionado con hipertrigliceridemia en roedores, sin embargo existe poca evidencia de esta relación en humanos. Objetivo: Describir la frecuencia de variaciones comunes del gen CAV1 en adultos con hipertrigliceridemia. Métodos: Se realizó un estudio de casos y controles con adultos del Caribe Colombiano. Fue usada una muestra de sangre venosa periférica para medir las concentraciones séricas de triglicéridos, glucosa, colesterol total y colesterol HDL. Fueron genotipificados seis Polimorfismos de Nucleótido Simple (SNP) en CAV1 (rs926198, rs3779512, rs10270569, rs11773845, rs7804372 y rs1049337). Las frecuencias alélicas y genotípicas se determinaron por conteo directo y se evaluó el equilibrio de Hardy-Weinberg. Los grupos de casos y controles se compararon con pruebas de hipótesis nula. Resultados: Se incluyeron un total de 220 casos y 220 controles. Para rs3779512 se encontró un exceso de homocigotos en el grupo de casos (40.4% (GG), 41.3% (GT) y 18.1% (TT); Fis= 0.13, p= 0.03). Fue encontrado otro exceso de homocigotos en el grupo de casos al analizar el rs7804372 (59.5% (TT), 32.3% (TA) y 8.2% (AA); Fis= 0.12, p= 0.04). En rs1049337, los casos también tuvieron un exceso en la frecuencia de homocigotos (52.7% (CC), 35.0% (CT) y 12.3% (TT); Fis= 0.16, p= 0.01). Finalmente, hubo diferencias en la distribución genotípica del rs1049337 entre los grupos de casos y controles (p <0.05). Conclusiones: Se encontró una elevada frecuencia de homocigotos en los sujetos con hipertrigliceridemia. Estos hallazgos sugieren que los alelos menores de los SNPs rs3779512, rs7804372 y rs1049337 podrían estar asociados con trigliceridemia elevada.

Variations in ADIPOR1 But Not ADIPOR2 are Associated With Hypertriglyceridemia and Diabetes in an Admixed Latin American Population.

BACKGROUND: Adiponectin is a hormone secreted by adipose tissue. It regulates glycolysis and lipolysis and is involved in the pathophysiology of diabetes and related disorders. Its activity is mainly mediated by the transmembrane receptors AdipoR1 and AdipoR2, which are encoded by ADIPOR1 (1q32.1) and ADIPOR2 (12p13.33) genes, respectively. In genetic association studies, single nucleotide polymorphisms (SNPs) in or near these genes have been associated with metabolic alterations. However, these relationships are still controversial. AIM: The aim of this work was to analyze possible associations between ADIPOR1/2 and diabetes and other metabolic disorders. METHODS: A genetic association study was carried out in an admixed Latin American population. A sample of 200 adults was analyzed. Clinical and serum-biochemical characteristics were measured to diagnose obesity, abdominal obesity, hypertension, hyperglycemia, hypertriglyceridemia, low HDLc, insulin resistance (HOMA-IR), and diabetes. Three SNPs were genotyped in ADIPOR1 (rs10494839, rs12733285, and rs2275737) and ADIPOR2 (rs11061937, rs11612383, and rs2286383). For the association analysis, an additive model was assessed through logistic regression. An admixture adjustment was performed using a Monte-Carlo-Markov-Chain method, assuming a three-hybrid substructure (k = 3). RESULTS: Two SNPs in ADIPOR1 were associated with diabetes: rs10494839 (OR = 3.88, adjusted p < 0.03) and rs12733285 (OR = 4.72, adjusted p < 0.03). Additionally, rs10494839 was associated with hypertriglyceridemia (OR = 2.16, adjusted p < 0.01). None of the SNPs in ADIPOR2 were associated with metabolic disorders. CONCLUSIONS: ADIPOR1 was consistently associated with diabetes and hypertriglyceridemia. This association was maintained even after adjusting for genetic stratification. There were no significant associations involving ADIPOR2.

Frequency of common polymorphisms in Caveolin 1 ( CAV1 ) gene in adults with high serum triglycerides from Colombian Caribbean Coast.

BACKGROUND: Caveolin 1 gene (CAV1) has been associated with insulin resistance, metabolic syndrome and hypertension in humans. Also, it has been related to high serum triglycerides in rodents, however there is little evidence of this relation in humans. AIM: To describe frequencies of common variations in CAV1 in adults with high serum triglycerides. METHODS: A case-control study was carried out with adults from Colombian Caribbean Coast. A whole blood sample was employed to measure serum concentrations of triglycerides, glucose, total cholesterol and HDLc. Six common Single Nucleotide Polymorphism (SNP) in CAV1 were genotyped (rs926198, rs3779512, rs10270569, rs11773845, rs7804372 and rs1049337). Allelic and genotypic frequencies were determined by direct count and Hardy-Weinberg Equilibrium (HWE) was assessed. Case and control groups were compared with null-hypothesis tests. RESULTS: A total of 220 cases and 220 controls were included. For rs3779512 an excess in homozygotes frequency was found within case group (40.4% (GG), 41.3% (GT) and 18.1% (TT); Fis=0.13, p=0.03). Another homozygotes excess among case group was found in rs7804372 (59.5% (TT), 32.3% (TA) and 8.2% (AA); Fis= 0.12, p= 0.04). In rs1049337, cases also showed an excess in homozygotes frequency (52.7% (CC), 35.0% (CT) and 12.3% (TT); Fis= 0.16, p= 0.01). Finally, for rs1049337 there were differences in genotype distribution between case and control groups (p <0.05). CONCLUSION: An increased frequency of homozygote genotypes was found in subjects with high serum triglycerides. These findings suggest that minor alleles for SNPs rs3779512, rs7804372 and rs1049337 might be associated to higher risk of hypertriglyceridemia.

INTRODUCCIÓN: En humanos, el gen Caveolina 1 (CAV1) ha sido asociado con resistencia a la insulina, síndrome metabólico e hipertensión. Además, ha sido relacionado con hipertrigliceridemia en roedores, sin embargo existe poca evidencia de esta relación en humanos. OBJETIVO: Describir la frecuencia de variaciones comunes del gen CAV1 en adultos con hipertrigliceridemia. MÉTODOS: Se realizó un estudio de casos y controles con adultos del Caribe Colombiano. Fue usada una muestra de sangre venosa periférica para medir las concentraciones séricas de triglicéridos, glucosa, colesterol total y colesterol HDL. Fueron genotipificados seis Polimorfismos de Nucleótido Simple (SNP) en CAV1 (rs926198, rs3779512, rs10270569, rs11773845, rs7804372 y rs1049337). Las frecuencias alélicas y genotípicas se determinaron por conteo directo y se evaluó el equilibrio de Hardy-Weinberg. Los grupos de casos y controles se compararon con pruebas de hipótesis nula. RESULTADOS: Se incluyeron un total de 220 casos y 220 controles. Para rs3779512 se encontró un exceso de homocigotos en el grupo de casos (40.4% (GG), 41.3% (GT) y 18.1% (TT); Fis= 0.13, p= 0.03). Fue encontrado otro exceso de homocigotos en el grupo de casos al analizar el rs7804372 (59.5% (TT), 32.3% (TA) y 8.2% (AA); Fis= 0.12, p= 0.04). En rs1049337, los casos también tuvieron un exceso en la frecuencia de homocigotos (52.7% (CC), 35.0% (CT) y 12.3% (TT); Fis= 0.16, p= 0.01). Finalmente, hubo diferencias en la distribución genotípica del rs1049337 entre los grupos de casos y controles (p <0.05). CONCLUSIONES: Se encontró una elevada frecuencia de homocigotos en los sujetos con hipertrigliceridemia. Estos hallazgos sugieren que los alelos menores de los SNPs rs3779512, rs7804372 y rs1049337 podrían estar asociados con trigliceridemia elevada.

APOA5 and APOA1 polymorphisms are associated with triglyceride levels in Mexican children.

BACKGROUND: Dyslipidemia is an important risk factor for the development of several diseases. The genetic component of hypertriglyceridemia has been studied in adults, but little is known in children. OBJECTIVE: The objective is to evaluate the association of two variants in APOA5 (rs662799) and APOA1 (rs5072) with triglyceride (TG) levels in Mexican children. METHODS: Anthropometric parameters were measured in 1559 Mexican children 5-14 years of age. DNA was isolated from blood samples. Lipid profiles and glucose concentrations were determined from serum and genotyping of rs662799, and rs5072 was performed using TaqMan® technology. Additive and dominant models adjusted for age, gender and body mass index were used to evaluate the association of these single nucleotide polymorphisms with TG levels. RESULTS: Children with high TG levels were found to have a higher body mass index and waist circumference as well as a worse lipids profile and glucose levels (p < 0.001). Additive and dominant models demonstrated a significant association between the rs662799 and rs5072 with TG. The dominant model showed the strongest significant association (OR = 1.81; 95% CI 1.46-2.24; p = 5.40 × 10-08 for rs662799 and OR = 1.54; 95% CI 1.05-2.25; p = 2.60 × 10-02 for rs5072). CONCLUSION: The minor alleles of rs662799 (APOA5) and rs5072 (APOA1) modulate TG levels in Mexican children.

Caveolin 1 Modulates Aldosterone-Mediated Pathways of Glucose and Lipid Homeostasis.

BACKGROUND: Overactivation of the aldosterone and mineralocorticoid receptor (MR) pathway is associated with hyperglycemia and dyslipidemia. Caveolin 1 (cav-1) is involved in glucose/lipid homeostasis and may modulate MR signaling. We investigated the interplay between cav-1 and aldosterone signaling in modulating insulin resistance and dyslipidemia in cav-1-null mice and humans with a prevalent variant in the CAV1 gene. METHODS AND RESULTS: In mouse studies, cav-1 knockout mice exhibited higher levels of homeostatic model assessment of insulin resistance, cholesterol, and resistin and lower ratios of high- to low-density lipoprotein (all P<0.001 versus wild type). Moreover, cav-1 knockout mice displayed hypertriglyceridemia and higher mRNA levels for resistin, retinol binding protein 4, NADPH oxidase 4, and aldose reductase in liver and/or fat tissues. MR blockade with eplerenone significantly decreased glycemia (P<0.01), total cholesterol (P<0.05), resistin (P<0.05), and described enzymes, with no effect on insulin or triglycerides. In the human study, we analyzed the CAV1 gene polymorphism rs926198 in 556 white participants; 58% were minor allele carriers and displayed higher odds of insulin resistance (odds ratio 2.26 [95% CI 1.40-3.64]) and low high-density lipoprotein (odds ratio 1.54 [95% CI 1.01-3.37]). Aldosterone levels correlated with higher homeostatic model assessment of insulin resistance and resistin and lower high-density lipoprotein only in minor allele carriers. CAV1 gene expression quantitative trait loci data revealed lower cav-1 expression in adipose tissues by the rs926198 minor allele. CONCLUSIONS: Our findings in mice and humans suggested that decreased cav-1 expression may activate the effect of aldosterone/MR signaling on several pathways of glycemia, dyslipidemia, and resistin. In contrast, hyperinsulinemia and hypertriglyceridemia are likely mediated by MR-independent mechanisms. Future human studies will elucidate the clinical relevance of MR blockade in patients with genotype-mediated cav-1 deficiency.