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.

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.

PAI-1 haplogenotype confers genetic susceptibility for obesity and hypertriglyceridemia in Mexican children. / Un haplogenotipo de PAI-1 confiere susceptibilidad genética para la obesidad y la hipertrigliceridemia en niños mexicanos

The presence of childhood obesity predisposes to the development of cardio vascular and metabolic diseases, such as coronary artery disease and type 2 diabetes mellitus, in adulthood. The polymorphisms described in PAI-1 gene have been linked with obesity and metabolic syndrome in several populations. The aim of this study was to investigate the as sociation of the -844 G/A (rs2227631), -675 4G/5G (rs1799889) and HindIII C/G (rs757716) PAI-1 polymorphisms with obesity and dyslipidemia in a sample of Mexican children. A cross-sectional study was performed in 222 children with an age range between 6-11 years; 104 children were classified as obese and 118 children with normal-weight. The PAI-1 poly morphisms were analyzed by PCR-RFLP. Linkage disequilibrium (LD) and haplogenotype analysis among the three polymorphisms were determined. The results showed significant as sociations with obesity of the -844 G/A genotype and the A allele (OR= 2.75, p<0.001 and OR= 1.76, p=0.01, respectively). The -844 G/A polymorphism was found in LD with -675 4G/5G PAI-1 polymorphism (D’= 0.77). We found that G-4G-C/A-5G-G is a risk haplogeno type for obesity [OR=2.6; 95% confidence interval (CI) 1.17-4.22; p= 0.01] and with marginal association with hypertriglyceridemia(OR= 2.6; 95% CI 1.04-6.35; p= 0.05). The G-4G-C/A 5G-G PAI-1 haplogenotype may be a genetic marker of susceptibility for obesity and hypertri glyceridemia in Mexican children.

La presencia de la obesidad en la infancia predispone al desarrollo de enfermedades cardiovasculares y metabólicas, como la enfermedad arterial coronaria y la diabetes mellitus tipo 2 en la edad adulta. Algunos polimorfismos en el gen PAI-1 se han relacionado con la obesidad y el síndrome metabólico en varias poblaciones. El objetivo del estudio fue investigar la asociación de los polimorfismos -844 G/A (rs2227631), -675 4G/5G (rs1799889) y HindIII C/G (rs757716) en el gen PAI-1 con la obesidad y las dislipidemias en una muestra de niños mexicanos. Se realizó un estudio transversal en 222 niños con un rango de edad de 6-11 años, de los cuales 104 niños fueron clasificados con obesidad y 118 con peso normal. Los poli morfismos en el gen PAI-1 fueron analizados por PCR-RFLP. También se determinó el desequilibrio de ligamiento y el análisis de haplogenotipos de los tres polimorfismos. Los resultados mostraron la asociación significativa de la obesidad con el genotipo -844 G/A y el alelo A (OR= 2,75, p<0,001 y OR= 1,76, p=0,01, respectivamente). El polimorfismo -844 G/A se encontró en desequilibrio de ligamiento con el -675 4G/5G (D’= 0.77). También se encontró que el haplogenotipo G-4G-C/A-5G-G es un marcador de riesgo para la obesidad [OR=2,6; 95% intervalo de confianza (CI) 1,17-4,22; p= 0,01], además de que este haplogenotipo presentó una asociación marginal con la hipertrigliceridemia (OR= 2,6; 95% CI 1,04-6,35; p= 0,05). El haplogenotipo G-4G-C/A-5G-G en el gen PAI-1 puede ser un marcador genético de susceptibilidad para obesidad e hipertrigliceridemia en niños mexicanos.

Dislipidemia em crianças e adolescentes / Dyslipidemia in childrem and adolescents

A aterosclerose é um processo que se inicia na infância e se intensifica na vida adulta, dependendo da carga de fatores genéticos e da interação com fatores ambientais. A estria gordurosa é a alteração inicial, presente no endotélio após o nascimento. Por aparecer tão precoce e sem correlação com fatores de risco determinantes da placa de ateroma, a estria gordurosa é considerada uma lesão benigna, universal. A transformação da estria gordurosa em placa fibrosa (lesão aterosclerótica) ocorrerá dependendo do tempo de exposição aos fatores de risco modificáveis e não modificáveis e levará anos para formar a placa aterosclerótica. A importância da avaliação desses fatores, na primeira infância, é fundamental para que seja estabelecido o diagnóstico de alterações como as dislipidemias, na tentativa de instituir um tratamento precoce que evite a progressão da estria gordura em placa fibrosa. Essas ações de prevenção na infância, resultarão em redução do risco de doenças cardiovasculares na vida adulta.

Atherosclerosis is a process that begins in childhood and is intensified in adulthood depending on the genetic and environmental interactions factors. The initial fatty streak is presente in the endothelium after birth without correlation with risk factors involved in atherogenesis, and is considered a benign and universal lesion. The transformation of the fatty streak to fibrous plaque (atherosclerotic lesions) occur depending on the time of exposure to risk factors modifiable and non-modifiable, and it will take years to form fibrous plaque. The importance of recognizing the risk factors early in childhood, is importante to institute early treatment to prevent the progression of fatty streak to fibrous plaque. These preventive measures in childhood result in reduced risk of cardiovascular disease in adulthood.

Hipertrigliceridemias de origen genético / Hypertriglyceridemias of genetic origen

Hypertriglyceridemia (HTG) is defined as plasma triglycerides (TG) > 150 mg/dL, and it is a frequent disease in the general population. When plasma TG reach concentrations > 500 mg/dL (severe HTG), there is usually a genetic defect involved. This defect can involve a single gene or be of polygenic inheritance. In polygenic HTG, the phenotypic expression of the disease is usually associated to the presence of certain diseases such as diabetes, obesity or insulin resistance. The most common known genes associated with monogenic hypertriglyceridemia are LPL and APOC2, but in recent years a few cases caused by mutant APOA5, GPIHBP1 and LMF1, have been identified. Furthermore, genome wide association studies (GWA) have brought up new genes that are related to discrete changes in triglyceride plasma levels of the general population. Among them, it is worth mentioning GCKR, TRIB1, MLXIPL, GALNT2, APOB, APOC2, APOA5, APOE, LPL, ANGPTL3 and NCAN. It is remarkable that most severe hypertriglyceridemias are of polygenic origin, and they could involve a major susceptibility gene. Only in a few cases of severe or very severe HTG (TG > 2.000 mg/dL) the genetic cause is known.

Impacto de la apolipoproteína A5 en el riesgo cardiovascular: Modulaciones genéticas y ambientales / Impact of apolipoprotein A5 on cardiovascular risk: Genetic and environmental modulation

Triglyceride concentrations are an independent risk factor for coronary heart disease. Apolipoprotein A5 gene (APOA5) has an important role determining triglyceride metabolism and it is a potential cardiovascular risk. However the mechanisms for these actions are not well-known. Despite the different allelic frequency of its major polymorphisms in different populations, multiple studies have shown consistent associations between these variants and fasting triglycerides. Variations in the APOA5 gene have also been associated with postprandial triglycerides, as well as with different sizes of lipoproteins and other markers. Moreover, some of the APOA5 gene variants have been associated with ischemic heart disease, stroke, and carotid intima media thickness, although the references on this issue are scanty and contradictory. This may be due to the presence of gene-environment interactions that have been poorly studied until now. Among the few studies that have examined the infuence of environmental factors on possible genetic variations, the most important are those that contemplate possible gene-diet interactions. However, the evidence is still scarce and more research is required in the feld of nutrigenomics. To understand the impact of this gene on cardiovascular disease, we review the genetic functionality and variability of APOA5, its associations with intermediate and fnal phenotypes and gene-environment interactions detected.

DNA Polymorphisms and Haplotypes of Apolipoprotein A5's Attribution to the Plasma Triglyceride Levels in Koreans

PURPOSE: Recent studies using human and mice reported that apolipoprotein A-V (APOA5) gene plays an important role in controlling triglyceride (TG) concentrations. The purpose of the present study was to investigate the correlation between single nucleotide polymorphisms (SNPs) and haplotypes in the APOA5 gene and TG in subjects and to search for possible associations of the APOA5 gene variants and common haplotypes with hypertriglyceridemia (HTG). MATERIALS AND METHODS: We examined the case-control subjects including 100 HTG patients and 243 unrelated healthy control. The genes were screened for SNPs by direct sequencing in 48 genetically unrelated individuals. Six SNPs (-1390C>T, -1020G>A, -3A>G, V150M, G182C and 1259T>C) were genotyped in case and control populations. RESULTS: In this study, our results indicated a strong association between APOA5 SNP -3A>G and G182C and elevated TG levels (p<0.001). Analysis of the SNPs from APOA5 gene has identified major haplotype showing very strong association with HTG, CGGGTT (p<0.001). Likelihood ratio test (LRT) of these six SNPs revealed that haplotypes were strong independent predictors of HTG (p<0.001). Haplotype-trend logistic regression (HTR) analysis revealed a significant association between the CGGGGC (haplotype 2) and CGGGTT (haplotype 4) and HTG (OR=2.48, 95% CI=1.06-5.76 and OR=8.54, 95% CI=2.66-27.42, respectively). CONCLUSION: We confirm that the APOA5 variants are associated with triglyceride levels and the haplotype may be strong independent predictors of HTG among Koreans.

[Hypertriglyceridemic waist phenotype, markers of systemic inflammation and endothelial dysfunction among women]

Although hypertriglyceridemic waist [HW] phenotype has received much attention over recent years for its association with other metabolic abnormalities, it remains unknown whether its effects are mediated through changes in plasma concentrations of inflammatory markers. We aimed to evaluate the association between hypertriglyceridemic waist [HW] phenotype and markers of systemic inflammation and endothelial dysfunction among women. Anthropometric and biochemical measurements were assessed in a cross-sectional study of 507 Iranian women aged 40-60 years. HW phenotype was defined as serum triacylglycerol concentration >/= 150 mg/dl and concurrent waist circumference >/= 89. The prevalence of hypertriglyceridemic waist [HW] phenotype was 32.2% [95% CI: 28.7, 35.7] among women. Individuals with HW phenotype had higher anthropometric measures, were older and less physically active. After control for potential confounding variables, women in different categories of WC had significantly different levels of CRP [WC main effect: P=0.001], TNF-alpha [P=0.01], IL-6 [P=0.001], E-selectin [P=0.007], sICAM-1 [P=0.01] and sVCAM-l [P=0.02, 2-factor ANOVA for all]. When the models were further adjusted for BMI, the difference in sICAM-1 and sVCAM-1 ceased to be significant. Significant differences in CRP [TG main effect: P=0.01], TNF-alpha [P=0.008], SAA [P=0.03], IL-6 [P=0.01], E-selectin [P=0.02] and sICAM-l [P=0.01, 2-factor ANOVA for all] were found between categories of TG concentration after control for confounders. Most of these differences remained significant even after additional adjustments for BMI, except for E-selectin. There was a significant interaction between WC and TG concentration with regard to CRP, IL-6, SAA, and E-selectin. This study provides evidence showing a positive association between HW phenotype and markers of systemic inflammation and endothelial dysfunction

Genetic variation of the Apo Al-CIII-AIV gene cluster in hypertriglyceridemic patients with chronic renal failure undergoing hemodialysis

Many patients with chronic renal failure (CRF) requiring hemodialysis present with hypertriglyceridemia (HTG). But the exact cause of HTG in CRF is still unknown. Genetic variation of the apo AI-CIII-AIV gene cluster was reported to be associated with primary HTG, atherosclerosis and coronary artery disease. This study was designed to evaluate the association between the restriction fragment length polymorphism (RFLP) of the apo AI-CIII-AIV gene cluster and HTG in patients with CRF undergoing hemodialysis. Genetic variations of the apo AI-CIII-AIV gene cluster were analysed in peripheral leukocyte samples from 59 patients with CRF undergoing hemodialysis: 17 patients with HTG (CRF-HTG) and 42 patients without HTG (CRF-NTG). The RFLP was achieved through the digestion of PCR products by two restriction enzymes, SstI and MspI. The frequency of SstI minor allele (S2) in CRF-HTG was 0.44, which was significantly higher than that in CRF-NTG (0.17). Frequencies of MspI minor allele (M2) in CRF-HTG and CRF-NTG were not significantly different (0.5 vs 0.32) (p=0.07). Frequencies of S2-M2 genotype were 0.65 in CRF-HTG, and 0.27 in CRF-NTG (p>0.005). These data indicate that genetic variation of the apo AI-CIII-AIV gene cluster may serve as one of the causes of HTG in CRF.

Genetic variation of the Apo Al-CIII-AIV gene cluster in hypertriglyceridemic patients with chronic renal failure undergoing hemodialysis

Many patients with chronic renal failure (CRF) requiring hemodialysis present with hypertriglyceridemia (HTG). But the exact cause of HTG in CRF is still unknown. Genetic variation of the apo AI-CIII-AIV gene cluster was reported to be associated with primary HTG, atherosclerosis and coronary artery disease. This study was designed to evaluate the association between the restriction fragment length polymorphism (RFLP) of the apo AI-CIII-AIV gene cluster and HTG in patients with CRF undergoing hemodialysis. Genetic variations of the apo AI-CIII-AIV gene cluster were analysed in peripheral leukocyte samples from 59 patients with CRF undergoing hemodialysis: 17 patients with HTG (CRF-HTG) and 42 patients without HTG (CRF-NTG). The RFLP was achieved through the digestion of PCR products by two restriction enzymes, SstI and MspI. The frequency of SstI minor allele (S2) in CRF-HTG was 0.44, which was significantly higher than that in CRF-NTG (0.17). Frequencies of MspI minor allele (M2) in CRF-HTG and CRF-NTG were not significantly different (0.5 vs 0.32) (p=0.07). Frequencies of S2-M2 genotype were 0.65 in CRF-HTG, and 0.27 in CRF-NTG (p>0.005). These data indicate that genetic variation of the apo AI-CIII-AIV gene cluster may serve as one of the causes of HTG in CRF.