Atherogenic Dyslipidemia in Children: Evaluation of Clinical, Biochemical and Genetic Aspects (original) (raw)
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Molecular Biology Reports
Apolipoprotein A5 (APOA5) and apolipoprotein E (APOE) play important roles in the metabolism of cholesterol and triglycerides. The aim of this study was to determine the allelic and genotypic distributions of the APOA5-1131T>C (rs 662799) and the APOE HhaI polymorphisms and to identify the association of both individual and combined APOA5–APOE genetic variants and the risk for dyslipidemia in children and adolescents. We genotyped 53 dyslipidemic and 77 normolipidemic individuals. The total cholesterol, triglycerides and HDL cholesterol were determined enzymatically. For APOA5 polymorphism, the presence of the allele C confers an individual risk for dyslipidemia (OR = 2.38, 95% CI = 1.15–4.89; P = 0.018). No significant differences were observed for lipid parameters among the APOA5 groups, except for a higher value of HDLc (P = 0.024) in C-carriers. The allelic and genotypic frequencies of APOE polymorphism were similar between groups and did not increase the susceptibility for dyslipidemia. None of the combined APOA5–APOE polymorphisms increased risk for dyslipidemia. We demonstrated an association between APOA5-1131T>C polymorphism and dyslipidemia in children and adolescents. This finding may be useful to guide new studies with genetic markers down a path toward a better characterization of the genetic risk factors for dyslipidemia and atherosclerotic diseases.
Haplotype analysis of the apolipoprotein A5 gene in obese pediatric patients
International Journal of Pediatric Obesity, 2011
Background: In this case-control study we investigated the relative contribution of commons APOA5 polymorphisms and haplotypes to the risk of metabolic syndrome in Moroccan patients. Methods: Using the International Diabetes Federation (IDF) criteria for metabolic syndrome, the study included 176 patients and 105 controls. We genotyped APOA5 polymorphisms (−1131 T > C, c.56C > G, c.553G > T and c.1259 T > C) by PCR-RFLP analysis. The effects of APOA5 polymorphisms and constructed haplotypes on metabolic syndrome were estimated using logistic regression analyses. Results: The statistical analysis showed a significant association between APOA5-1131 T > C and APOA5 c.56C > G polymorphisms with metabolic syndrome in both Codominant and Dominant models. The APOA5-1131 T > C polymorphism was associated with increased fasting glucose (p = 0.0295) and reduced HDL levels (p = 0.0091). Carriers of the APOA5 c.56G allele had increased triglyceride levels (p = 0.0435) and waist circumference (p = 0.0122). Similarly the APOA5 1259 T > C variant was associated with increased waist circumference (p = 0.0463). The haplotypes CCGT (OR = 3.223; p = 0.00278) and CGGT (OR = 8.234; p = 0.00534) were significantly associated with susceptibility to metabolic syndrome. Conclusions: Our results confirms the association of APOA5-1131 T > C and c.56C > G variants with the predisposition to metabolic syndrome complications.
Comparison of lipid profiles with APOA1 MspI polymorphism in obese children with hyperlipidemia
In vivo (Athens, Greece)
Obesity is a multifactorial, chronic disorder leading to adverse metabolic effects on plasma lipid levels. Apolipoprotein AI (Apo AI) is the major structural component of high-density lipoprotein (HDL) and is involved in the esterification of cholesterol as a cofactor of lecithin-cholesterol acyltransferase (LCAT) and thus plays a major role in cholesterol efflux from peripheral cells. The APOA1 gene is associated with changes in lipid metabolism. A common gene polymorphism described in the APOA1 promoter region consists of the exchange of guanine (G) for adenine (A) at a position -75 bp upstream of the transcription origin. The relationship between lipid levels in obese children and the APOA1 MspI polymorphisms, was examined. Three separate groups were included, the patient group of obese children with hyperlipidemia; the obese control group (control group I) consisted of obese children without hyperlipidemia; and the healthy control group (control group II) contained healthy child...
Haplotype analyses of the APOA5 gene in patients with familial combined hyperlipidemia
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2007
Background: Familial combined hyperlipidemia (FCH) is the most common genetic lipid disorder with an undefined genetic etiology. Apolipoprotein A5 gene (APOA5) variants were previously shown to contribute to FCH. The aim of the present study was to evaluate the association of APOA5 variants with FCH and its related phenotypes in Dutch FCH patients. Furthermore, the effects of variants in the APOA5 gene on carotid intima-media thickness (IMT) and cardiovascular disease (CVD) were examined. Materials and methods: The study population consisted of 36 Dutch families, including 157 FCH patients. Two polymorphisms in the APOA5 gene (− 1131T > C and S19W) were genotyped. Results: Haplotype analysis of APOA5 showed an association with FCH (p = 0.029), total cholesterol (p = 0.031), triglycerides (p < 0.001), apolipoprotein B (p = 0.011), HDL-cholesterol (p = 0.013), small dense LDL (p = 0.010) and remnant-like particle cholesterol (p = 0.001). Compared to S19 homozygotes, 19W carriers had an increased risk of FCH (OR = 1.6 [1.0-2.6]; p = 0.026) and a more atherogenic lipid profile, reflected by higher triglyceride (+ 22%) and apolipoprotein B levels (+ 5%), decreased HDL-cholesterol levels (−7%) and an increased prevalence of small dense LDL (16% vs. 26%). In carriers of the −1131C allele, small dense LDL was more prevalent than in −1131T homozygotes (29% vs. 16%). No association of the APOA5 gene with IMT and CVD was evident. Conclusion: In Dutch FCH families, variants in the APOA5 gene are associated with FCH and an atherogenic lipid profile.
2002
Combined hyperlipidemia (CHL) is a common disorder of lipid metabolism that leads to an increased risk of cardiovascular disease. The lipid profile of CHL is characterised by high levels of atherogenic lipoproteins and low levels of high-density-lipoprotein-cholesterol. Apolipoprotein (APO) A5 is a newly discovered gene involved in lipid metabolism located within 30kbp of the APOA1/C3/A4 gene cluster. Previous studies have indicated that sequence variants in this cluster are associated with increased plasma lipid levels. To establish whether variation at the APOA5 gene contributes to the transmission of CHL, we performed linkage and linkage disequilibrium (LD) tests on a large cohort of families (n=128) with familial CHL (FCHL). The linkage data produced evidence for linkage of the APOA1/C3/A4/A5 genomic interval to FCHL (NPL = 1.7, P = 0.042). The LD studies substantiated these data. Two independent rare alleles, APOA5 c.56G and APOC3 c.386G of this gene cluster were over-transmitted in FCHL (P = 0.004 and 0.007, respectively), and this was associated with a reduced transmission of the most common APOA1/C3/A4/A5 haplotype (frequency 0.4425) to affected subjects (P = 0.013). The APOA5 c.56G allele was associated with increased plasma triglyceride levels in FCHL probands, whereas the second, and independent, APOC3 c.386G allele was associated with increased plasma triglyceride levels in FCHL pedigree founders. Thus, this allele (or an allele in LD) may mark a quantitative trait associated with FCHL, as well as representing a disease susceptibility locus for the condition. This study establishes that sequence variation in the APOA1/C3/A4/A5 gene cluster contributes to the transmission of FCHL in a substantial proportion of affected families, and that these sequence variants may also contribute to the lipid abnormalities of the metabolic syndrome, which is present in up to 40% of persons with cardiovascular disease.
A novel mutation of the apolipoprotein A-I gene in a family with familial combined hyperlipidemia
Atherosclerosis, 2008
We report a large family in which four members showed a plasma lipid profile consistent with the clinical diagnosis of familial combined hyperlipidemia (FCHL). One of these patients was found to have markedly reduced HDL cholesterol (HDL-C) (0.72 mmol/l) and Apo A-I (72 mg/dl) levels, a condition suggestive of the presence of a mutation in one of the HDL-related genes. The analysis of APOA1 gene revealed that this patient was heterozygous for a cytosine insertion in exon 3 (c.49-50 ins C), resulting in a frame-shift and premature stop codon at position 26 of pro-Apo A-I (Q17PFsX10). This novel mutation, which prevents the synthesis of Apo A-I, was also found in four family members, including three siblings and the daughter of the proband. Carriers of Apo A-I mutation had significantly lower HDL-C and Apo A-I than non-carriers family members (0.77 ± 0.15 mmol/l vs. 1.15 ± 0.20 mmol/l, P < 0.005; 71.4 ± 9.1 mg/dl vs. 134.0 ± 14.7 mg/dl, P < 0.005, respectively). Two of the APOA1 mutation carriers, who were also heavy smokers, had fibrous plaques in the carotid arteries causing mild stenosis (20%). The intimal-media thickness in the two other adult carriers was within the normal range. The other non-carriers family members with FCHL had either overt vascular disease or carotid atherosclerosis at ultrasound examination. This observation suggests that the low HDL-C/low Apo A-I phenotype may result from a genetic defect directly affecting HDL metabolism, even in the context of a dyslipidemia which, like FCHL, is associated with low plasma HDL-C.
Diabetologia, 2008
Aims/hypothesis Common genetic variants influence plasma triacylglycerol, HDL-cholesterol (HDL-C) and glucose levels in cross-sectional studies. However, the longitudinal effects of these established variants have not been studied. Our aim was to examine the longitudinal associations of four such variants in the apolipoprotein A-V (APOA5), lipoprotein lipase (LPL), and glucokinase (GCK) genes with fasting glucose or lipid levels. Methods The individuals analysed were participants in the Busselton Health Survey (n=4,554). Cross-sectional analyses of family data used the total association test. Longitudinal association analyses of unrelated participant data (n=2,864) used linear mixed-effects models. Results The findings of cross-sectional association analyses replicated those of previous studies. We observed associations of the G and C alleles at the APOA5 single nucleotide polymorphisms (SNPs) rs662799 and rs3135506 with raised triacylglycerol levels (p=0.0003 and p<0.0001, respectively), the 447X allele at the LPL SNP rs328 with reduced triacylglycerol levels (p=0.0004) and raised HDL-C levels (p=0.0004), and the A allele of the GCK SNP rs1799884 with raised fasting glucose level (p=0.015). Longitudinal association analyses showed that most of these associations did not change in the same individuals over an average follow-up time of 17.4 years, though there was some evidence that the association of the 447X allele of rs328 with raised HDL-C level significantly increased with age (p=0.01), and that the association of the C allele of rs3135506 with raised triacylglycerol level significantly increased over time (p=0.0007). Conclusions/interpretation The current study suggests that the effects of established gene variants on lipid and glucose traits do not tend to alter with age during adulthood or over time.