Hyperlipidemias: Choumerianou DM

Choumerianou DM, Dedoussis GV. · Department of Science of Dietetics-Nutrition, Harokopio University of Athens, Greece. · Clin Chem Lab Med. · Pubmed #16201887 No free full text.

Abstract: Familial hypercholesterolemia is an autosomal dominant disease defined at the molecular level mainly by the presence of mutations in the low-density lipoprotein receptor gene and is characterized by elevated low-density lipoprotein cholesterol, tendon xanthomas and increased risk of early cardiovascular disease. The type of mutation in the low-density lipoprotein receptor gene has been associated with different phenotype expression and response to statins. Several studies have been undertaken to assess the efficacy of statins and evaluate the influence of mutations on the response to treatment with statins. Not all patients respond to statin therapy with a reduction in cardiovascular disease. In this review paper, we will discuss the results available to date that correlate the low-density lipoprotein receptor genotype to the response to statins, and the interest in developing diagnostic systems which will allow identification of patients at increased risk of adverse drug reactions or patients in which a therapeutic effect is lacking.

Kolovou GD, Dedoussis GV, Anagnostopoulou KK, Hatzigeorgiou GCh, Salpea KD, Choumerianou DM, Rammos S, Mikhailidis DP, Cokkinos DV. · 1st Cardiology Department, Onassis Cardiac Surgery Center, Athens, Greece. · Angiology. · Pubmed #17235114 No free full text.

Abstract: A 13-year-old Greek boy with severe dyslipidemia, large tuberous xanthomas over the knees and elbows, Achilles' tendon xanthomas, and a bilateral corneal arcus was referred to the Lipid Clinic. He had a supravalvular aortic stenosis, 50% to 60% stenosis of both carotid arteries, and normal coronary arteries. Familial hypercholesterolemia was clinically diagnosed. A V408M null low-density lipoprotein receptor (LDLR) mutation was identified in homozygosity. He responded to lipid-lowering drugs by decreasing total cholesterol by 32%, low-density lipoprotein cholesterol by 33%, and triglyceride levels by 30%. Additional treatment with low-density lipoprotein-apheresis further decreased total cholesterol by 52%, low-density lipoprotein cholesterol by 55%, and triglycerides by 43%. Low-density lipoprotein cholesterol levels between apheresis sessions showed a declining pattern. A significant regression of tuberous xanthomas was noted. A suitable combination of lipid-lowering drugs is effective even in this case of homozygosity for a null LDLR mutation. Furthermore, the coadministration of statins, cholestyramine, and ezetimibe during low-density lipoprotein-apheresis tends to counterbalance the postapheresis relapse in low-density lipoprotein cholesterol levels.

Dedoussis GV, Maumus S, Choumerianou DM, Skoumas J, Pitsavos C, Stefanadis C, Visvikis-Siest S. · Laboratory of Molecular Biology, Department of Science of Dietetics-Nutrition, Harokopio University of Athens, Kallithea-Athens, Greece. · Genet Test. · Pubmed #17020471 No free full text.

Abstract: Familial Hypercholesterolemia (FH) is a genetic disorder characterized by high low-density lipoprotein cholesterol (LDL-C) concentrations that frequently gives rise to premature coronary artery disease. The clinical expression of FH is highly variable, even in patients carrying the same LDL receptor gene mutation. This variability may be due to environmental and other genetic factors. We investigated the effect of APOCIII T1100C, FV Gln506Arg, ADRB2 Glu27Gln, SELE Ser128Arg, SELE Leu554Phe, and ENaCa Ala663Thr polymorphisms on the HDL-C variations in 84 patients with FH. For ApoCIII T1100C, subjects with the TT genotype presented higher HDL-C levels than the other genotype groups (p = 0.046). Similarly the presence of the Gln allele in ADRB2 27 Glu/Gln heterozygotes and ADRB2 27 Gln/Gln homozygotes was associated with higher HDL-C levels (p = 0.014). Among the other polymorphisms tested, none of them were associated with variations in HDL-C levels. The influence of each polymorphism on lipid concentrations was evaluated with linear regression analyses after adjustment for age and sex. Among the variables studied including total cholesterol, LDL-C, high-density lipoprotein (HDL)-C, triglycerides, apolipoprotein A (Apo-A) and B (Apo-B), and lipoprotein alpha (LP alpha), HDL-C concentration was significantly different in models applied for polymorphisms ApoCIII T1100C, FV Gln506Arg, and ADRB2 Glu27Gln (p = 0.01, p = 0.018, p = 0.04, respectively). These results suggest that HDL-C levels in FH heterozygotes may be affected by several different genetic variants.

Choumerianou DM, Maumus S, Skoumas J, Pitsavos C, Stefanadis C, Visvikis-Siest S, Dedoussis GV. · Laboratory of Molecular Biology, Department of Science of Dietetics-Nutrition, Harokopio University of Athens, Athens, Greece. · Clin Chem Lab Med. · Pubmed #16776623 No free full text.

Abstract: BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disorder characterized by high low-density lipoprotein-cholesterol (LDL-C) concentrations, which frequently gives rise to premature coronary artery disease. The clinical expression of FH is highly variable, even in patients carrying the same LDL receptor (LDLR) gene mutation. This variability may be due to environmental and other genetic factors. METHODS: We investigated paraoxonase 2 (PON 2) Ser311Cys, lipoprotein lipase (LPL) Asn291Ser, plasminogen activator inhibitor-1 (PAI-1) T11053G, beta-fibrinogen (FGB) -455 G>A and nitric oxide synthase gene (NOS) -922 A>G polymorphisms in 84 patients with FH. The effect of polymorphisms as independent factors of high lipid values was evaluated. RESULTS: The PON 2 Cys311 allele was correlated with high total cholesterol and LDL-C and apolipoprotein B levels, while LPL Asn291, PAI-1 T11053, FGB -455 G and NOS -922 A alleles were correlated with high apolipoprotein B levels. CONCLUSIONS: These results suggest that apolipoprotein B levels in FH heterozygotes may be affected by several different genetic variants.

Dedoussis GV, Maumus S, Skoumas J, Choumerianou DM, Pitsavos C, Stefanadis C, Visvikis-Siest S. · Laboratory of Molecular Biology, Department of Dietetics and Nutrition, Harokopio University of Athens, Athens, Greece. · J Clin Lab Anal. · Pubmed #16721833 No free full text.

Abstract: Atrial natriuretic peptide (ANP or NPPA) is the precursor protein of the form of amyloidosis called isolated atrial amyloid (IAA), which is related to the increased incidence of cardiac pathological conditions with age. Familial hypercholesterolemia (FH) patients are characterized by high concentrations of low-density lipoprotein cholesterol (LDL-C), which frequently gives rise to premature coronary artery disease (CAD). However, not all FH patients have the same clinical phenotype. The aim of the present study was to assess the relationship between ANP polymorphisms and apolipoprotein (Apo) A1 levels and CAD risk in FH patients. Transition T2238C, which leads to ANP with two additional arginines, and G664A (Val7Met) were investigated with lipid values and clinical phenotype in 83 FH patients. ApoA1 and HDL cholesterol levels were lower in GA patients compared to GG homozygotes for the G664A polymorphism. No association was found between the G664A polymorphism and CAD in our population. Moreover, ApoA1 and high-density lipoprotein cholesterol (HDL-C) levels did not differ among the different genotypes of the T2238C polymorphism, even after adjusting for age and sex. The 664A allele of the ANP polymorphism is associated with lower levels of ApoA1 and HDL-C in FH patients, but not with CAD risk. Concerning the T2238C polymorphism, no effect was found on lipid parameters or CAD incidence.

Pitsavos C, Choumerianou DM, Skoumas J, Maumus S, Stefanadis C, Dedoussis GV, Visvikis-Siest S. · Department of Cardiology, Hyperlipidemic Clinic, Hippocratio Hospital, Medical School of Athens, Greece. · Clin Exp Med. · Pubmed #16362800 No free full text.

Abstract: Familial hypercholesterolaemia is a genetic disorder characterised by high low-density lipoprotein (LDL) cholesterol concentrations, which frequently gives rise to premature coronary artery disease (CAD). The clinical expression of familial hypercholesterolaemia is highly variable even in patients carrying the same LDL receptor gene mutation. This variability may be due to environmental and other genetic factors. Apolipoprotein E (Apo-E) has been extensively studied for its effects on the phenotype of familial hypercholesterolaemia. In this study we examined the influence of Apo-E genotype on lipid parameters and the incidence of CAD in 93 Greek patients with familial hypercholesterolaemia. Apo-E E2, E3 and E4 allele frequencies were 0.06, 0.86 and 0.09 respectively. The levels of total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apolipoproteins A and B and lipoprotein alpha did not differ significantly among carriers and non-carriers of the E4 allele. The prevalence of CAD and hypertension did not differ either. Our results suggest that the E4 allele is not associated with lipid levels or with the prevalence of CAD among familial hypercholesterolaemia patients of the Greek population.

Dedoussis GV, Skoumas J, Pitsavos C, Choumerianou DM, Genschel J, Schmidt H, Stefanadis C. · Laboratory of Molecular Biology, Department of Science of Dietetics-Nutrition, Harokopio University of Athens, Athens, Greece. · Eur J Clin Invest. · Pubmed #15200491 No free full text.

Abstract: BACKGROUND: Familial hypercholesterolaemia (FH) is caused by mutations in the low-density lipoprotein receptor gene and the gene encoding apolipoprotein B-100, affecting one in 500 individuals. METHODS: One hundred and eighty-three Greek FH patients were screened for mutations on the LDLR and ApoB genes. RESULTS: We identified mutations in 67 probands and 11 relatives. Sixteen mutations located in eight different exons and the promoter of the LDLR were discovered. Among them 10 were missense mutations (C6W, S265R, A370T, Q363P, D365E, V408M, A410T, A517T, G528D, G571E), two were nonsense mutations (Q363X and C660X), three were splice defects (2140 + 5G-->A and 2140 + 9C-->T, 1706 - 10G-->A), and one was a nucleotide substitution (- 45delT) on the promoter. None of the subjects carried any apoB mutation. The detection rate of mutations in this study was 43%. From the above mutations, A410T, A519T and the splice site defects 2140 + 9C-->T were detected for the first time in the Greek population. Among them V408M, G528D, C6W and S265R account for 73% of heterozygous FH probands. V408M mutation is more common in Central West, while C6W is more common in Central East. Separating the patients into two groups (receptor defective and receptor negative) we found that the receptor negative group had higher levels of total cholesterol, low-density lipoprotein cholesterol and higher prevalence of tendon xanthomas compared with the receptor-defective group. DISCUSSION: The homogenous molecular basis of familial hypercholesterolaemia in Greece facilitates the application of a DNA diagnostic strategy based on the origin of the patient. The early mutation analysis would add valuable information on the severity of the disease.

Dedoussis GV, Pitsavos C, Kelberman D, Skoumas J, Prassa ME, Choumerianou DM, Stefanadis C, Humphries SE, Toutouzas P. · Laboratory of Molecular Biology, Department of Science of Dietetics-Nutrition, Harokopio University of Athens, Greece. · Clin Genet. · Pubmed #14616764 No free full text.

Abstract: In a patient with familial hypercholesterolemia (FH), we have identified a new mutation (-45delT) in repeat 3 of the low-density lipoprotein receptor (LDLR) gene promoter. Analysis of a neutral polymorphism in the LDLR mRNA from the patient's white blood cells showed that the expression of one allele was significantly reduced, and cells have only 24% of LDLR activity by binding and uptake of DiI-LDL. Transient transfection studies using a luciferase gene reporter revealed that the -45delT mutation considerably reduces the transcriptional activity of the LDLR promoter and strongly suggest that the mutation is the cause of the FH phenotype.