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Journal Article 2001; 22(1): 53-73 PubMed PMID: 11393163 Citation  Keywords:  Adrenal Glands:physiology, Animals, Biological Clocks, Blood Pressure:physiology, Chronobiology Disorders:physiopathology, Chronobiology Phenomena, Chronotherapy, Circadian Rhythm:physiology, Drug Administration Schedule, Genomics, Homeostasis, Humans, Pi.   

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Journal Article 2012; 33(Suppl 2): 22-25 PubMed PMID: 23183505 Citation  Keywords:  Adult, Aged, Atorvastatin Calcium, Cholesterol, HDL:blood, Cholesterol, LDL:blood, Dyslipidemias:drug therapy, Female, Genotype, Heptanoic Acids:administration & dosage, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors:therapeutic use, Male, Middle .   

OBJECTIVES: A significant inter-individual variability in statin treatment efficacy is likely to have a strong genetic background. A candidate gene with the potential to influence statin treatment efficacy is SLCO1B1. This gene codes for the solute carrier organic anion transporter, which has been shown to regulate the hepatic uptake of statins and some other drugs.

MATERIALS AND METHODS: The SLCO1B1 rs4149056 (T>C) polymorphism was successfully analysed in a group of 253 patients with dyslipidemia (treated with simvastin or atorvastatin, 10 or 20 mg per day) and 470 healthy normolipidemic controls. The polymorphism was analysed using nested PCR-RFLP. Lipid levels (total, LDL and HDL cholesterol; triglycerides) were analysed before and after 10-13 weeks of treatment.

RESULTS: After treatment, as expected, there was a significant decrease both in the total cholesterol (7.60±1.36 → 5.37±1.12 mmol/L, p<0.001) and LDL cholesterol (5.04±1.34 → 3.17±0.99 mmol/L, p<0.001) levels. The distribution of the individual genotypes in the patients (TT=61.7%, CT=31.6%, CC=6.7%) was similar (p=0.35) to that of the normolipidemic controls (TT=64.4%, CT=31.3%, CC=4.3%). Homozygous CC males exhibited the lowest (Δ -21.2±7.2%) decrease of total cholesterol in contrast to the females, in whom the same genotype was associated with the highest (Δ -33.5±7.6 %) decrease (p=0.04 for gene-gender interaction).

CONCLUSIONS: The results of our pilot study suggest possible gender-dependent effects of the rs4149056 variant within the SLCO1B1 gene on statin treatment efficacy....

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Journal Article 2012; 33(Suppl 2): 13-16 PubMed PMID: 23183503 Citation  Keywords:  Acute Coronary Syndrome:epidemiology, Adult, Angiopoietins:genetics, Czech Republic:epidemiology, Female, Genetic Predisposition to Disease:epidemiology, Genetic Variation:genetics, Genotype, Hepatocyte Nuclear Factor 1-alpha:genetics, Humans, Male, Middl.   

BACKGROUND: Atherosclerosis is a complex arterial disease involving interactions between multiple genetic and environmental factors. A large number of genetic polymorphisms associated with atherosclerotic diseases have been identified in recent years. We investigated the possible association between hepatic nuclear factor (HNF1-α) and angiopoietin-like 4 (ANGPTL4) single nucleotide polymorphisms and the risk of acute coronary syndrome (ACS) in the Czech population.

MATERIALS AND METHODS: A total of 1,182 patients with ACS (835 males and 347 females) and 1,200 healthy controls (827 males and 373 females) were included in the study. All patients were younger than 65 years of age. rs7310409 (A>G within the HNF1-α gene) and rs116843064 (G>A within the ANGPTL4 gene) were genotyped using TaqMan genotyping assays.

RESULTS: The frequencies of the genotypes in patients with ACS did not significantly differ from the control group for the rs7310409 polymorphism (AA=17.1%, AG=46.6%, GG=36.2% vs. AA=14.4%, AG=50.3%, GG=35.3%, respectively; p=0.12) or the rs116843064 polymorphism (AA=0.1%, AG=3.5%, GG=96.4% vs. AA=0.1%, AG=4.2%, GG=95.7%, respectively; p=0.69). There was no interaction with gender. In addition, gene variants were not associated with common cardiovascular risk factors (dyslipidaemia, hypertension, smoking, obesity and diabetes).

CONCLUSIONS: No association was observed between polymorphisms within the HNF1-α and ANGPTL4 genes and the risk of ACS in the Czech population....

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Journal Article 2012; 33(5): 499-504 PubMed PMID: 23090267 Citation  Keywords:  Adult, Erectile Dysfunction:blood, Follicle Stimulating Hormone:blood, Genetic Predisposition to Disease:genetics, Genotype, Humans, Luteinizing Hormone:blood, Male, Methylenetetrahydrofolate Reductase (NADPH2):genetics, Middle Aged, Polymorphism, Single .   

OBJECTIVES: The methylenetetrahydrofolate reductase (MTHFR) enzyme activity plays an important role in the metabolism of folate within methionine-homocysteine pathway and, consequently, in the development of vascular diseases. The C677T polymorphism (rs1801133) of the MTHFR gene affects the MTHFR activity, modifies the homocysteine plasma concentration and, among others, increases the risks for idiopathic male infertility, including erectile dysfunction (ED). As this sexual dysfunction is related to sex hormone levels, we investigated a possible relationship between the C677T polymorphism of the MTHFR gene and plasma concentrations of follicle-stimulating hormone (FSH) as well as luteinizing hormone (LH) in male patients with ED.

METHODS: We conducted our study on 90 healthy men with ED between the age of 32 and 61 (mean age was 51.1 ± 11.5) years. The subjects were genotyped and their FSH and LH plasma levels were analysed.

RESULTS: The analysis results of ED patients and their genotypes of the MTHFR gene did not provide evidence supporting any causal association of T allele in CT and TT genotypes with studied clinical parameters. However, we found that patients with the CC genotype had significantly higher plasma levels of LH than patients with the CT and/or TT genotypes.

CONCLUSIONS: Our observations suggest that the C677T polymorphism of MTHFR gene has no direct relationship to erectile dysfunction, but does exhibit a relationship between this rs1801133 polymorphism and plasma LH concentrations....

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Journal Article 2012; 33(3): 321-330 PubMed PMID: 22635093 Citation  Keywords:  Adult, Case-Control Studies, Databases, Genetic, Female, Genetic Predisposition to Disease:genetics, Genotype, Humans, Insulin Receptor Substrate Proteins:genetics, Male, Middle Aged, Polymorphism, Single Nucleotide:genetics, Schizophrenia:genetics,.   

OBJECTIVES: Since there are clear indications that schizophrenia is a systemic disorder, we sought for a common molecular basis for schizophrenia abnormalities in brain and body. Our hypothesis was that an impaired insulin and insulin-like growth factor signalling in cells might underlie changes in both brain and body in schizophrenia. In this regard, the insulin receptor substrates 1-4, linking both the insulin and insulin-like growth factor-1 receptors with intracellular pathways, might be of interest to study genetically. In the present study, we chose to study the insulin receptor substrate-3 (IRS-3) gene as a candidate gene in schizophrenia.

METHODS: The IRS-3 gene of 93 patients with the diagnosis of schizophrenia according to DSM-IV criteria and 57 healthy control subjects was screened for DNA sequence variations, followed by case-control analyses of total 10 detected polymorphisms.

RESULTS: The A/G genotype of the single nucleotide polymorphism (SNP) rs117078492 in the IRS-3 gene occurred in 5.3% of the control subjects compared with in 0% of the patients (p=0.05). Similarly, the haplotypes 5 and 3X, constructed from polymorphisms in the IRS-3 gene and including the A allele of this A/G SNP, occurred only in the control subjects and not in the patients (5.3% vs 0%, p=0.05).

CONCLUSION: Our findings suggest that individuals carrying the A allele of this A/G SNP in the IRS-3 gene as well as the estimated haplotypes 5 or 3X including this A allele, have a protection against schizophrenia development....

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Journal Article 2012; 33(2): 236-244 PubMed PMID: 22592207 Citation  Keywords:  Adolescent, Adult, Aged, Alleles, Antipsychotic Agents:adverse effects, Cytochrome P-450 CYP2D6:genetics, Female, Genotype, Humans, Male, Middle Aged, Prospective Studies, Psychiatric Status Rating Scales:statistics & numerical data, Psychotic Disorders:d.   

OBJECTIVE: The objective of this prospective, naturalistic study, conducted in first-episode psychosis patients from a Central-European population, was to assess the utility of Cytochrome P-450 2D6 (CYP2D6) genotype testing under normal clinical setting.

METHODS: A total of 35 patients diagnosed for the first time with schizophrenia or acute schizophrenia-like psychotic disorder and treated with risperidone were enrolled in the study. These patients underwent sequentiation of the CYP2D6 gene and evaluations of symptoms and severity of adverse effects using the PANSS and UKU scales, respectively. Doses of antipsychotics and other co-medication were monitored as well. In statistical analysis, Fisher's exact test was used to compare ratios and the Wilcoxon rank-sum test was used in the comparison of continual variables.

RESULTS: PM patients showed a significantly lower reduction in psychotic symptoms and a greater severity of psychotic symptoms following risperidone treatment and higher doses of antipsychotics not metabolized by CYP2D6, which were used as co-medication.

CONCLUSIONS: Based on these results, patients with the PM genotype experiencing first-episode schizophrenia don't appear to be optimal recipients of risperidone treatment. However, as the main limitation of this study was the relatively small sample-size, replication with a larger scale study is needed to confirm these findings....

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Journal Article 2012; 33(2): 183-190 PubMed PMID: 22592199 Citation  Keywords:  DNA Copy Number Variations:genetics, Genetic Predisposition to Disease:genetics, Genome, Human:genetics, Genome-Wide Association Study:statistics & numerical data, Humans, Schizophrenia:genetics,.   

OBJECTIVES: The term "copy number variation/variant" (CNV) denotes a DNA sequence with a magnitude of 1 kb at least which is differently represented among individuals based on its deletion or duplication. Since 2008, multiple studies have reported copy number variations in schizophrenia, and they seem to fill in a gap in our knowledge on the genetic background of schizophrenia. The aim of this review is to sum up the current findings related to CNVs in schizophrenia in order to facilitate further research.

METHODS: We searched the PubMed computer database using the key words "schizophrenia AND CNVs" on 26th October 2011. Out of 91 obtained results, we selected the references based on their relevance.

RESULTS: The CNVs at genome loci 1q21.1, 2p16.3, 3q29, 15q11.2, 15q13.3, 16p13.1 and 22q11.2 were associated with schizophrenia most frequently. The data provide evidence for low prevalent, but highly penetrant CNVs associated with schizophrenia. CNV deletions show higher penetrance than duplications. Larger CNVs often have higher penetrance than smaller CNVs. Although the vast majority of CNVs are inherited, CNVs that have newly occurred as de novo mutations have more readily been implicated in schizophrenia. De novo CNVs may be responsible for the presence of schizophrenia in only one of the two monozygotic twins, who otherwise have identical genomes.

CONCLUSION: Identifying CNVs in schizophrenia can lead to changes in the treatment and genetic counselling. Our knowledge on the genetic background of neurodevelopmental disorders may also reduce stigma in schizophrenia....

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Journal Article 2012; 33(1): 48-52 PubMed PMID: 22467112 Citation  Keywords:  ADP Ribose Transferases, Case-Control Studies, Genotype, Humans, Infertility, Male, Male, Sperm Count, Spermatozoa,.   

OBJECTIVES: In about 50% of male infertility the underlying pathogenesis remains unknown. A recent Japanese study provided evidence that the rs6836703: G>A single-nucleotide polymorphism (SNP) from the ADP-ribosyltransferase 3 (ART3) gene is significantly associated with non-obstructive azoospermia. However, the functional significance of this association is unknown and replication studies in unrelated populations are thus necessary.

DESIGN: In this study, 257 fertile Czech controls of proven paternity and 98 sub-/infertile patients selected according to stringent exclusion / inclusion criteria were genotyped by High Resolution Melting (HRM) of small amplicons.

SETTING: This study was performed at University Hospital Motol - Laboratory of reproductive genetics using routinely analyzed cases.

RESULTS: Significant differences in allele distribution between fertile and sub-/infertile men were found (OR=1.78, 95% CI: 1.17-2.70; p=0.007). Following sub-stratification of cases according to their sperm counts we found that observed differences in allele distributions were increased in oligozoospermic men with sperm counts of <15 million sperm/mL (OR=1.98, 95% CI: 1.28-3.07; p=0.002). This difference was also reflected in genotype distributions between fertile and sub-/infertile men (p=0.008), and fertile versus oligozoospermic men (p=0.004).

CONCLUSIONS: Our study serves as a first replication of the original Japanese report and opens new avenues of research. Compared to the Japanese patient cohort, we provided evidence that the analyzed ART3 variant is associated with quantitative impairment of spermatogenesis....

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