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1.
Drug Metab Pers Ther ; 33(2): 91-98, 2018 Jun 27.
Article in English | MEDLINE | ID: mdl-29738309

ABSTRACT

BACKGROUND: The focus of the study is to determine the prevalence of CYP2C19 alleles, associated with the risk of changes in the pharmacological response to clopidogrel and proton pump inhibitors in patients with acute coronary syndrome (ACS) and gastric ulcer from Russian and Yakut ethnic groups. METHODS: The research included 411 patients with ACS (143 Russians and 268 Yakuts) and 204 patients with histologically confirmed gastric ulcer (63 Russians and 141 Yakuts). Genotyping of 681G>A and 636G>A polymorphisms was performed by using polymerase real-time chain reaction. RESULTS: In both ethnic groups, Hardy-Weinberg equilibrium was followed in a distribution of alleles and genotypes in the population (p>0.05). The 681A allele frequency in the Yakut ethnic group was higher than in the Russian group: 17.53% vs. 8.39% (p=0.001). No statistically significant difference was found in the frequency of 636A in Yakuts and Russians with ACS: 3.92% vs. 3.50% (p=0.840). While comparing the frequency distribution of alleles 681A (13.49% vs. 14.54%, p=0.878) and 636A (7.94% vs. 7.80%, p=1) in patients with a gastric ulcer from Russian and Yakut ethnic groups, no significant difference was found in carrier frequency. CONCLUSIONS: The results of the present study may be helpful for developing guidelines for CYPC19 genotype-directed antiplatelet therapy for Yakut and Russian patients.


Subject(s)
Acute Coronary Syndrome/drug therapy , Clopidogrel/therapeutic use , Cytochrome P-450 CYP2C19/genetics , Pharmacogenomic Testing/methods , Pharmacogenomic Variants , Platelet Aggregation Inhibitors/therapeutic use , Polymorphism, Single Nucleotide , Proton Pump Inhibitors/therapeutic use , Stomach Ulcer/drug therapy , Acute Coronary Syndrome/enzymology , Acute Coronary Syndrome/ethnology , Acute Coronary Syndrome/genetics , Aged , Clinical Decision-Making , Clopidogrel/pharmacokinetics , Cytochrome P-450 CYP2C19/metabolism , Female , Gene Frequency , Genotype , Humans , Male , Middle Aged , Platelet Aggregation Inhibitors/adverse effects , Platelet Aggregation Inhibitors/pharmacokinetics , Precision Medicine , Predictive Value of Tests , Proton Pump Inhibitors/adverse effects , Proton Pump Inhibitors/pharmacokinetics , Siberia/epidemiology , Stomach Ulcer/enzymology , Stomach Ulcer/ethnology , Stomach Ulcer/genetics
2.
Hum Mol Genet ; 26(1): 173-183, 2017 01 01.
Article in English | MEDLINE | ID: mdl-28013294

ABSTRACT

Mucopolysaccharidoses (MPS) are a group of genetic deficiencies of lysosomal enzymes that catabolize glycosaminoglycans (GAG). Here we describe a novel MPS-like disease caused by a specific mutation in the VPS33A gene. We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG. However, these patients could not be diagnosed enzymatically as MPS. They showed extremely high levels of plasma heparan sulphate (HS, one of GAG); 60 times the normal reference range and 6 times that of MPS patients. Additionally, most patients developed heart, kidney, and hematopoietic disorders, which are not typical symptoms for conventional MPS, leading to a fatal outcome between 1 and 2-years old. Using whole exome and Sanger sequencing, we identified homozygous c.1492C > T (p.Arg498Trp) mutations in the VPS33A gene of 13 patients. VPS33A is involved in endocytic and autophagic pathways, but the identified mutation did not affect either of these pathways. Lysosomal over-acidification and HS accumulation were detected in patient-derived and VPS33A-depleted cells, suggesting a novel role of this gene in lysosomal functions. We hence propose a new type of MPS that is not caused by an enzymatic deficiency.


Subject(s)
Glycosaminoglycans/metabolism , Mucopolysaccharidoses/genetics , Mucopolysaccharidoses/metabolism , Mutation/genetics , Vesicular Transport Proteins/genetics , Adolescent , Adult , Case-Control Studies , Cells, Cultured , Child , Female , Fibroblasts/metabolism , Fibroblasts/pathology , Humans , Male , Pedigree , Severity of Illness Index , Young Adult
3.
Res Pharm Sci ; 11(3): 259-64, 2016.
Article in English | MEDLINE | ID: mdl-27499796

ABSTRACT

Allele frequencies of single nucleotide polymorphisms (SNPs) are variable among different populations; therefore the study of SNPs in ethnic groups is important for establishing the clinical significance of the screening of these polymorphisms. The main goal of the research is to study the polymorphisms of CYP2C9, CYP2C19, VKORC1, and SLCO1B1 in Yakuts. Genomic DNA from 229 Yakut subjects were analyzed by real-time polymerase chain reaction (PCR) (SLCO1B1 +521T > C, VKORC1 -1639G>A, CYP2C19 +681G>A, +636G>A, CYP2C9 +430С>T, +1075A>C). Genotype frequencies of polymorphisms in the population of the Yakuts were more characteristic of the Asian population. The results have been included in the software application "Lekgen" that we developed for the interpretation of pharmacogenetic testing. The data of our study obtained on frequency carriers of polymorphisms of genes SLCO1B1, CYP2C19, CYP2C9, VKORC1 among the Yakuts may be useful in developing recommendations for a personalized therapy.

4.
Wiad Lek ; 69(2 Pt 2): 295-8, 2016.
Article in English | MEDLINE | ID: mdl-27487552

ABSTRACT

INTRODUCTION: Tyrosinemia type 1 (HT1) (OM IM 276700) is an inborn error of tyrosine catabolism caused be fumarylacetoacetate hedralase deficiency (FAH). In tyrosinemia type I, dietary therapy and nitisinone (Orfandin®), liver transplantation are effective . AIM: We present here the first report on identification of FAH mutation in HT1 Yakut patient from Russia with a novel one. MATERIAL AND METHODS: The material for the clinical study is based on the genetic data of the patient card with tyrosinemia type 1, which is observed in the medical-genetic consultations Republican Hospital №1-National Medical Center of the Republic of Sakha (Yakutia). For molecular genetic analysis has been used venous whole blood, taken with the written consent from the patient, his relatives and 200 healthy Yakuts. All regions of the FAH gene spanning exons were amplified by PCR and mutational analyses was carried out by direct sequencing. Results of sequencing were confirmed by restriction fragment length polymorphism (PCR-RELF) analyses. RESULTS: 1 one-year-old child was identified with a diagnosis hereditary tyrosinemia type Ia, acute form. In exon 13 of the FAH gene a novel mutation c.1090 G>C (GLu364GLn) in the homozygous state was found in patient, and in heterozygous state in both parents. The child is treated Nitisinone therapy. DNA diagnostics of c.1090 G>C mutation frequency in the FAH gene was conducted using PCR and RFLP analysis in 200 unrelated Yakuts. The frequency of heterozygous carrier was 1.0%.


Subject(s)
Hydrolases/genetics , Mutation , Tyrosinemias/genetics , DNA Mutational Analysis , Humans , Infant , Russia
5.
J Med Genet ; 47(8): 538-48, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20577004

ABSTRACT

BACKGROUND: Hereditary short stature syndromes are clinically and genetically heterogeneous disorders and the cause have not been fully identified. Yakuts are a population isolated in Asia; they live in the far east of the Russian Federation and have a high prevalence of hereditary short stature syndrome including 3-M syndrome. A novel short stature syndrome in Yakuts is reported here, which is characterised by autosomal recessive inheritance, severe postnatal growth retardation, facial dysmorphism with senile face, small hands and feet, normal intelligence, Pelger-Huët anomaly of leucocytes, and optic atrophy with loss of visual acuity and colour vision. This new syndrome is designated as short stature with optic atrophy and Pelger-Huët anomaly (SOPH) syndrome. AIMS: To identify a causative gene for SOPH syndrome. METHODS: Genomewide homozygosity mapping was conducted in 33 patients in 30 families. RESULTS: The disease locus was mapped to the 1.1 Mb region on chromosome 2p24.3, including the neuroblastoma amplified sequence (NBAS) gene. Subsequently, 33 of 34 patients were identified with SOPH syndrome and had a 5741G/A nucleotide substitution (resulting in the amino acid substitution R1914H) in the NBAS gene in the homozygous state. None of the 203 normal Yakuts individuals had this substitution in the homozygous state. Immunohistochemical analysis revealed that the NBAS protein is well expressed in retinal ganglion cells, epidermal skin cells, and leucocyte cytoplasm in controls as well as a patient with SOPH syndrome. CONCLUSION: These findings suggest that function of NBAS may associate with the pathogenesis of short stature syndrome as well as optic atrophy and Pelger-Huët anomaly.


Subject(s)
Dwarfism/complications , Dwarfism/genetics , Neoplasm Proteins/genetics , Optic Atrophy/complications , Optic Atrophy/genetics , Pelger-Huet Anomaly/complications , Pelger-Huet Anomaly/genetics , Adolescent , Adult , Amino Acid Sequence , Amino Acid Substitution/genetics , Base Sequence , Body Height/genetics , Child , Child, Preschool , Chromosomes, Human, Pair 2/genetics , Dwarfism/diagnosis , Dwarfism/diagnostic imaging , Female , Genetic Loci/genetics , Humans , Immunohistochemistry , Infant , Infant, Newborn , Male , Molecular Sequence Data , Neoplasm Proteins/chemistry , Optic Atrophy/diagnostic imaging , Optic Atrophy/pathology , Pelger-Huet Anomaly/diagnostic imaging , Pelger-Huet Anomaly/pathology , Radiography , Syndrome , Young Adult
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