[Genetic risk factors for development of myocardial infarction in young men living in North-West region of Russia].

With the aim to detect genetic factors of risk of development of early myocardial infarction (MI) we studied 29 allele variants of 19 genes in 206 men who had survived MI in the age before 45 years and in 195 men of similar age without cardiovascular diseases. All subjects were inhabitants of North-West region of Russia. The following factors were associated with history of myocardial infarction: genotype RR191 of paraoxonase-1 (PON1) gene (RR 2.8 [95% CI: 1.24 - 6.30]), P1A2 allele of glycoprotein (GP) IIIa subunit of platelet fibrinogen receptor GPIIb/IIIa (RR 1.8 [95% CI: 1.11 - 2.93]), and Met145 allele of GPIbalpha platelet von Willebrand factor receptor gene. Genotype CC ( - 108) PON1 was associated with lowered risk of MI development (RR 0.6 [95% CI: 0.40 - 0.91]). During 7 years of follow-up 30 men from MI group died of recurrent acute coronary syndromes. In the group of those who died we noted increased prevalence of P1A2 GPIIIa allele compared with those who survived (p < 0.03). The results allow to suggest that contribute to development of MI in young men factors associated with elevation of functional state of platelets and levels of oxidized lipids in blood plasma.

[Novel mutation of the GPIIIa gene in the Russian population, Leu40Arg, linked to the Leu33Pro].

Glycoprotein IIb/IIIa complex, a platelet surface fibrinogen receptor, plays a key role in producing primary hemostasis. At present, only a single mutation in the GPIIla gene, Leu33Pro, and a single mutation in the GPIIb gene, lle843Ser, has been described. The mutations are known to enhance signaling functions of the receptor and are associated with the development of arterial thromboses. In the present study, we describe a novel GPIIIa mutation, which is T to G nucleotide substitution in position 1585, resulting in the replacement of Leu for Arg in position 40 of the amino acid sequence of the protein.

[Clinical value of allele variants of cytochrome CYP2C9 gene for anticoagulation therapy with warfarin].

Warfarin is metabolized by cytochrome CYP2C9 and its pharmacokinetic properties depend on structural polymorphisms of CYP2C9 gene. We studied frequencies of allele variants of CYP2C9 gene and associations of individual reaction to warfarin intake with genotype of CYP2C9 gene. Population frequencies of CYP2C9x1, CYP2C9x2, CYP2C9x3 alleles of CYP2C9 gene in St-Petersburg were 82.66, 11.11, and 6.32%, respectively. Carriers of CYP2C9x2 and CYP2C9x3 alleles more rapidly achieved therapeutic levels of hypocoagulation and required significantly lower weekly doses of warfarin.

[Allele Frequency Analysis of Four Single Nucleotide Polymorphisms Locating in Promoter and 5'-Untranslated Regions of ABCAI Gene in Young Men - Survivors From Myocardial Infarction]. / Analiz chastoty vyiavleniia chetyrekh strukturnykh polimorfizmov DNK v promotornoi i 5'-netransliruemykh oblastiakh gena ABCA1 u muzhchin, perenesshikh infarkt miokarda v molodom vozraste.

Analysis of allele distribution of four single nucleotide polymorphisms (C-17G, C69T, G-191C and 319insG) of promoter and 5'-untranslated regions of the ABCA1 gene was carried out in a sample of 171 men, who had survived myocardial infarction before 45 years, and in controls. Two-fold increase of T69 and C-191 allele frequencies were observed in Russian population in comparison to Dutch one. While comparing allele and genotype distributions of the polymorphisms in the samples under study no statistically significant differences were found, so as no influence of different alleles on lipid spectrum data was observed. Role of polymorphisms under study appears to be insignificant in formation of genetic susceptibility to myocardial infarction in young men.

Gene-gene interactions between glutathione-s transferase M1 and matrix metalloproteinase 9 in the formation of hereditary predisposition to chronic obstructive pulmonary disease.

The incidence of allele variants of glutathione-S transferase M1 xenobiotic detoxification gene and matrix metalloproteinase 9 gene was analyzed in patients with chronic obstructive pulmonary disease. A strict gene-gene interaction between these two genes in the formation of hereditary predisposition to this disease was first demonstrated. The combination of glutathione-S transferase M1 genotype 0/0 and matrix metalloproteinase 9 mutant allele (-15621) is a risk factor for chronic obstructive pulmonary disease (OR-7.7).

[Clinical and molecular genetic investigation of Waardenburg syndrome type 1]. / Klinicheskoe i molekuliarno-geneticheskoe issledovanie sindroma Vaardenburga I tipa]

Hypoacusis is a common sensory defect in humans which creates problems in communication. Heredity is essential in etiology of hypoacusis and deafness. Genes PAX3 and MITF were studied in patients with Vaardenburg syndrome in 14 unrelated families. Five mutation defects in the gene PAX3 were found. This provided the final diagnosis of the syndrome in these families.

[I/D polymorphism in the angiotensin-converting enzyme gene in men with myocardial infarction at young age]. / I/D polimorfizm gena angiotenzinprevrashchaiushchego fermenta u muzhchin, perenesshikh infarkt miokarda v molodom vozraste.

The rate of D allele did not differ between patients with ischemic heart disease (IHD) who had myocardial infarction before the age 45, and healthy males. The DD genotype of the ACE gene was much more frequently encountered in the patients than in healthy males. The findings suggest that the DD genotype is an independent risk factor of the IHD and myocardial infarction in young patients.

[Interstrain differences in enzymatic activity of CYP2B1 and expression of its gene in the rat liver during induction with phenobarbital and triphenyldioxane]. / Mezhlineinye razlichiia v fermentativnoi aktivnosti CYP2B1 i ékspressii ego gena v pecheni krys pri induktsii fenobarbitalom i trifenildioksanom.

The interstrain differences in hepatic 7-pentoxyresorufin-O-dealkylase and 16 beta-androstendione hydroxylase activities specific for cytochrome P450 2B1 have been found in Sprague-Dawley, Brattleboro and Wistar rats treated with with phenobarbital, triphenyldioxane. Similar differences were found in the accumulation of corresponding mRNAs suggesting differences in expression of cytochrome P450 gene. Analysis of the enzymatic activity and mRNA level revealed positive correlation between these parameters. Thus, differences in transcriptional activity of CYP2B1 gene during induction by phenobarbital and triphenyldioxane may be one of reasons for interstrain differences between enzymatic activities of rat liver cytochrome P4502B1.

[DNA polymorphism in the region of APOB100, APOCIII, APOE, and angiotensin-converting enzyme genes and indicators of the lipid spectrum in children and adolescents in St. Petersburg]. / Polimorfizm DNK v oblasti genov APOB100, APOCIII, APOE, angiotenzin- konvertiruiushchego fermenta i pokazateli lipidnogo spektra u detei i podrostkov Sankt-Peterburga.

Polymorphisms of 3 apolipoprotein genes Xba I apoB, Sstl apoCIII, and apoE and the insertion-deletion polymorphism of the angiotensin-converting enzyme gene (I/D ACE) and lipid levels were studied in a random sample of 403 children and adolescents aged 6 to 18 years living in St. Petersburg. The children were divided in 4 age groups with consideration for the relative body weight index: group 1.6 to 9 years; II, 10-12; III, 13-15; and IV, 16-18 years. The first three groups were divided by sex, the fourth was not because it was the smallest. Relationships between lipid levels and DNA polymorphisms of the above genes were analyzed in all groups. Effects of apoB Xbal, apoCIII Sstl, apoE, and ACE genotypes on the levels of the blood basic lipids were analyzed using Statgraphics software. A marked effect of the apoE (E3/E4) genotype on the total and LDL-cholesterol variability was observed in group IV. The individuals carrying the E4 apoE allele had increased levels of total and LDL-cholesterol (p < 0.02 and p < 0.03, respectively). The level of triglycerides was higher in the subjects carrying the S2 apoCIII allele in the third group (p < 0.04). A statistically reliable difference was however observed only in girls (p < 0.01). We failed to detect reliable correlations between lipid levels and various apoB and ACE genotypes. Hence, the genetic variants of apoCIII and apoE genes affect the blood lipid levels as early as in adolescence.

[Simple methods of enzymatic amplification of DNA for clinical practice]. / Prostye metody énzimaticheskoi amplifikatsii DNK dlia klinicheskoi praktiki.

The methods for enzymatic DNA amplification in vitro that allow to avoid the step of preliminary DNA extraction and purification are proposed. Lysates of blood cells in the solution or immobilized on the nylon membrane filters and dried blood spots on the filter paper blotters were used directly in amplification permitting one to solve the problems of adapting the method of polymerase chain reaction in clinical practice, for instance, in massive screening of genome mutations, viral infections etc.

[Allele polymorphism of the DNA loci MET, D7S8, D7S23, linked to the cystic fibrosis gene in some populations of the USSR, in high risk families and in cystic fibrosis patients]. / Allel'nyi polimorfizm DNK-lokusov MET, D7S8, D7S23, stseplennykh s genom mukovistsidoza, v nekotorykh populiatsiiakh SSSR, v sem'iakh bysokogo riska i u bol'nykh mukovistsidozom.

RELP analysis of DNA loci MET, D7S8 and D7S23 was carried out in Leningrad population and partially in populations of Moscow, Azerbaijan, Ukraine, Buryatia as well as in individuals from high risk families and in cystic fibrosis (CF) patients by means of blot hybridization and polymerase chain reaction. Allelic polymorphism of all loci studied in these three groups was found to be quite similar to that in the North-Western Europe and in whites of the North America. Linkage disequilibrium of the alleles studied with the CF gene was especially pronounced for alleles of the D7S23 locus and gradually decreases from KM-19 through CS-7 to XV-2c DNA probes. The data witness genetic homogeneity of the CF mutation in European populations of the USSR and its similarity to this mutation in Western Europe. The significance of these data for potential diagnosis of CF and for heterozygous carrier detection is discussed.

[Identification of a nature of mutation in the 12th exon of phenylalanine hydroxylase gene in patients with phenylketonuria]. / Opredelenie prirody mutatsionnogo povrezhdeniia v 12-om ékzone fenilalaningidroksilaznogo gena u bol'nykh fenilketonuriei.

Upon amplification in vitro of the 12th exon area of the human phenylalanine hydroxylase gene followed by allele-specific hybridisation of the amplification product with synthetic probes and its sequencing by the Maxam-Gilbert method, a C----T transition causing phenylketonuria has been identified in Latvian patients.

[Character of two mutations of the beta-globin gene in beta 0-thalassemia in Azerbaijan]. / Kharkter dvukh mutatsionnykh povrezhdenii beta-globinnovogo gena pri beta 0-talassemii v Azerbaidzhane.

Molecular nature of two beta 0-thalassaemia-causing mutations in beta-globin gene in Azerbaijanian population has been elucidated, viz., C-T transition in 39 codon (nonsense mutation) and previously unknown G deletion in 82/83 codons.