[FREQUENCY OF OCCURRENCE OF POLYMORPHIC VARIANTS OF IL28B GENE AND GENOTYPES OF HEPATITIS C VIRUS IN POPULATION OF YAKUTIA: CLINICAL OUTCOMES].

AIM: Study clinical outcomes in patients with chronic hepatitis C depending on genotype of hepatitis C virus (HCV) and IL28B gene polymorphism. MATERIALS AND METHODS: 592 indi- viduals Were examined, 75 ofthosehad HCVRNAgenotypes determined by PCR. Genotyping of single nucleotide polymorphisms (SNP) - rs12979860 (C/T) and rs8099917 (T/G) in IL28B gene was carried out by real-time PCR. RESULTS: HCV RNA was detected in 72 examined residents of Yakutia. HCV lb genotype was determined in 74.2% of cases, 3a - in 11.4%, la and 2 - 5.7% each. Frequency of polymorph variant rs12979860 CC was 72.2%, CT - 27.8%, rs8099917 TT - 61.1%, TG - 23.2%. CONCLUSION: Combination of HCV lb with polymorphic variants of IL28B'gene rs12979860 CC and rs8099917 CT showed a less aggressive course of the disease. On the other hand, HCV infection of individuals with geno- type 3a and polymorphism rs12979860 CC or rs809917 TT of IL28B gene showed a more severe clinical presentation. The presence ofpolyorirphvariants rs8099917 T/G and rs12979860 C/T showed more severe clinical outcomes of HCV infection (viral load up to 19035212 copies, cirrhosis with ascite, hepatocarcinoma).

[COMPARATIVE CHARACTERISTICS OF IMMUNE STATUS OF PATIENTS WITH CHRONIC FORMS OF VIRAL HEPATITIS B, C, D AND HEALTHY INDIVIDUALS].

AIM: Evaluate immune status in patients with chronic hepatitis (CH) depending on type of causative agent and severity of the infectious process. MATERIALS AND METHODS: 232 residents of Yakutia including 127 patients with various forms of chronic hepatitis and 105 healthy individuals were examined. Relative levels of mature T-lymphocytes (CD3⁺), T-helpers (CD4⁺), T-suppressors (CD8⁺), B-lymphocytes (CD72⁺) and naturalkillers (CD16⁺) were studied by flow cytometry, as well as concentration of sera immune globulins of classes A, M and G by ELISA. RESULTS: In patients with chronic hepatitis of various forms, a decrease of expression of differentiating antigens - CD3⁺, CD4⁺, CD72⁺ on the surface of lymphocytes and concentration of sera immune globulins was established. In CHD patients in phase of monoreplication high activity of the infectious process is accompanied by a shift of immune regulatory index to the increase of activity of cytotoxic cells with simultaneous development of deficiency of mature functionally active T-lymphocytes. In the -group of patients with hepatitis D virus with liver cirrhosis normal concentration of sera immune globulins is retained against the decrease of the number of T-helpers and B-lymphocytes. CONCLUSION: In patients with various forms of viral hepatitis acquired immune deficiency can emerge, which is often accompanied by enhancement of NK-cell activity. The noted reduction of the number of mature functionally active T-cells, as well as main classes of sera antibodies could be con- nected with immune system load during a chronic infectious process.

[THE ANALYSIS OF LIFE SPAN AND MORTALITY OF PATIENTS WITH SPINOCEREBELLAR ATAXIA TYPE I].

The article presents results of investigation of certain unclear aspects of mortality of patients with spinocerebellar ataxia type I including patients with the same number of CAG-repetitions. The analysis of mortality of patients observed from 1993 to nowadays was implemented. Sampling included 112 patients during that period 53 patients died. The comparative analysis was implemented concerning received data and results of analysis of mortality of patients died prior to 1980. According received data, average value of CAG-repetitions of normal allele was equal to 30.2, and ofpathologic allele--48.7. The average life span made up to 52.8 years, average age of disease onset--38 years and natural duration of disease--14.8 years. The analysis of life span of patients with equal length of repetitions demonstrated that range of life span of patients makes up to from 8 to 23 years. It is established that life of patients becomes shorter because of accidents, cancer and concomitant diseases of cardiovascular system. The presence of such concomitant disease as tuberculosis of lungs results in no shortening of life of patients. The comparative analysis of mortality during the period over 34 years demonstrated that age of disease onset turned out to be more conservative and stable indicator of morbidity. Despite of lacking of effective methods of treatment of disease, the natural duration of disease increased statistically reliable up to 1.8 times during period of observation. The analysis of life span ofpatients with spinocerebellar ataxia type I demonstrated that their life span except length of CAG-expansion depends on a number of factors accelerating and retarding development of disease. At that, life span of patients with the same number of CAG-repetitions can significantly differ The malignant neoplasms, diseases of cardiovascular system and external causes are to be referred to factors accelerating and retarding development of main disease. The addition oftuberculosis in our case resulted in no alteration of natural course of disease. The other factors exist prolonging life of patients, including factors of social economic and medical character They require additional specification and thorough investigation with the purpose of developing methods ofpreventive correction of neuro-degeneration processes.

[The first results of a combined all-Russian study on clinical genetics of multiple sclerosis].

Multiple sclerosis is a classic multifactorial disease in which etiology interaction of external factors and structural features of a large number of genes plays an important role. Identifying risk factors for multiple sclerosis and creating an integrated model of pathogenesis are urgent tasks of neurology. Revealing true risk factors is possible only in studies with sufficient statistical power, so with a large amount of samples. We conducted the association study of CD40 gene's polymorphisms and multiple sclerosis among residents of the Russian Federation. The results demonstrated the need to combine data from different researchers in clinical studies to increase the power of the study.

[Polymorphism of CTG-repeats in the DMPK gene in populations of Yakutia and central Asia].

Allele frequency distribution of CTG-repeat in the 3'-flanking region of DMPK gene was analyzed in populations of Yakutia (three ethnogeographical groups of Yakuts, Evenks, Evens, Yukaghirs, Dolgans) and Central Asia (Kazakhs, Uzbeks, Uighurs). Frequencies of CTG alleles were found to be significantly different in two regions. Allele frequency distribution in populations of Yakutia was similar to Asian populations, whereas Central Asian populations showed similarity to European populations. The features of allele spectrum in Yakut populations were discussed in terms of high prevalence of myotonic dystrophy in Yakuts. Our result supports the hypothesis of founder effect in spread of myotonic dystrophy in Yakuts. The phylogenetic relationships between the investigated populations based on polymorphism of CTG-locus of the DMPK gene have been analyzed as well.

Unstable triplet repeat and phenotypic variability of spinocerebellar ataxia type 1.

A Siberian kindred with spinocerebellar ataxia genetically linked to the SCA1 locus on chromosome 6p has been screened for the CAG triplet expansion within the coding region of the SCA1 gene. The kindred includes 1,484 individuals, 225 affected and 656 at risk, making this collection the largest spinocerebellar ataxia type 1 (SCA1) pedigree known. Each of the studied 78 SCA1 patients carried an expanded allele containing a stretch of 39 to 72 uninterrupted CAG repeats. Normal alleles had 25 to 37 trinucleotide repeats. Expanded alleles containing 40 to 55 repeats were found in 26 at-risk relatives. The number of CAG repeats in the mutated allele was inversely correlated with age at disease onset. Cerebellar deficiency was present in each patient and its severity was moderately affected by the number of CAG repeats. In contrast, the associated signs, dysphagia, diffuse skeletal muscle atrophy with fasciculations, and tongue atrophy were absent or mild in patients with low CAG repeat numbers, but severely complicated the course of illness in patients with a larger number of repeat units. One female mutation carrier was asymptomatic at age 66, more than 2 standard deviations beyond the average age of risk, suggesting incomplete penetrance. In 2 symptomatic individuals who had an expanded number of CAG repeats on both chromosomes, age at onset, rate of progression, and clinical manifestation corresponded to the size of the larger allele.

Autosomal dominant spinocerebellar ataxia (SCA) in a Siberian founder population: assignment to the SCA1 locus.

In seven families from a Siberian founder population with autosomal dominant spinocerebellar ataxia (SCA) genetic analysis of the polymorphisms flanking the SCA1 locus on chromosome 6p showed allelic association with disease inheritance. While the association was absolute in the case of microsatellite D6S274, an allele switch was observed for D6S89 in two families, suggesting a historic recombinant. Further genetic and physical study of this recombinant event could be instrumental for the precise localization and identification of the SCA1 gene.