Polymorphic Variants Of Genes Research Articles

The relationship between Multidrug Resistance Protein 1(rs1045642) and Cholesterol 24-hydroxylase (rs754203) genes polymorphism with type 2 diabetes mellitus

Background: The involvement of genetic factors like gene polymorphisms has been found to contribute significantly to the development and progression of type 2 diabetes (T2DM). Thousands of single nucleotide polymorphisms in various genes have been found to be associated with risk of T2DM. The present study was aimed to investigate association of Multidrug resistance 1 (MDR1) (rs1045642) and CYP46A1 (rs754203) genes polymorphism with T2DM.Subjects & Methods: Study includes 333 subjects, 183 T2DM cases and 150 healthy controls. Single nucleotide polymorphism was evaluated by PCR-PFLP. Alleles and genotype frequencies between cases and controls were compared using χ2 and Student’s t-tests. Odds ratios and 95% confidence intervals were calculated by logistic regression to assess the relative association between disease and genotypes.Results: In case of CYP46A1 gene, CC (p < 0.001) and CT (p = 0.001) genotypes and C allele (p < 0.001) were found to be a positive risk factor and TT genotype (p < 0.001) and T allele (p < 0.001) as negative risk factor for T2DM whereas, no association of MDR1 gene was found with T2DM (P values of all genotypes and alleles were greater than 0.001). MDR1 (rs1045642) and CYP46A1 (rs754203) genes polymorphism was not found associated with Fasting Blood Sugar (FBS), Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP).Conclusion: CYP46A1 gene polymorphism is associated with the risk of T2DM whereas, MDR1 gene polymorphism was not found to confer any risk of T2DM in North Indian Ethnic group.

Polymorphic variants of the immune response genes as risk factors for primary progressive multiple sclerosis

To analyze the involvement of immune response genes in the pathogenesis of primary progressive multiple sclerosis (PPMS). This multicenter study included 111 patients with PPMS from the Russian ethnic group. The association of PPMS with genes of immune system was analyzed by the study of polymorphic variants of genes of cytokines and genes of antigen-presenting cells. The genotypes of IL-4 (rs2243250)*C/C and CLEC16A (rs6498169)*G/G were associated with PPMS in Russians. The association between the HLA-DRB1*15 and PPMS found out in other populations was confirmed in Russians.

Genetic Basis of Diabetic Nephropathy

It is well known that all patients with Type 2 Diabetes Mellitus (T2DM) do not develop chronic kidney disease (CKD). Several metabolic, hemodynamic and intracellular mechanisms have been proposed to play role in the pathogenesis of Diabetic Nephropathy (DN). Clustering of patients with DN in certain ethnic groups and families suggests the role of genetic factors. We have studied various facets about genetic determinants which may influence the development of kidney disease in patients with T2DM. We have found that Angiotensin Converting Enzyme (ACE) DD genotype conferred the maximum risk, whereas ACE II genotype seemed to confer protective role against development of diabetic and nondiabetic CKD. Further, we found that oxidative stress (OS) plays a significant role in the development of DN and that Glutathione S-transferase theta-1and/or Glutathione S-transferase Mu-1 null genotypes are associated with higher OS in patients with DN. In addition, we also found that increased levels of inflammatory mediators, i.e. Tumor necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hsCRP) and Urinary Monocyte Chemoattractant Protein-1 (uMCP-1) play a significant role in contributing to OS. We have shown that genetic polymorphism of NF-kB gene and TNF-α gene plays a role in determining serum level of various inflammatory markers and oxidant stress parameters. We found significant association of -429T/C and Gly82Ser Receptors for Advanced Glycation End-products (RAGE) polymorphisms with the development of macrovascular and microvascular complications, respectively in T2DM subjects. Further, we have observed that AGE-mediated exacerbation of RAGE expression may play a role in pathogenesis of various vascular complications in T2DM. To conclude, polymorphisms of various genes involved in renin-angiotensin aldosterone system (RAAS), inflammatory, oxidant stress, cytoprotective and nitrous oxide pathways and enhanced RAGE mRNA expression may adversely influence final common pathway through oxidant stress mechanisms, and influence the levels of various cytokines and intracellular signaling mechanisms, thereby influencing the susceptibility of patients with diabetes mellitus for development of kidney disease and vascular complications.

Association of GCLM -588C/T and GCLC -129T/C Promoter Polymorphisms of Genes Coding the Subunits of Glutamate Cysteine Ligase with Ischemic Heart Disease Development in Kazakhstan Population.

Background Glutamate cysteine ligase (GCL) is a rate-limiting enzyme in synthesis of glutathione. Evidence suggests that genetic variations in the promoter region of genes coding a catalytic subunit (GCLC -129T/C) and a modifier subunit (GCLM -588C/T) of GCL have a functional impact on their transcriptional activity and were associated with various disorders. Hence, we hypothesize whether these two polymorphic variants of GCLM and GCLC genes are associated with the risk of ischemic heart disease (IHD) development in the population of Kazakhstan. Methods We evaluated 360 patients with IHD and 341 control subjects. Allele frequencies of studied promoters' polymorphisms were detected by PCR-RFLP analysis. Multiple logistic regression analysis was applied to assess the risk for different genotypes obtained. Results The presence of -588T allele in GCLM and -129T allele in GCLC gene genotypes was associated with an increased risk of IHD (GCLM -588T: OR = 3.92, p = 0.003; GCLC -129T: OR = 3.22, p = 0.03) for general ethnically mixed group. Analysis of each ethnical groups separately showed the higher risk tendency for Kazakhs as for GCLM -588T (OR = 4.79; p = 0.03) and as for GCLC -129T (OR = 4.79, p = 0.03). For Russians, statistically differences for two polymorphisms were not observed. Conclusion The two promoter polymorphisms of GCLM (-588C/T) and GCLC (-128T/C) are associated with an increased risk of IHD in Kazakhstan population.

Classification, regulation of activity, and genetic polymorphism of matrix metalloproteinases in health and disease

Matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that catalyze the degradation reactions of the extracellular matrix components. In humans, 23 enzymes of this family are known, which are subdivided into 6 groups based on their structure and substrate types: collagenases, gelatinases, stromelysins, matrilizines, MMP membrane type and other MMPs. MMP functions are diverse, and an imbalance of their activity may be one of the etiological factors of various diseases. The review considers classification, regulation of activity and genetic polymorphism of matrix metalloproteinases in health and in various pathological processes in the human body. A list of the most studied polymorphic variants of MMP genes is given, their functional effects are described and the results of associative studies are presented.

The clinical features of Parkinson's disease in patients with mutations and polymorphic variants of GBA gene

Mutations in the glucocerebrosidase gene (GBA) increase the risk of Parkinson's disease (PD) by 6-10 times in all populations and are associated with the early-onset of PD, development of cognitive impairment and presence of psychotic disorders. At the same time, polymorphic variants associated with the twofold increase in the risk of PD were also described in the GBA gene. To estimate the clinical features of PD in patients with mutations and polymorphic variants of the GBA gene. Evaluation of motor, cognitive, emotional, psychotic and autonomic dysfunctions in patients with mutations (N370S, L444P) and polymorphic variants (E326K, T369M) in the GBA gene was performed using clinical scales. Patients with mutations (mGBA-PD), and with polymorphic variants (pGBA-PD) in the GBA gene were compared with the group of patients with sporadic PD (sPD). Compared to sPD, affective disorders (depression and anxiety) were more expressed in the mGBA-PD group (p=0.001) and the general GBA-PD group (p=0.001) assessed with Sheehan anxiety rating scale, in the pGBA-PD group (p=0.012) and the general GBA-PD group (p=0.05) assessed with the NPI, in the mGBA-PD (p=0.003), pGBA-PD (p=0.022), and general GBA-PD groups (p=0.001) assessed with the Hospital Anxiety and Depression scale (HADS 'A'), and in the pGBA-PD group (p=0.005) assessed with the HADS 'D'. Non-motor symptoms assessed with the PD-NMS were more expressed in the pGBA-PD patients (p=0.007) and in the total group with GBA-PD (p=0,014) compared to sPD. Cognitive impairment measured with MMSE was more marked in mGBA-PD patients (p=0.022). Differences in motor and non-motor clinical symptoms between pGBA-PD and mGBA-PD groups were not found. Thus, clinical features of non-motor symptoms were described both in carriers of GBA mutations and polymorphisms. Identification of the specific clinical phenotype of PD in carriers of GBA polymorphic variants is important due to their relatively high prevalence in PD patients.

Association of polymorphic variants of PIP5K2A and HTR2C genes with response to antidepressant therapy of patients with a current depressive episode

To study the association between polymorphisms of PIP5K2A and HTR2C genes and response to antidepressant therapy in patients with a current depressive episode. The study included 222 patients (168 women and 54 men) with a current depressive episode. The assessment of the severity of the current depressive episode and the efficacy of treatment was performed using the Hamilton depression scale (HDRS-17) and the Clinical global impression scale (CGI-S, CGI-I). The association of treatment efficacy with PIP5K2A polymorphisms rs10430590, rs10828317 and HTR2C polymorphisms rs6318, rs569959, rs3813929, rs12858300 was studied. Polymorphisms rs10828317 and rs10430590 in the PIP5K2A gene were associated with the CGI-S total score at day 28 of therapy. Polymorphism rs6318 in the HTR2C gene was associated with response to antidepressant therapy followed by clinical improvement of patients with current depressive episode on the 28th day of antidepressant therapy.

Distribution of the most common polymorphisms in TYMS gene in Slavic population of central Europe.

Thymidylate synthetase (TS) plays a critical role in the de novo synthesis of dTMP inside the cell. Therefore, TS is a suitable target for cytotoxic drugs such as fluoropyrimidines. Drug efficacy and toxicity depend on the intracellular level of TS, which is significantly influenced by the polymorphisms in the 5'UTR (TSER - rs45445694, TSER*3G>C - rs2853542) and 3'UTR (1494del TTAAAG - rs151264360) of TYMS gene. Polymorphic variants of TYMS gene affect TS activity via gene expression and transcript stability. Patients who undergo fluoropyrimidine therapy may benefit from genetic testing prior to the administration of chemotherapy. At the 5' terminus of TYMS, there is a polymorphic region represented by a variable number of 28bp long tandem repeats (2-9 tandems) with the G or C nucleotide variant (SNP G>C). The 3'end of TYMS gene may decrease the stability of mRNA in the case of 6 base deletion (1494del6, D). In our study, we have focused on testing of TYMS gene polymorphisms, determination of TYMS variant frequencies in Western Slavic population and comparison of Slovak population with other populations.We performed identification of 5'UTR (rs45445694 - TSER*2 or TSER*3; rs2853542 - TSER*3G>C; TSER*3+ins6) and 3'UTR (rs151264360/1494del6/D) polymorphic regions of TYMS gene among 96 volunteers by PCR-RFLP and fragment analysis. Slovak frequencies of selected polymorphisms were established as follows: the frequency of TSER*2, TSER*3, TSER*3G>C, 1494del6/D and I to be 41%, 59%, 34%, 37.5% and 62.5% respectively. The high resolution of the capillary electrophoresis technique allowed among TSER*3 group identification of a subgroup of four individuals with rare 6bp insertion in 3R allele, id est 2.1% TSER*3+ins6 allele frequency. In our study, we have revealed individuals with rare G>C substitution in the first 28bp tandem repeat of TSER*2 promoter enhancer region (rs183205964) as well, the overall frequency of this polymorphic allele in Slovak population was 2.1%. Our results proved that Slovak population is in Hardy-Weinberg equilibrium and proportion of TYMS polymorphisms is in accordance with other published data.

DISTRIBUTION OF POLYMORPHIC VARIANTS OF GENES SYSTEM HEMOSTASIS AND FOLATE METABOLISM CHILDREN IN THE ACUTE GLOMERULONEPHRITIS

PURPOSE OF THE RESEARCH: to study the prevalence of prothrombotic polymorphisms of the hemostatic system in children with acute glomerulonephritis. PATIENTS AND METHODS: analysis of carriers of prothrombotic polymorphisms in acute glomerulonephritis in children. Genes are candidates for predisposition to increased thrombus formation was investigated by PCR the allelic variants of genes of factors II prothrombin (G20210А); factor V Leiden (G1691A), factor VII clotting (G10976A); factor XIII of blood coagulation (G226A); fibrinogen G(-455)A; inhibitor of plasminogen activator PAI-1 4G(-675)5G; and polymorphic gene variants of folate cycle disorders: methylenetetrahydrofolate reductase – (MTHFR C677T, MTHFR А1298С), B12-dependent methionine synthase (MTR А2756G) and methionine synthase reductase – (MTRR A66G), 31 children: 20 children with endocrine nephrotic syndrome; 11 children with acute glomerulonephritis nephritic syndrome. RESULTS: it was found that the frequency of the major allele 5G (-675) of the gene PAI-1 50% statistically significantly (p=0,042) above was determined in children with endocrine NS group than in healthy children. When comparing the distribution of allele frequencies, genotypes of the genes of the hemostatic system and folate metabolism in patients with acute GN nephritic syndrome and the control group, statistically significant differences were revealed. In the study found that in children with acute glomerulonephritis often have a combination of prothrombotic polymorphisms – 48,4% (p<0.05), dominated by compounds of the genotype 677 CT MTHFR gene and genotype (-675) 4G5G PAI-1 gene in 40% of children. Coagulation status associated with dysfunction of hemostasis is more pronounced in the combination of acute glomerulonephritis and gene-genych Association of prothrombotic polymorphisms than in the control group. CONCLUSION: the Heterozygous genotype 677 CT MTHFR gene is 60% and the heterozygous genotype AD 66 gene MTRR 70% occur with greater frequency than in the control group.

ASSESSMENT OF THE POLYMORPHIC GENES VARIANTS OF THE LIPID AND CARBOHYDRATE METABOLISM, VASCULAR INFLAMMATION AND NEUROTRANSMITTER SYSTEM IN THE FIRST ISCHEMIC STROKE

Aim. To study the relations of polymorphic variants of the genes: АРОЕ, MTHFR, IL8, IL6, TNF-а, VEGFA, ADIPOQ, ADIROR, APOB, APOА-V, APOC-IV, LPL, LP(a), BDNF, GRM1, GRM3 and development of the first ischemic stroke (IS). Material and methods . The alleles frequencies and genotypes assessed for 20 mono-nucleotide polymorphic gene variants in 435 patients, who had first IS, and 229 persons with no stroke, comparable with age, gender, place of living and ethnicity. Genotyping of polymorphisms was done with the prepared TaqMan probes. Results . For polymorphisms АРОВ (rs676210) and IL8 (rs1803205) there was significant difference between groups in the variety of minor alleles and genotypes. Conclusion . There is significant relation of mononucleotide polymorphisms of the genes АРОВ (rs676210) and IL8 (rs1803205) with the development of first IS in the studied groups.

Association of rs2294008 and rs9297976 Polymorphisms in PSCA Gene with Gastric Cancer Susceptibility in Uzbekistan.

Introduction:Genetic factors play an important role in the development of gastric cancer (GC), a prevalent malignancy in Central Asia. Recent studies have shown that single-nucleotide polymorphisms (SNPs) in several genes are associated with increased GC risk, indicating that genetic variation contributes to gastric carcinogenesis. Located on chromosome 8q24.2, the prostate stem cell antigen (PSCA) gene encodes a 123-amino acid glycoprotein related to the cell-proliferation inhibition and cell-death induction activity. SNPs in PSCA gene have been found to be associated with gastric cancer risk in a genome-wide association study, but results were not conclusive. This study aimed to investigate the association between two polymorphic variants of PSCA gene (rs2294008 and rs9297976) and the susceptibility to gastric cancer in Uzbekistan.Methods:Two hundred sixty eight patients with gastric cancer and a control group of 248 healthy individuals were included in this study. DNA samples isolated from these groups were genotyped using PCR-RFLP method. Comparative analysis of resulting genotypes showed a statistically significant association between CT genotype and gastric cancer (p=0.03, additive model of inheritance, Cochran-Armitage trend test).Results:Comparative analysis of the distribution of genotypes of rs2976392 polymorphism did not show a statistically significant difference; however, analysis of the distribution of the rs2976392 genotypes in a subgroup of young women revealed a statistically significant (p = 0.04, additive model of inheritance, Cochran-Armitage trend test) increase in the incidence of AA (38%) and AG (56%) genotypes in patients with GC, compared to the controls (20% and 40%).Conclusion:Our findings support that PSCA rs2294008 and rs9297976 polymorphism may contribute to the susceptibility to gastric cancer. Genotyping of these polymorphisms can potentially be recommended as one of the criteria for identification of high risk groups for gastric cancer development in Uzbekistan.

Evaluation of polymorphic variants in apoptotic genes and their role in susceptibility and clinical progression to systemic lupus erythematosus.

Background Systemic lupus erythematosus (SLE) is an autoimmune disease marked by the disruption of the immune homeostasis. Patients exhibit a wide range of clinical manifestations, and environmental and genetic factors are involved in SLE pathogenesis. Evidence suggests that abnormalities in the cellular and molecular events that coordinate apoptosis may favour the generation of autoantigens involved in autoimmunity. In this way, the apoptotic deregulation may be affected by polymorphic variants in apoptotic-related genes. Methods We analyzed FAS, FASL, BCL-2 and BAX polymorphisms in order to correlate to SLE susceptibility and clinical features. A total of 427 SLE patients from the Hospital de Clínicas de Porto Alegre and 543 controls from southern Brazil were evaluated. Results We observed higher frequencies of the FASL -844CC genotype and -844C allele, as well as of the FASL-844C/IVS2nt-124A haplotype in African-derived SLE patients when compared to controls ( P < 0.001). FASL -844C, which is related to high FasL expression, could contribute to increased apoptosis and to the breakdown of immunological tolerance, favouring autoantibody production and inflammation. On the other hand, the BAX -248GA genotype and the -248A allele , related to low protein expression, were observed as a protective factor against SLE in this same population. The rate of apoptosis and cell death was evaluated in peripheral lymphocytes, and SLE patients presented a higher percentage of dead lymphocytes (CD3+Annexin V+ 7-AAD+) compared to the control group. Conclusion Our data support a role for apoptosis in SLE susceptibility.

Значення гетерохроматину і поліморфних варіантів генів фолатного циклу у жінок з репродуктивними втратами

The article presents data from surveys of women of losses of pregnancy (LP) in history, conducted within the medical genetic counseling, given the urgency of specifying genetic factors that actually are in causal connection with the LP specification clinical effects of epigenetic variability. The objective: to clarify the meaning of the changes in women heterochromatin (chromosomal polymorphism) and polymorphic variants of genes folat cycle enzymes as potential risk factors and pathogenic primordial LP. Patients and methods. The study involved two groups of women: I - 154 observations with complicated obstetric history in LP and II - 32 healthy women with uncomplicated reproductive history, held preconception planning to prevent pregnancy. Studied genealogical history, especially of internal organs, genitalia. Special studies included cytogenetic analysis, identification of gene polymorphisms system folat cycle methylentetrahydrofolate reductase [MTHFR] (C677T, A1298C, G1793A); methionine synthase reductase [MTRR] (A66G). Results. Women with a history of LP in 36.4% identified chromosome polymorphisms (SNPs extreme variants of chromosome polymorphism) on the background of various risk alleles of polymorphic variants of genes folat cycle; 7.1% of them is a polymorphism of the 21st chromosome. These genetic features are interpreted as a significant risk factor for LP as grounds for targeted in-depth medical and genetic examination. Prevalence among women with a history of PL undifferentiated forms cjnnective tissue and mesoderm dysplasia, benign tumors and «precancerous» states, as well as the prevalence of cardiovascular and psycho-neurological disease in pedigree suggests pathogenetic link these phenomena, the role of chromosomal polymorphism and polymorphic variants of genes of pathogenic folat cycle as primordial. Conclusion. The data on the place and role of heterochromatin and gene polymorphisms folat cycle in the origin LP should be mandatory option when examining women within the medical genetic counseling. Key words: pregnancy, reproductive losses, chromosomal instability, folat cycle genes, ancestry.

Frequency of 3’ VNTR Polymorphism in the Dopamine Transporter Gene SLC6A3 in Humans Predisposed to Antisocial Behavior

Predisposition to antisocial behavior can be related to the presence of certain polymorphic variants of genes encoding dopaminergic system proteins. We studied the frequencies of allele variants and genotypes of variable number tandem repeat polymorphism in 3' untranslated region (3' VTNR) of the dopaminergic transporter SLC6A3 gene in Caucasian men committed socially dangerous violent and non-violent crimes. Alleles with 9 and 10 repeats were most frequent in both the control group and group of men predisposed to antisocial behavior. At the same time, the 10/10 genotype was more frequently observed in the group of men prone to antisocial non-violent behavior. Hence, the presence of certain variants of 3' VTNR polymorphism of SLC6A3 gene in men is associated with predisposition to certain forms of antisocial behavior.

P.5.d.005 - CYP2D6 and catechol-O-methyltransferase gene polymorphisms in Parkinson patients with levodopa-induced dyskinesias

Parkinson's disease (PD), a common neurodegenerative disorder caused by the loss of the dopaminergic input to the basal ganglia, is commonly treated with levodopa (L-DOPA). Use of this drug, however, is severely limited by the development of side effect. Levodopa-induced dyskinesias (LID) are involuntary muscle movements that occur as a consequence of chronic levodopa (L-DOPA) treatment. LID are a substantial barrier to effective symptomatic management of Parkinson's disease (PD), up to 45% of L-DOPA users develop LID within 5 years [1]. Clinical heterogeneity of LID suggests a significant role of endogenous factors in determining their prevalence. Some evidence suggest a relationship between LID and specific genetic changes, such as changes in the genes controlling enzymes responsible for drug and monoamine metabolism, neurotransmitter receptors and proteins involved in oxidative stress or antioxidant function [2-4]. Objective: To investigate contribution of polymorphic variants of CYP2D6 and COMT genes in the development of LID in PD patients. Methods: 212 patients with Parkinson's disease on levodopa therapy were investigated. Dyskinesias were estimated with use of Abnormal Involuntary Movement Scale (AIMS). DNA extraction and fluorogenic 5'-exonuclease TaqMan genotyping assays were conducted according to standard protocols and blind to the clinical status of the subjects. Genotyping was carried out on 2 SNPs of CYP2D6 (CYP2D6∗3, rs35742686; CYP2D6∗4, rs3892097) and 7 SNPs of COMT genes (rs4680, rs6269, rs4633, rs4818, rs769224, rs165774, rs174696). The SPSS software was used for statistical analysis. Results: Patients in our cohort demonstrated typical PD demographics, with a mean age of onset of 60.04±9.46 years, a mean disease duration of 9.79±5.57 years. Dyskinesias were reported in 57 (26.9%) patients. The distribution of genotypes of studied genes corresponded to the Hardy-Weinberg equilibrium. Association of polymorphisms in CYP2D6 gene with side effects was not revealed. We found that rs4680 polymorphism in COMT gene is significantly associated with LID (χ2 = 6.048, p = 0.049). Odds ratio for carriers of the genotype AA is 2.14 [95% CI: 1.11- 4.11], which indicates the predisposing effect of this genotype on the development of dyskinesias. Rs4680 is a functional SNP in genes encoding the catechol-O-methyltransferase enzyme, which catabolizes dopamine. A valine to methionine substitution at codon 158 of the COMT gene produces a Met variant that catabolizes dopamine up to four times slower than its Val counterpart. Conclusions: Polymorphisms in the COMT gene play significant role in the therapy response to L-DOPA as well as in various adverse effects. COMT is an extracellular enzyme which inactive variants increase the extracellular concentration of dopamine. This may increase the uptake of dopamine by indirect pathway MSN and therefore increase oxidative stress. We hypothesized that functional single nucleotide polymorphism rs4680 in COMT gene may result in a clinical phenotype contributing to an increased risk of LID. Thus, the polymorphism of gene possessing predisposing effects in development of levodopa induced dyskinesia in PD has been revealed that would allow predicting risk of development of movement disorders.

ASSOCIATION OF POLYMORPHIC LOCI HSP1A GENES WITH THE DEVELOPMENT OF CHRONIC MERCURY INTOXICATION

The present study investigated the association between polymorphic variants of HSP1A genes (HSP70 gene family) and chronic mercury intoxication (CMI) development in 87 workers of caustic soda production plant, who have been chronically exposed to mercury vapor. The polymorphic loci HSPA1B (+1267A/G и +2074G/C) and HSP1AL (+2437T/C) were studied. Genotyping was performed using PCR-RFLP and logistic regression analysis was used for three genetic models for the investigation of the required associations. We found that frequency of genotype GG HSPA1B (+1267A/G) in group of patients with CMI (n = 45) was higher (p = 0.003) compared with the group of workers without the disease (n = 42). Recessive genetic model found a strong association of the homozygous GG genotype for rare allele with the development of CMI (OR = 13.26, p = 0.001). The obtained associations indicate that the HSPA1 could be important in mechanisms of CMI development and progression and help to develop the criteria for assessing individual's susceptibility to its development.

Полиморфизм гена CYP2C9 и риск развития гепатотоксичности при проведении антиретровирусной терапии

Целью исследования было изучение ассоциации полиморфных вариантов генов CYP2C9 с риском возникновения лекарственного поражения печени при проведении антиретровирусной терапии ВИЧ-инфицированным пациентам. Анализ исследуемых полиморфных вариантов генов CYP2C9*2 (Arg144Cys) и CYP2C9*3 (Ile359Leu) в исследуемой выборке показал, что доминирующим генотипом гена CYP2C9*2 было гомозиготное носительство СС, а по гену CYP2C9*3 — преобладание генотипа АА, частота встречаемости которых в популяции оказалась одинаковой и составила 80 %. Не обнаружена ассоциация изучаемых генотипов с риском развития лекарственного поражения печени. Носительство отдельных аллелей C или Т в случае гена CYP2C9*2, а также А или С при CYP2C9*2 не является прогностическим признаком поражения гепатоцита антиретровирусными лекарственными средствами.

Circadian CLOCK Gene Variants, Parameters of Arterial Stiffness and Blood Pressure Levels in Subjects Without Arterial Hypertension

CLOCK gene polymorphic variants, parameters of arterial stiffness and blood pressure (BP) variability were studied in 115 normotensive Russian patients without cardiovascular diseases (62 men, 53 women; mean age 36.4+/-1.01 years). Examination included ECG, 24h BP monitoring, duplex scan of carotid arteries, registration of vascular stiffness parameters, and genotyping of the following polymorphic markers of CLOCK: 3111T>C (3-untranslated region), 862T>C (exon 9) and 257T>G (promoter region) by PCR-RFLP method. Pulse wave velocity was not significantly different among carriers of various 257T>G, 862T>C, 3111T>C genotypes. Augmentation index (Aix night, Aix max) values were lower in individuals with genotypes allegedly associated with essential hypertension and ischemic heart disease (257GG, 862CC, 3111CC). Arterial stiffness index (ASI) was significantly higher in men having CC genotype of 862T>C. Polymorphic variants 257T>G and 862T>C SNPs of CLOCK gene were found to be associated with parameters reflecting BP variability (morning rise of diastolic BP and rate of BP rise). These results provide a basis for suggestion that the CLOCK gene polymorphism is one of factors determining elastic properties of vascular wall. The suggestion is supported by discussion of possible molecular mechanisms of circadian genes impact on elasticity and rigidity of vessel.

DNA Methyltransferase Gene Polymorphisms for Prediction of Radiation-Induced Skin Fibrosis after Treatment of Breast Cancer: A Multifactorial Genetic Approach.

PurposeThis study was conducted to investigate the role of four polymorphic variants of DNA methyltransferase genes as risk factors for radiation-induced fibrosis in breast cancer patients. We also assessed their ability to improve prediction accuracy when combined with mitochondrial haplogroup H, which we previously found to be independently associated with a lower hazard of radiation-induced fibrosis.Materials and MethodsDNMT1 rs2228611,DNMT3A rs1550117,DNMT3A rs7581217, and DNMT3B rs2424908 were genotyped by real-time polymerase chain reaction in 286 Italian breast cancer patients who received radiotherapy after breast conserving surgery. Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue–Subjective Objective Management Analytical (LENT-SOMA) scale. The discriminative accuracy of genetic models was assessed by the area under the receiver operating characteristic curves (AUC).ResultsKaplan-Meier curves showed significant differences among DNMT1 rs2228611 genotypes in the cumulative incidence of grade ≥ 2 subcutaneous fibrosis (log-rank test p-value= 0.018). Multivariate Cox regression analysis revealed DNMT1 rs2228611 as an independent protective factor for moderate to severe radiation-induced fibrosis (GG vs. AA; hazard ratio, 0.26; 95% confidence interval [CI], 0.10 to 0.71; p=0.009). Adding DNMT1 rs2228611 to haplogroup H increased the discrimination accuracy (AUC) of the model from 0.595 (95% CI, 0.536 to 0.653) to 0.655 (95% CI, 0.597 to 0.710).ConclusionDNMT1 rs2228611 may represent a determinant of radiation-induced fibrosis in breast cancer patients with promise for clinical usefulness in genetic-based predictive models.

Polymorphic Variants 279R and 668Q Augment Activity of Matrix Metalloproteinase-9 in Breath Condensates of Children with Asthma.

Matrix metalloproteinase (MMP)-9 is involved in pathophysiology of asthma, mainly asthma-associated airway remodeling. Exhaled breath condensates (EBC) of asthmatics contain increased amounts of MMP-9 with activity higher, than in healthy controls. The increased activity of MMP-9 may originate from its excessive production and activation, but may also result from variations in MMP-9 structure, which are determined by single nucleotide polymorphisms (SNPs). In this pilot study we aimed to assess the possible influence of two functional MMP-9 polymorphisms, Q279R and R668Q, on enzymatic activity of MMP-9, measured in EBC of asthmatic children. The concentration and activity of MMP-9 were analyzed in EBC of 20 children with allergic asthma using specific standard ELISA and novel immunoenzymatic activity assay. The SNPs of MMP-9 were assessed using real-time PCR-based genotyping test. We have found that MMP-9 concentration in breath condensates of children with stable asthma was slightly higher in ELISA, than in the activity assay. Moreover, these results and activity-to-amount ratio have revealed some relationship with a presence of specific 279R and/or 668Q MMP-9 gene variants. Our observation suggests that at least in some patients MMP-9 hyperactivity may result from genetic predisposition, determined by polymorphic variants of MMP-9 gene. Moreover, it supports previous reports postulating significance of MMP-9 in pathogenesis of asthma. However, this issue still requires further studies.