Polymorphic Variants Of Genes Research Articles

Polymorphic variants of detoxification genes and possible gestational complications in pregnant women with retrochorial and retroplacental hematomas

Polymorphic variants of detoxification genes and possible gestational complications in pregnant women with retrochorial and retroplacental hematomas

MOLECULAR GENETIC TESTING OF ACCP-POSITIVE PATIENTS WITH RHEUMATOID ARTHRITIS AND HIGH INFLAMMATORY DISEASE ACTIVITY (A REMARCA STUDY)

Rheumatoid arthritis (RA) is a multifactorial disease, in which the interaction of the genetic component and environmental factors, determines not only the development of the disease, but also its pronounced clinical polymorphism. We assume that the high inflammatory activity of RA may be determined by the genes, the products of which trigger inflammatory processes. Objective: to investigate allele and genotype distribution of gene polymorphic variants in active anti-cyclic citrullinated peptide (aCCP)-positive patients with RA from the REMARCA program versus a control group of healthy blood donors. Subjects and methods . A molecular genetic study enrolled 146 aCCP-positive patients from the REMARCA program and a control group of 314 healthy blood donors without autoimmune diseases and their presence in the history, who were matched with the study group for gender and sex. The polymorphic variants of the genes PTPN22 (+1858C>T, rs2476601), TNFAIP3 (rs6920220, rs10499194), CTLA4 (+49A>G, rs231775), TNFА (-308A>G, rs1800629), IL6 (-174G>C, rs1800795), IL6R (+358A>C, rs8192284), IL10 (-592A>C, rs1800872, -892 C>T, rs1800871, -1082 A>G, rs1800896), and MCP1/CCL2 (+2518A>G, rs1024611) were genotyped by a real-time polymerase chain reaction assay. Results and discussion. The genotype and allele frequencies of polymorphic variants of the genes CTLA4 (+49A>G), IL-6R (+358A>C), and IL10 (592A>C) in the RA group significantly differed from those in the control group. When comparing with the control group, the minor alleles of the CTLA4 and IL10 genes were markers for the risk of aCCP-positive RA with a high inflammatory activity (OR=1.4 [1.1; 1.9], p=0.02 and OR=1.9 [1.4; 2.5]; p=0.0001, respectively). At the same time, the minor C allele of the IL6R gene served as a marker of protection (OR=0.7 [0.5; 0.9]; p=0.03). Logistic regression analysis revealed that there was a statistically significant correlation of the high inflammatory activity indices SDAI, CDAI, and DAS28 with the minor homozygous GG genotype of the CTLA4 gene (OR=2.5 [1.1; 6.0]; p=0.03, OR=2.6 [1.1–6.4], p=0.03 and OR=3.4 [1.3–8.8]; p=0.01, respectively). In addition, the inflammatory activity indices SDAI and CDAI rather than DAS28-ESR were associated with at least one minor A allele (the AA/AC genotypes) of the IL10 gene (OR=2.4 [1.2; 5.1], p=0.02 and OR=2.2 [1.1; 4.7]; p=0.03, respectively). The levels of ESR and CRP were not associated with the examined polymorphisms. Conclusion. The findings may suggest that there is a relationship of the polymorphisms of the genes CTLA4 (+49A>G, rs231775), IL6R (+358A>C, rs8192284), and IL10 (-592A>C, rs1800872) to high inflammatory activity in the group of aCCP-positive patients from the REMARCA study.

IL12B, IL23A, IL23R and HLA-C*06 genetic variants in psoriasis susceptibility and response to treatment

The role of interleukin-23 is crucial in the pathogenesis of psoriasis, and IL23A, IL12B and IL23R genetic variants have been associated with the disease in genome-wide association studies. In the current paper we have conducted a confirmation study of the abovementioned genetic factors in a case-control analysis of 507 psoriatic patients and 396 controls from a Polish population, and subsequently analyzed the impact of genetic variants on response to topical and NB-UVB therapy in a subset of 306 patients. Case-control analysis revealed an association of IL12B rs3212227 and IL23R rs11209026 minor allele carrier status with reduced odds for psoriasis (OR = 0.66, 95%CI: 0.50–0.87, and OR = 0.41, 95%CI: 0.26–0.67, respectively), while HLA-C*06 allele carriers were more frequent in patients group (OR = 4.56, 95%CI: 3.41–6.10). The studied polymorphic variants of IL12B, IL23A, and IL23R genes did not influence therapy outcome, i.e. there were no significant differences in PASI reduction between patients with different genotypes. However, HLA-C*06 carriers showed poorer response to the applied treatment, when compared to non-carriers. The results of the current study confirm an association between IL12B and IL23R genetic polymorphism and psoriasis vulgaris (with a protective effect of minor alleles). HLA-C*06 carriers show reduced effectiveness of topical/NB-UVB therapy, and that observation could be potentially used in treatment personalization.

Association of polymorphic variants of IL-1β and IL-1RN genes in the development of Graves’ disease in Kashmiri population (North India)

PurposeGraves’ disease (GD) is a multigenic, organ specific autoimmune disorder with a strong genetic predisposition and IL-1β has been shown to be involved in its pathogenesis. The present study was aimed to determine the genetic associations between polymorphisms of IL-1β gene promoter region (−511 T>C) (rs16944), exon 5 (+3954 C>T) (rs1143634) and IL-1RN gene VNTR (rs2234663) polymorphism in patients with GD in ethnic Kashmiri population. MethodsA total of 135 Graves’ disease patients and 150 healthy individuals were included in the study. PCR and PCR-based restriction analysis methods were done for IL-1RNVNTR and IL-1β gene polymorphisms respectively. ResultsWe found statistically significant increased frequencies of the C/C + CT genotype (P = 0.001; odds ratio (OR) = 5.04, 95% confidence interval (CI) = 3.02–8.42) and the C allele (P = 0.001; OR = 3.10, 95% CI = 2.14–4.50) in IL-1β gene promoter polymorphism (rs16944) with GD patients compared to normal controls. Also in the exon 5 (rs1143634), a significant increase in frequency of the C/C homozygous genotype (P = 0.001; OR = 0.18, 95% CI = 0.11–0.30) and C allele (P = 0.001; OR = 0.31, 95% CI = 0.20–0.48) was observed in GD cases as against controls. For IL-1RNVNTR (rs2234663), we didn’t observe any significant difference in the allelic and genotypic frequencies between cases and controls. ConclusionOur findings suggest that both promoter and exon polymorphisms of IL-1β gene have a significant role in the risk of developing GD, whereas IL-1RNVNTR has no association with GD.

The reversion of A23525T of polymorphism of FTO gene in persons with overweight in conditions of hypocaloric diet

ObjectiveTo study the association of A23525T polymorphism of the FTO gene with overweight/obesity and the possibility of reversion of single-nucleotide replacements rs9939609 in a hypocaloric diet. Materials and methodsPolymorphisms of the FTO gene (A23525T, rs9939609) are typified by the SNP method (single nucleotide polymorphism) with allele-specific primers on the test systems of the NPF "Liteh".The frequencies rs9939609 were studied in persons with overweight, I–III degree of obesity (n = 84) compared with the control group (n = 32). The reversion of polymorphic variants of genes under the influence of a hypocaloric diet has been analyzed. The experimental data are processed in SPSS Statistics 22.0. ResultsIn the pilot study, unlike previously published studies, a reliable association of the genotype of the FTO gene with a violation of lipid metabolism (OR = 2.33, CI 95%) was shown not by A23525A, but by T23525T. A positive correlation was established between the mean force between the TT genotype and the weight of the participants in the experiment (r = + 0.625, p = 0.022), fat mass (r = + 0.610; p = 0.046), body mass index (BMI) (r = + 0.577; p = 0.039) and the circumference of the hips (r = + 0.636; p = 0.039). In 25 out of 84 participants (29.7%) after RTD, a partial or complete reversal (reversal) of nucleotides occurred in rs9939609: 40% of them were mutations transversion caused by the replacement of T→A nucleotides and the A23525T, T23525T transition of genotypes into the homozygous A23525A variant. ConclusionThe TT genotype of the FTO gene is associated with obesity. The reversal of polymorphisms in the FTO gene under the influence of RDT is mainly associated with transversion of nucleotides (А→Т) at the corresponding site (23525) of the intron mutation (rs9939609).

Pleiotropy and Promiscuity in Pharmacogenomics for the Treatment of Alzheimer's Disease and Related risk factors

Patients with Alzheimer's disease are current consumers of polypharmacy with a high risk for drug–drug interactions. Antidementia drugs and other pharmacological treatments for vascular risk factors associated with dementia exert pleiotropic effects which are promiscuously regulated by different gene products. The aim of this review is to highlight the influence of genes involved in pharmacogenetics (i.e., pathogenic, mechanistic, metabolic, transporter and pleiotropic genes) as major determinants of response to treatment in Alzheimer's disease. Patients harboring poor or ultrarapid geno-phenotypes display more irregular profiles in drug efficacy and safety than extensive or intermediate metabolizers. Polymorphic variants of genes associated with lipid metabolism influence the therapeutic response to hypolipemic agents. Understanding these effects is very useful for optimizing polytherapy in dementia.

Evaluation of a novel, non-invasive iPSC based cell therapy for neuronopathic Gaucher disease

Lead (Pb) is neurotoxic and children are highly susceptible to this effect, particularly within the context of continuous low-level Pb exposure. A current major challenge is identification of children who may be uniquely susceptible to Pb toxicity because of genetic predisposition. Learning and memory are among the neurobehavioral processes that are most notably affected by Pb exposure, and modification of N-methyl-D-aspartate receptors (NMDAR) that regulate these processes during development are postulated to underlie these adverse effects of Pb. We examined the hypothesis that polymorphic variants of genes encoding glutamate receptor, ionotropic, NMDAR subunits 2A and 2B, GRIN2A and GRIN2B, exacerbate the adverse effects of Pb exposure on these processes in children. Participants were subjects who participated as children in the Casa Pia Dental Amalgam Clinical Trial and for whom baseline blood Pb concentrations and annual neurobehavioral test results over the 7 year course of the clinical trial were available. Genotyping assays were performed for variants of GRIN2A (rs727605 and rs1070503) and GRIN2B (rs7301328 and rs1806201) on biological samples acquired from 330 of the original 507 trial participants. Regression modeling strategies were employed to evaluate the association between genotype status, Pb exposure, and neurobehavioral test outcomes. Numerous significant adverse interaction effects between variants of both GRIN2A and GRIN2B, individually and in combination, and Pb exposure were observed particularly among boys, preferentially within the domains of Learning & Memory and Executive Function. In contrast, very few interaction effects were observed among similarly genotyped girls with comparable Pb exposure. These findings support observations of an essential role of GRIN2A and GRIN2B on developmental processes underlying learning and memory as well as other neurological functions in children and demonstrate, further, modification of Pb effects on these processes by specific variants of both GRIN2A and GRIN2B genes. These observations highlight the importance of genetic factors in defining susceptibility to Pb neurotoxicity and may have important public health implications for future strategies aimed at protecting children and adolescents from potential health risks associated with low-level Pb exposure.

Associations of polymorphisms in the cytokine genes IL1β (rs16944), IL6 (rs1800795), IL12b (rs3212227) and growth factor VEGFA (rs2010963) with anthracosilicosis in coal miners in Russia and related genotoxic effects.

Anthracosilicosis (AS), a prevalent form of pneumoconiosis among coal miners, results from the accumulation of carbon and silica in the lungs from inhaled coal dust. This study investigated genotoxic effects and certain cytokine genes polymorphic variants in Russian coal miners with АS. Peripheral leukocytes were sampled from 129 patients with AS confirmed by X-ray and tissue biopsy and from 164 asymptomatic coal miners. Four single-nucleotide polymorphisms were genotyped in the extracted DNA samples: IL1β T-511C (rs16944), IL6 C-174G (rs1800795), IL12b A1188C (rs3212227) and VEGFA C634G (rs2010963). Genotoxic effects were assessed by the analysis of chromosome aberrations in cultured peripheral lymphocytes. The mean frequency of chromatid-type aberrations and chromosome-type aberrations, namely, chromatid-type breaks and dicentric chromosomes, was found to be higher in AS patients [3.70 (95% confidence interval {CI}, 3.29-4.10) and 0.28 (95% CI, 0.17-0.38)] compared to the control group [2.41 (95% CI, 2.00-2.82) and 0.09 (95% CI, 0.03-0.15)], respectively. IL1β gene T/T genotype (rs16944) was associated with AS [17.83% in AS patients against 4.35% in healthy donors, odds ratio = 4.77 (1.88-12.15), P < 0.01]. A significant increase in the level of certain chromosome interchanges among AS donors is of interest because such effects are typical for radiation damage and caused by acute oxidative stress. IL1β T allele probably may be considered as an AS susceptibility factor among coal miners.

Association between single nucleotide polymorphisms of TPH1 and TPH2 genes, and depressive disorders.

Tryptophan catabolites pathway disorders are observed in patients with depression. Moreover, single nucleotide polymorphisms of tryptophan hydroxylase genes may modulate the risk of depression occurrence. The objective of our study was to confirm the association between the presence of polymorphic variants of TPH1 and TPH2 genes, and the development of depressive disorders. Six polymorphisms were selected: c.804‐7C>A (rs10488682), c.‐1668T>A (rs623580), c.803+221C>A (rs1800532), c.‐173A>T (rs1799913)—TPH1, c.‐1449C>A (rs7963803), and c.‐844G>T (rs4570625)—TPH2. A total of 510 DNA samples (230 controls and 280 patients) were genotyped using TaqMan probes. Among the studied polymoorphisms, the G/G genotype and G allele of c.804‐7C>A—TPH1, the T/T homozygote of c.803+221C>A—TPH1, the A/A genotype and A allele of c.1668T>A—TPH1, the G/G homozygote and G allele of c.‐844G>T—TPH2, and the C/A heterozygote and A allele of c.‐1449C>A—TPH2 were associated with the occurrence of depression. However, the T/T homozygote of c.‐1668T>A—TPH1, the G/T heterozygote and T allele of c.‐844G>T—TPH2, and the C/C homozygote and C allele of c.‐1449C>A—TPH2 decreased the risk of development of depressive disorders. Each of the studied polymorphisms modulated the risk of depression for selected genotypes and alleles. These results support the hypothesis regarding the involvement of the pathway in the pathogenesis of depression.

Rabbit myostatine gene polymorhism (c.747+34C&gt;T and c.194A&gt;G) as a marker for meat production

Myostatin gene (MSTN or GDF-8) affects both, the amount and composition of muscle fibers. MSTN plays a key role in muscle growth and it has applications in breeding and animal husbandry. Polymorphic variants of this gene are associated with growth rates and carcass yield of different species. This study is focused on two single nucleotide polymorphisms: MSTN SNP c.747+34C>T and MSTN SNP c.194A>G and their effect on selected production traits. Genomic DNA was extracted from whole blood. Polymorphic variants of MSTN gene were detected using PCRRFLP method. Association studies revealed significant positive effect of allele T (c.747+34C>T) and allele G (c.194A>G) on meat performances in tested rabbit population.

The association of hemostasis system genes with the development of ischemic stroke in patients under the age of 50 years

To study an influence of polymorphic variants of hemostasis system genes on the risk of ischemic stroke (IS) in patients of the Slavic population under the age of 50 years. Ninety-two patients (19 women and 73 men), aged 18-50 years, were examined. The diagnosis of stroke was confirmed by neuroimaging (CT or MRI) in all patients. Polymorphic alleles of GP1BA, F2, F5 were studied by a real-time polymerase chain reaction using the TaqMan technology. An analysis of the GP1BA -5T/C polymorphism showed that it was associated with IS in young men, lacunar stroke and stroke due to thrombosis of the brachiocephalic arteries. This association was not found in young women. The F5 G1691A polymorphism was associated with lacunar stroke. The F2 G20210A polymorphism was associated with stroke due to thrombosis of the brachiocephalic arteries.

Genetic and Epigenetic Mechanisms of Endometral Reciptivity Disorder in Patients Born with Low Weight

The aim is to study genetic and intrauterine epigenetic mechanisms of endometrial receptivity disorders in patients with reproductive failures. 96 girls of adolescents with disturbed menstrual function as anomalous uterine bleeding (AUB PP) and 210 women of reproductive age, suffering from uterine infertility or miscarriage, due to thin endometrium were examined. All the patients were born on the deadline. Within the main cohorts, the patients were stratified according to their birth weight. Clinical anamnestic data and molecular genetic studies of polymorphic variants of sex steroids receptor genes, endothelial function regulation genes, angiogenesis and thrombophilia were analyzed using the real-time allele-specific polymerase chain reaction with melting curves of the amplification products using a set of reagents and protocols of the company Test Gen LTD (Russia). The risk of reproductive failures due to impaired receptivity of the endometrium is associated with the carrier of the polymorphic allele A of the VEGF2578C gene> A: for patients with infertility (OR = 2.73 (1.36-5.45), p = 0.01) and miscarriage OR = 4.61 (2.19-9.71), p = 0.01) and bearing the polymorphic allele 675 4G of the PAI-1 gene 675 5G> 4G: for patients with infertility (OR = 8.45 (3, 96-18,21), p = 0,001) and miscarriage (OR = 9.98 (4.61-21.74), p = 0.001). The carrier of polymorphism pVull-СС of the gene ESR1 397T> C is associated with an increased risk of disruption of the development of the menstrual function, manifested by abnormal uterine bleeding of the pubertal period (OR = 4.58 (0.97-21.68) p = 0.04), and the risk of developing in the reproductive age of miscarriage, caused by a thin endometrium (OR = 6.79 (1.94-23.75), p = 0.01). In women born with low weight, a significantly higher frequency of genotypes containing polymorphic allele 786C of the gene for endothelial NO-synthase NOS3 786 T> C was determined: for women with infertility OR = 6.173 (1.83-20.83); p = 0.001; for women with miscarriage OR = 4.902 (1.69-14.08); p = 0.002; for girls OR = 2.56 (1.01-6.50); p = 0.04. The genetic network containing the described variable alleles coordinates the pathological nature of the regulation of the endometrial function, which can lead to the formation of a thin non-receptive endometrium in response to traumatic injury.

ПОЛИМОРФИЗМ ГЕНОВ TOLL-ПОДОБНЫХ РЕЦЕПТОРОВ КАК ВОЗМОЖНЫЙ ФАКТОР ПРЕДРАСПОЛОЖЕННОСТИ К РАЗВИТИЮ ТУБЕРКУЛЕЗА

The objective of the study : to detect genotypes and frequency of gene alleles of Toll-receptors (Arg753Gln – for TLR2; Phe412Leu – for TLR3; Asp299Gly – for TLR4; Ser249Pro – for TLR6) among respiratory tuberculosis patients in Zabaykalsky Kray. Subjects and methods . The distribution of genotypes of allele variants of Toll-receptors genes was analyzed in 120 respiratory tuberculosis patients and 30 healthy volunteers with a compatible gender and age distribution. Genomic DNA was isolated from leukocytes of the whole blood. In order to detect polymorphic variants of Toll-receptors genes, real-time PCR was used. The distribution of genotypes as per investigated polymorphic loci was tested for relevance using Hardy – Weinberg equilibrium. The frequency of genotype distribution in the groups was compared by Pearson's chi-square test with Yates's correction for continuity using 4-field contingency tables. The decision of the association between genotypes and the disease was made based on the value of the odds ratio with 95% of confidence intervals. Additionally, to confirm and analyze the correlation force of genotypes and development of tuberculosis based on the principle of mutual contingency, φ test (Kramer test, Chuprov test) was calculated. Results. Polymorphism of TLR2, TLR3 and TLR6 genes predispose the development of tuberculosis. The following genotypes make the biggest contribution to the formation of predisposition to tuberculosis: Asp/Asp genotype of TLR4 gene (Asp299Gly), Ser/Ser polymorphism of TLR6 gene (Ser249Pro), heterozygous Asp/Gly of TLR4 gene (Asp299Gly) and mutation Pro/Pro polymorphism of TLR6 gene (Ser249Pro). The protective effect against the development of tuberculosis is related to carriage of homozygous Arg/Arg genotype of TLR2 polymorphism, homozygous Phe/Phe genotype of TLR3 gene and heterozygous Ser/Pro polymorphism of TLR6 gene.

The influence of the vitamin D3 level in the blood serum of lactase gene polymorphism on the development of chronic polypous rhinosinusitis

The objective of the present study was to elucidate the possible correlations between the vitamin D3 level in the blood serum and lactase gene polymorphism (LCT-13910 T>C) in the patients presenting with chronic polypous rhinosinusitis (CPRS). The study included 50 patients with this condition and 14 subjects comprising the control group. The variants of lactase gene polymorphism (LCT-13910 T>C) were identified with the use of polymerase chain reaction (PCR) in real time. The total level of serum vitamin D3 (VD3) was determined by means of the immunochemical analysis (the electrochemiluminescence technique). In the group of patients presenting with chronic polypous rhinosinusitis, the level of VD3 in the blood serum ranged from 48 nm/l to 85 nm/l (mean 60 nm/l) compared with that in the patients of the control group (from 78 nm/l to 112 nm/l; mean 97 nm/l) . The level of vitamin D3 'below the normal values' was documented in 71% of the patients with CPRS in comparison with 7% in the control subjects. Lactase gene polymorphism (LCT-13910 CC, CT) suggesting pronounced and latent hypolactasia was identified in 94% of the patients with CPRS compared with 78.6% in the control group. The occurrence of the CC genotype in the patients of both study groups was virtually identical: 52% in the patients presenting with chronic polypous rhinosinusitis and 57% in the control group. CT polymorphism was identified in 42% of the patients with CPRS and in 21% of the control subjects. The significant difference between the patients of the two groups was documented for the occurrence of TT polymorphism: 6% among the patients with CPRS and 21% in the controls (i.e. much higher in the healthy subjects). There was no significant difference between the serum levels of vitamin D3 either among the patients with CPRS having LCT-13910 gene polymorphisms (CC, CT, TT) or among the control subjects. It is concluded that the study revealed the higher levels of vitamin D3 in the blood sera from the control subjects in comparison with that in the patients with chronic polypous rhinosinusitis. Moreover, the patients of the latter group more frequently exhibited the variant of the LCT CT-13910 gene polymorphism suggesting latent hypolactasia whereas the subjects comprising the control group more frequently had the variant of the LCT CT-13910 gene polymorphism indicative of the normal tolerance of lactose.

P2.06-004 Role of Polymorphic Variants of BER and DSBR Pathway Genes in Modulating Lung Cancer Susceptibility and Prognosis of North Indian Population

DNA repair system uphold individuals’ genomic content from consistence impertinence implicated by continuous exposure to DNA damaging agents present in tobacco smoke, ionizing radiations,air pollution etc. BER (Base excision repair) and DSBR (Double strand break repair) are the two important pathways in this respect. However, polymorphic DNA repair genes might modulate the repair capacity and ultimately the survival.

Genetic polymorphisms in the ALDH2 gene and the risk of ischemic stroke in a Chinese han population.

BackgroundPrevious studies have shown that aldehyde dehydrogenase 2 (ALDH2) plays a role in ischemic stroke progression. In recent years, the activation of the ALDH2 pathway have been reported serving as a useful index in the identification of stroke-prone participants, and the ALDH2 pathway may be a potential target for the therapeutic intervention in ischemic stroke.Materials and MethodsWe evaluated six tagging single-nucleotide polymorphisms (SNPs) of the ALDH2 gene in a case–control study from Hainan of China (488 cases, 503 controls). We used SPSS version 17.0 statistical software, Excel software and other analysis software to explore associations between SNPs and the risk of ischemic stroke various genetic models (additive, dominant, and recessive).ResultsThrough statistical analysis, we found that ALDH2 rs886205 [odds ratio (OR) = 6.39; 95% confidence interval (CI) = 1.19-34.38; p = 0.03] and rs7296651 (OR = 9.29; 95% CI = 1.37-63.21; p = 0.02) were associated with increased risk of ischemic stroke in recessive model analysis. In addition, we established that the “AA” genotype (OR = 5.99; 95% CI = 1.11-32.23; p = 0.037) for rs886205 and the “AA” genotype (OR = 8.93; 95% CI = 1.31-60.78; p = 0.025) for rs7296651 were associated with increased ischemic stroke risk.ConclusionsOur results provide evidence that variants of ALDH2 gene polymorphisms influence the risk of developing ischemic stroke in Han Chinese population.

One-carbon genetic variants and the role of MTHFD1 1958G>A in liver and colon cancer risk according to global DNA methylation.

Several polymorphic gene variants within one-carbon metabolism, an essential pathway for nucleotide synthesis and methylation reactions, are related to cancer risk. An aberrant DNA methylation is a common feature in cancer but whether the link between one-carbon metabolism variants and cancer occurs through an altered DNA methylation is yet unclear. Aims of the study were to evaluate the frequency of one-carbon metabolism gene variants in hepatocellular-carcinoma, cholangiocarcinoma and colon cancer, and their relationship to cancer risk together with global DNA methylation status. Genotyping for BHMT 716A>G, DHFR 19bp ins/del, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, TCII 776C>G and TS 2rpt-3rpt was performed in 102 cancer patients and 363 cancer-free subjects. Methylcytosine (mCyt) content was measured by LC/MS/MS in peripheral blood mononuclear cells (PBMCs) DNA. The MTHFD1 1958AA genotype was significantly less frequent among cancer patients as compared to controls (p = 0.007) and related to 63% reduction of overall cancer risk (p = 0.003) and 75% of colon cancer risk (p = 0.006). When considering PBMCs mCyt content, carriers of the MTHFD1 1958GG genotype showed a lower DNA methylation as compared to carriers of the A allele (p = 0.048). No differences were highlighted by evaluating a possible relationship between the other polymorphisms analyzed with cancer risk and DNA methylation.The MTHFD1 1958AA genotype is linked to a significantly reduced cancer risk. The 1958GG genotype is associated to PBMCs DNA hypomethylation as compared to the A allele carriership that may exert a protective effect for cancer risk by preserving from DNA hypomethylation.

P.5.d.009 - Predictive genetic model for levodopa-induced dyskinesia in patients with Parkinson’s disease

Predictive genetic model for levodopa-induced dyskinesia in patients with Parkinson's disease S.A. Ivanova(1), V.M. Alifirova(2), M.B. Freidin(3), I.V. Pozhidaev(4), O.Y. Fedorenko(4), N.A. Bokhan(4), I.A. Zhukova(5), N.G. Zhukova(5), B. Wilffert(6), A.J.M. Loonen(6) (1)Mental Health Research Institute, Molecular Genetics and Biochemistry Laboratory, Tomsk, Russia (2)Siberian State Medical University, Department of Neurology and Neurosurgery, Tomk, Russia (3)Tomsk National Research Medical Center of the Russian Academy of Sciences, Research Institute of Medical Genetics, Tomsk, Russia (4)Tomsk National Research Medical Center of the Russian Academy of Sciences, Mental Health Research Institute, Tomsk, Russia (5)Siberian State Medical University, Department of Neurology and Neurosurgery, Tomsk, Russia (6)University of Groningen, Groningen Research Institute of Pharmacy, Groningen, The Netherlands 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). The use of this drug, however, is severely limited by adverse effects. Levodopa-induced dyskinesia (LID) is one of these and characterized by involuntary muscle movements that occur as a consequence of chronic levodopa treatment. LID is a substantial barrier to effective symptomatic management of PD as 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 evidences suggest a relationship between LID and specific genetic variants, such as polymorphisms 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 a contribution of polymorphic variants of neurotransmitter receptors and cytochrome genes in the development of LID in PD patients. Methods: A total of 212 PD patients who received L-DOPA therapy were studied. Dyskinesia was assessed by using the Abnormal Involuntary Movement Scale (AIMS). DNA extraction and genotyping were conducted according to standard protocols and blind to the clinical status of the subjects. Genotyping was carried out for 72 SNPs of DRD1, DRD2, DRD2/ANKK1, DRD3, DRD4, HTR2C, HTR3A, HTR3B, HTR6, HTR2A, HTR1A, HTR1B, CYP1A2*1F, CYP2D6*3, CYP2D6*4, CYP2C19*3, CYP2C19*17, CYP2C19*2, and GSTP1 genes using MassARRAY® Analyzer 4 (Agena Bioscience™) and the set SEQUENOM Consumables iPLEX Gold 384. Discriminant analysis and receiver operating curve (ROC)-analysis were carried out to build a genetic predictive model for dyskinesia. Results: Group of PD patients consists of 149 females and 83 males (age ranging from 40 to 86 years, average age 68.7 ± 7.6 years). The mean age of onset is 60.04 ± 9.46 years, average disease duration is 9.79 ± 5.57 years. Dyskinesia was reported in 57 (26.9%) patients. The best discriminant model was obtained with the following predictors: rs11721264, rs165774, rs3758653, rs4245147, rs6313, rs1364043, rs2734849, rs324035, rs6311, rs11246226 and rs4244285. These polymorphisms are localized in the following genes: DRD3 (rs11721264, rs324035), DRD4 (rs3758653, rs11246226), DRD2 (rs4245147, rs2734849), HTR2A (rs6313, rs6311), HTR1A (rs1364043). The discriminant model using this set of SNPs gives the error of classification about 13% and the AUC 0.795. Depending on the anticipated frequency of LID, positive and negative predictor values varied between 0.745–0.834 and 0.864–0.916, respectively. We hypothesized in our previous studies that the pathological basis of LID might be degeneration of indirect pathway medium spiny neurons [5]. These indirect pathway medium spiny neurons carry type 2 family dopamine receptors (DRD2, DRD3, DRD4), and HTR2A receptors. Moreover, dopamine release may be promoted by inhibiting serotonergic neurotransmission. Hence, the current findings are well in line with this hypothesis. Conclusion: The resulting panel of 11 SNPs provides a sufficiently high accuracy of LID prediction. The use of this panel in a prospective study will clarify the prospects for its application in clinical practice for predicting risk of LID in patients with PD.

The Combined Effect of ACE, TCF7L2, and PPARGC1A Gene Polymorphisms in Diabetic Nephropathy

Objective: This study was performed for investigation the relationship between variants of ACE, TCF7L2 and PPARGC1A gene polymorphisms individually or in combination with the development of nephropathy in T2DM. Subject and Methods: The study was included 85 T2DM patients (45 with nephropathy and 40 without nephropathy), and 45 healthy control subjects. The I/D polymorphism of ACE gene was evaluated by PCR method. The polymorphisms rs7903146 (C/T) of TCF7L2 gene and Gly482Ser (G/A) and Thr394Thr (G/A) of PPARGC1A gene were evaluated by PCR-RFLP analysis. Results: The frequency of ACE DD genotype and D allele was significantly higher in DN patients when compared to diabetic without nephropathy. The frequency of TCF7L2 rs7903146 TT genotype and T allele were significantly associated with DN patients compared to T2DM. Moreover, a significant association in A allelic frequencies was observed in DN cases compared to T2DM patients without nephropathy. No differences in the genotypic and allelic frequencies between T2DM patients with and without nephropathy were found for the Thr394Thr polymorphism. Conclusions: Our study suggested that candidate gene polymorphisms I/D of ACE, rs7903146 of TCF7L2 and Gly482Ser of PPARGC1A individually or in combination may act as susceptibility biomarkers for nephropathy in T2DM.

Association of obesity susceptibility gene variants with metabolic syndrome in women

Aim. The aim of the study was a replicative analysis of the association of polymorphic variants of genes associated with obesity revealed by results of wide-genomic studies (GWAS) with the development of a cluster of metabolic syndrome risk parameters in women of Bashkir and Tatar ethnicity. The polymorphic markers of the following genes were analyzed: SEC16B, FADS1, KCTD15, MAF, MAP2K5, NEGR1, BDNF, TMEM18.&#x0D; Materials and methods. The study involved 243 women with metabolic syndrome and 298 women without the metabolic syndrome. Amplification of DNA fragments was performed using real-time PCR and TaqMan technique.&#x0D; Results. We found the association the metabolic syndrome with genetic markers of genes MAF and TMEM18 from Tatar. Protective informative marker of the metabolic syndrome among Tatar and Bashkir was the TT haplotype TMEM18 gene (rs2860323 and rs6548238) (р=0.005 and р=0.001, respectively). We identified the association marker rs2241423 MAP2K5 gene with the level of waist circumference (p=0.003) and with the level of cholesterol (p=0.014), the marker rs11084753 KCTD15 gene with glucose levels after exercise (p=0.002), the level of triglycerides (p=0.003) and HDL (p=0.0008) among Tatar women. We identified the association rs2241423 MAP2K5 gene marker to glycated hemoglobin level (p=0.002) and a marker gene rs174550 FADS1 with triglyceride levels (p=0.02) among Bashkir women.&#x0D; Conclusion. It can be assumed that the polymorphic variants FADS1, KCTD15, MAF, MAP2K5, TMEM18 genes are an important part of the genetic structure of predisposition to metabolic syndrome and/or to a cluster of clinical and biochemical indicators of the risk of metabolic syndrome.